History of database changes

14 June, 2025 (Version: 20250614AU) (Latest version)

New Ceritinib in Non-small cell lung cancer with ALK Amplification: 4

Retrospective study. ALK-positive NSCLC. Median PFS on sequential crizotinib and ceritinib was 17.4 months, with ceritinib showing significant antitumor activity even after crizotinib treatment, and no difference in PFS on ceritinib between patients with or without ALK resistance mutations. Updated 2025-06-14. References: 25724526

New Avapritinib in Solid tumours with KIT D816V, V654A, N655K, Y672C, D677N, T670A: 4

Cell line study. Midostaurin and avapritinib, ATP-competitive inhibitors targeting active KIT conformation, exhibit distinct resistance profiles to secondary kinase domain mutations in exon 17-mutant KIT, with avapritinib being selectively vulnerable to the T670I gatekeeper mutation. References: 31270078

New Crizotinib in Non-small cell lung cancer with ALK C1156Y, Fusion and Amplification, L1196M, S1206Y, G1269A, T1151ins: R2

Retrospective study. ALK-positive NSCLC. Median PFS on sequential crizotinib and ceritinib was 17.4 months, with ceritinib showing significant antitumor activity even after crizotinib treatment, and no difference in PFS on ceritinib between patients with or without ALK resistance mutations. Updated 2025-06-14. References: 25724526

New Crizotinib in Non-small cell lung cancer with ALK Fusion AND Amplification, L1196M, C1156Y, F1174L, F1174V, G1202R, G1269A, I1171T, I1171S, L1152R, L1152V, T1151R, T1151M, L1198F, S1206F, D1203E: R2

Phase 2 trial. NCT03215693. Ensartinib showed activity in crizotinib-resistant, ALK-positive NSCLC patients with an ORR of 52% and intracranial ORR of 70% in patients with measurable brain metastases. Data updated 2025-06-14. References: 31628085

New Ensartinib in Non-small cell lung cancer with EGFR Oncogenic mutations: R2

Phase 2 trial. NCT03215693. Ensartinib showed activity in crizotinib-resistant, ALK-positive NSCLC patients with an ORR of 52% and intracranial ORR of 70% in patients with measurable brain metastases. Data updated 2025-06-14. References: 31628085

New Ensartinib in Non-small cell lung cancer with ERBB2 Oncogenic mutations: R2

Phase 2 trial. NCT03215693. Ensartinib showed activity in crizotinib-resistant, ALK-positive NSCLC patients with an ORR of 52% and intracranial ORR of 70% in patients with measurable brain metastases. Data updated 2025-06-14. References: 31628085

New Avapritinib in Solid tumours with KIT V560D, V560D and V654A, V560D and and V670I, T670I, T670V: R2

Cell line study. Midostaurin and avapritinib, ATP-competitive inhibitors targeting active KIT conformation, exhibit distinct resistance profiles to secondary kinase domain mutations in exon 17-mutant KIT, with avapritinib being selectively vulnerable to the T670I gatekeeper mutation. References: 31270078

New Midostaurin in Solid tumours with KIT V654A, N655K, Y627C, D677N, T670I, T670A, T670V: R2

Cell line study. Midostaurin and avapritinib, ATP-competitive inhibitors targeting active KIT conformation, exhibit distinct resistance profiles to secondary kinase domain mutations in exon 17-mutant KIT, with avapritinib being selectively vulnerable to the T670I gatekeeper mutation. References: 31270078

New Ensartinib in Non-small cell lung cancer with KRAS Oncogenic mutations: R2

Phase 2 trial. NCT03215693. Ensartinib showed activity in crizotinib-resistant, ALK-positive NSCLC patients with an ORR of 52% and intracranial ORR of 70% in patients with measurable brain metastases. Data updated 2025-06-14. References: 31628085

Removed Midostaurin in Gastrointestinal stromal tumour with KIT alterations V654A, T670I: Tier R2   (First curated: 2020-05-15)

Changed Ensartinib in Non-small cell lung cancer with ALK : 4

Alterations changed: Fusion AND Amplification, L1196M, C1156Y, F1174L, F1174V, G1202R, G1269A, I1171T, I1171S, L1152R, L1152V, T1151R, T1151M, L1198F, S1206F, D1203EAmplification, protein expression. Comments changed: Phase 2 trial. NCT03215693. Ensartinib showed activity in crizotinib-resistant, ALK-positive NSCLC patients with an ORR of 52% and intracranial ORR of 70% in patients with measurable brain metastases. Data updated 2025-06-14.. References changed: 31628085, 25724526. (First curated: 2020-04-25)

Changed Therapy in Solid tumours with BRAF Class III mutations, D287, D287H, V459, V459L, G466, G466V, G466E, G466A, S467, S467L, N581, N581S, N581I, D594, D594N, D594G, D594A, D594H, F595, F595L, G596, G596D, G596R: 4

Therapy changed: Vociprotafib + CobimetinibRMC-4630 + Cobimetinib. (First curated: 2020-11-03)

Changed Midostaurin in Solid tumours with KIT D816V, T670A, T670V: 4

Comments changed: Cell line study. Midostaurin and avapritinib, ATP-competitive inhibitors targeting active KIT conformation, exhibit distinct resistance profiles to secondary kinase domain mutations in exon 17-mutant KIT, with avapritinib being selectively vulnerable to the T670I gatekeeper mutation.. (First curated: 2020-06-18)

Changed Sorafenib in Thymic carcinoma with KIT : 4

Alterations changed: Exon 11 mutation, Exon 11 deletion. Comments changed: Case report. A relapsed thymic carcinoma patient with C-KIT exon 11 deletion mutation showed positive response to sorafenib.. (First curated: 2022-07-27)

Changed Bezuclastinib in Gastrointestinal stromal tumour with KIT Exon 11 mutation, Exon 11 deletion, K642E, D816E, D816F, D816H, D816I, D816V, D816Y, D820E, D820Y, Y823D, A829P: 4

Comments changed: Phase 1b/2a trial. NCT02401815. N=39. Combination of type I KIT inhibitor PLX9486 and type II KIT inhibitor sunitinib showed clinical benefit in patients with refractory GIST, with median PFS of 12.1 months and clinical benefit rate of 80% at the recommended phase 2 dose.. (First curated: 2023-06-27)

Changed Therapy in Thymic carcinoma with KIT Exon 11 mutation, Exon 11 deletion, V560del: 4

Therapy changed: ImatinibSorafenib. Comments changed: Case report. Thymic carcinoma with overexpressed mutated KIT showed response to imatinib.. (First curated: 2022-07-27)

Changed Imatinib in Thymic carcinoma with KIT Exon 11 mutation, Y553N: 4

Comments changed: Case report. A heavily pretreated patient with metastatic c-KIT mutated thymic carcinoma showed an impressive response to imatinib.. (First curated: 2022-07-27)

Changed Sorafenib in Thymic carcinoma with KIT Exon 17 mutation, D820E: 4

Comments changed: Case report. A heavily pretreated patient with metastatic thymic carcinoma responded to sorafenib, with a c-kit missense mutation (D820E) on exon 17 potentially explaining the clinical response.. (First curated: 2022-07-27)

Changed Cabozantinib in Gastrointestinal stromal tumour with KIT : 4

Alterations changed: Exon 9 mutations, A502_Y503dup, Exon 11 mutations, Exon 11 deletion, K558_G565delinsR, Exon 17 mutations, D820G, V559A, V559D, V560G, K642E, D816E, D816F, D816H, D816I, D816V, D816Y, D820E, D820Y, Y823D, A829PExon 9 mutations, A502_Y503dup, Exon 11 mutations, K558_G565delinsR, Exon 17 mutations, D820G. (First curated: 2021-08-13)

Changed Axitinib in Gastrointestinal stromal tumour with KIT L576P, V669D, V559A, V559G, T670I, V654A, N822K, A829P: 4

Comments changed: Preclinical study. Axitinib showed potent activity against various cKIT primary and secondary mutations, including imatinib-resistant T670I and V654A mutants, in GIST preclinical models and patient-derived primary cells.. (First curated: 2020-06-27)

Changed LOP628 in Solid tumours with KIT Overexpression: 4

Comments changed: Preclinical study. c-KIT-directed antibody-drug conjugate LOP628 exhibited potent antiproliferative activity against c-KIT-positive cell lines and demonstrated regressions or stasis in GIST and SCLC xenograft models, including an imatinib-resistant GIST model.. (First curated: 2020-04-16)

Changed Therapy in Solid tumours with KRAS G12: 4

Therapy changed: AvutometinibCH5126766. Comments changed: Phase 1 dose-escalation and basket dose-expansion study. NCT02407509. Avutometinib, a RAF-MEK inhibitor, demonstrated antitumour activity in RAS/RAF-mutant solid tumours and multiple myeloma, with 7 (27%) of 26 response-evaluable patients achieving objective responses at the recommended phase 2 dose of 4.0 mg twice per week.. (First curated: 2020-11-10)

Changed Therapy in Solid tumours with KRAS G12, Amplification: 4

Therapy changed: Vociprotafib + CobimetinibRMC-4630 + Cobimetinib. (First curated: 2020-11-03)

Changed Therapy in Solid tumours with NF1 Oncogenic mutations: 4

Therapy changed: Vociprotafib + CobimetinibRMC-4630 + Cobimetinib. (First curated: 2020-11-03)

Changed Therapy in Colorectal adenocarcinoma with ERBB2 ERBB2-GRB7 fusion: R2

Therapy changed: Afatinib, Trastuzumab, Cetuximab, Cetuximab + irinotecan. Comments changed: Case series. Targetable kinase alterations (RTK alterations and MAP2K1 mutations) identified in 8% of colorectal carcinoma, preferentially associated with wild-type RAS/RAF, and may predict poor response to anti-EGFR therapy.. (First curated: 2023-04-20)

Changed Afatinib, Dacomitinib, Neratinib, Pyrotinib in Solid tumours, Non-small cell lung cancer with ERBB2 Exon 20 insertion except G778ins, S779ins, P780ins: R2

Comments changed: Preclinical study. ERBB2 mutations characterized across 25 tumor types, with poziotinib showing potent activity against HER2 mutants, and enhancing T-DM1 activity in pre-clinical models, and showing 42% confirmed objective response rate in ERBB2 exon 20-mutant NSCLC patients.. (First curated: 2020-06-15)

Changed Lapatinib in Solid tumours with ERBB2 L755S, L755P, A775_G776insYVMA (Y772_A775dup), G778ins, P780_Y781insGSP (G778_P780dup), P780ins, V842I, L869R: R2

Comments changed: Preclinical study. ERBB2 mutations characterized across 25 tumor types, with poziotinib showing potent activity against HER2 mutants, and enhancing T-DM1 activity in preclinical models, with a 42% confirmed objective response rate in ERBB2 exon 20-mutant NSCLC patients in Phase 2 clinical testing.. (First curated: 2020-05-15)

13 June, 2025 (Version: 20250613AU)

New Brigatinib in Non-small cell lung cancer with ROS1 Fusions: 3

Phase 2. Barossa study. N=51. Brigatinib showed an ORR of 71% and median PFS of 12.0 months in TKI-naive NSCLC patients, and 32% ORR with 7.3 months median PFS in crizotinib-pretreated NSCLC patients. References: 39018589

New Azenosertib in Solid tumours with CCNE1 Amplification: 4

Preclinical study. Azenosertib demonstrated broad antitumor activity across solid tumors in Phase I monotherapy studies. Preclinical data revealed tumor growth inhibition >60% in CCNE1-amplified models (2/2) and FBXW7-mutated models (3/5). References: 34423975

New Azenosertib in Solid tumours with FBXW7 Oncogenic mutations: 4

Preclinical study. Azenosertib demonstrated broad antitumor activity across solid tumors in Phase I monotherapy studies. Preclinical data revealed tumor growth inhibition >60% in CCNE1-amplified models (2/2) and FBXW7-mutated models (3/5). References: 34423975

New Paclitaxel in Oesophageal squamous cell carcinoma with LGALS1 Protein expression: R2

Preclinical study. Galectin-1 is a key mediator of paclitaxel resistance in esophageal squamous cell carcinoma, acting through the interaction with β-catenin and enhancing MDR1 transcription, thereby increasing resistance to paclitaxel. References: 39186691

New Tazemetostat in Solid tumours with SMARCB1 Oncogenic mutations: R2

Phase 2 NCI-COG Pediatric MATCH trial Arm C. NCT03213665. N=20. Tazemetostat showed limited objective response (ORR 5%) in pediatric patients with tumors harboring EZH2 mutations or SMARCB1/SMARCA4 loss, but achieved prolonged stable disease in 33% of patients, suggesting potential disease stabilization. References: 10.1200/JCO.2022.40.16_suppl.10009

Removed Palbociclib in Triple-negative breast cancer with CDKN2A alterations Oncogenic mutations: Tier R2   (First curated: 2020-04-25)

Changed Obinutuzumab in Follicular lymphoma with CD20 Protein expression: 1

Comments changed: Phase 3 trial. TOWER. NCT02013167. N=405. Blinatumomab significantly improved overall survival (7.7 vs 4.0 months), remission rates (44% vs 25%), and event-free survival (31% vs 12%) in adults with relapsed or refractory B-cell precursor ALL, including both Ph-positive and Ph-negative subtypes. Note that surface antigen CD-19 is lineage-specific to B-cells and constitutively expressed on the majority of B-cell precursor ALL blasts and does not represent a biomarker selection criteria.PBS reimbursed. (First curated: 2020-06-15)

Changed Gemtuzumab Ozogamicin in Acute myeloid leukaemia with CD33 Protein expression: 1B

Comments changed: TGA approved. Not PBS reimbursed. Phase 3 AAML0531 trial (N=1022) demonstrated that gemtuzumab ozogamicin, a CD33-targeted immunoconjugate, added to chemotherapy improved event-free survival (53.1% vs 46.9%) by reducing relapse risk (32.8% vs 41.3%) in children and adolescents with de novo acute myeloid leukemia.. (First curated: 2020-06-17)

Changed Daratumumab + Hyaluronidase-fihj in Multiple myeloma with CD38 Overexpression: 2

Comments changed: Phase 3 COLUMBA trial. NCT03277105. Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of overall response (41% vs 37%).. (First curated: 2020-06-15)

Changed BOS172738 in Medullary thyroid cancer with RET Fusions: 3

Comments changed: Phase 1 study. NCT03780517. BOS172738, a potent and selective RET inhibitor, showed an ORR of 33% in RET-altered tumors, including 33% in NSCLC and 44% in MTC (7/16, including 1 CR), with a favorable safety profile and durable responses.ORR 44% (7/16), including 1 CR. (First curated: 2021-06-05)

Changed Vandetanib in Non-small cell lung cancer with RET Fusions: 3

Comments changed: Phase 2 LURET trial. UMIN000010095. Vandetanib showed an ORR of 53% (9/17) and median PFS of 4.7 months in patients with RET-rearranged advanced NSCLC, indicating RET rearrangement as a targetable alteration.Single-arm phase 2. LURET. ORR 47%. PFS 4.7mo. References changed: 2782561627825636. (First curated: 2020-11-17)

Changed Cabozantinib in Non-small cell lung cancer with RET : 3

Alterations changed: Fusions, KIF5B-RET fusion, Rearrangement. Comments changed: Phase 2 trial. NCT01639508. N=26. Cabozantinib yielded an ORR of 28% in patients with RET-rearranged non-small-cell lung cancer, with KIF5B-RET being the predominant fusion type.Not TGA approved. Single-arm phase 2. ORR 28%. (First curated: 2020-04-27)

Changed Cabozantinib in Non-small cell lung cancer with ROS1 Fusions: 4

Comments changed: Case report. Cabozantinib showed effectiveness in treating a CD74-ROS1-positive advanced NSCLC patient for 1.5 years, and subsequent crizotinib therapy remained effective after cabozantinib resistance developed.. References changed: 32103985, NCT01639508. (First curated: 2020-06-16)

Changed Tazemetostat in Ovarian small cell carcinoma with SMARCA2 Loss-of-function mutations: 4

Comments changed: Preclinical study. Xenograft and cell line SCCOHT models deficient in SMARCA2 and SMARCA4 showed antiproliferative and antitumour effects when treated with EZH2 inhibitor tazemetostat, exemplifying an additional class of rhabdoid-like tumours dependent on EZH2 activity for survival.Xenograft and cell line SCCOHT models. Induces potent antiproliferative and antitumour effects.. (First curated: 2020-06-15)

Changed Palbociclib in Non-small cell lung cancer with SMARCA4 Loss-of-function mutations: 4

Comments changed: Preclinical study. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in NSCLC, due to reduced cyclin D1 expression caused by restricted CCND1 chromatin accessibility and suppressed c-Jun, a transcription activator of CCND1.SMARCA4 loss is synthetic lethal with palbociclib in NSCLC cell line.. (First curated: 2021-04-14)

Changed Pembrolizumab in SMARCA4-deficient thoracic sarcoma with SMARCA4 Oncogenic mutations: 4

Comments changed: Case report. Exceptional response to pembrolizumab observed in a SMARCA4-deficient thoracic sarcoma overexpressing PD-L1, suggesting pembrolizumab as a potential treatment strategy for PD-L1-positive SMARCA4-DTS.. (First curated: 2023-01-11)

Changed BET inhibitor in Solid tumours with SMARCA4 Oncogenic mutations: 4

Comments changed: Preclinical study. Bromodomains are acetyl lysine 'reader' modules with potential anticancer activities, and BET inhibitor programmes provide insights for developing non-BET bromodomain-targeting drugs.. (First curated: 2020-04-16)

Changed Pembrolizumab, Durvalumab, Atezolizumab, Nivolumab in Pancreatic adenocarcinoma with SMARCB1 Oncogenic mutations: 4

Comments changed: Retrospective case series. In PDAC harbouring alterations in the SWI/SNF complex, 8 of 9 patients had response to ICI (including 1 CR) irrespective to MSI, low TMB, PD-L1 expression status, with median PFS and OS of 9 and 15 months, respectively, and 2 patients having ongoing responses at 33+ and 36+ months.Retrospective case series. In PDAC harbouring alterations in the SWI/SNF complex, 8 of 9 patients had response to ICI (including 1 CR) irrespective to MSI, low TMB, PD-L1 expression status.. (First curated: 2022-02-09)

Changed Itraconazole, Arsenic trioxide in Basal cell carcinoma, Medulloblastoma with SMO D477G, E522K, G457S, S391N, D388N, N223D, L225R: 4

Comments changed: Preclinical study. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation, showing activity against tumors with acquired resistance to Smoothened antagonists, including SMO(D477G) mutant.Preclinical study. Itraconazole and arsenic trioxide block resistant SMO mutation activity in vitro.. (First curated: 2022-03-04)

Changed Posaconazole in Basal cell carcinoma with SMO Oncogenic mutations: 4

Comments changed: Preclinical study. Posaconazole inhibits Hedgehog signaling pathway by antagonizing Smoothened (SMO) with a distinct mechanism, showing robust activity against drug-resistant SMO mutants and inhibiting Hh-dependent basal cell carcinoma growth in vivo.Cell-line evidence only. (First curated: 2020-04-16)

Changed JQ1 in Solid tumours with SMO Oncogenic mutations: 4

Comments changed: Preclinical study. BET bromodomain inhibition through JQ1 effectively targets Hedgehog-driven tumors, including those with genetic lesions conferring resistance to Smoothened antagonists, by directly regulating GLI transcription.. (First curated: 2020-04-16)

Changed Everolimus in Perivascular epithelioid cell tumour with TSC1 Oncogenic mutations: 4

Comments changed: Phase 3 EXIST-2 trial. NCT00790400. Everolimus showed significant angiomyolipoma response rate of 42% (50% reduction in total volume) compared to 0% with placebo in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.. (First curated: 2022-03-20)

Changed Everolimus in Renal cell carcinoma with TSC1 Oncogenic mutations: 4

Comments changed: Mutations in MTOR, TSC1, or TSC2 were more common in responders (28%) than nonresponders (11%) to rapalogs in metastatic renal cell carcinoma, indicating a potential association between mTOR pathway gene mutations and treatment response.Drug is PBS reimbursed but not biomarker selected. (First curated: 2020-04-27)

Changed Everolimus in Perivascular epithelioid cell tumour with TSC2 Oncogenic mutations: 4

Comments changed: Phase 3 EXIST-2 trial. NCT00790400. Everolimus showed significant angiomyolipoma response rate of 42% (50% reduction in total volume) compared to 0% with placebo in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.. (First curated: 2022-03-20)

Changed Everolimus in Renal cell carcinoma with TSC2 Oncogenic mutations: 4

Comments changed: Phase 2 RECORD-3 study. NCT00903175. No significant difference in OS between first-line everolimus followed by sunitinib and first-line sunitinib followed by everolimus in metastatic RCC.No survival benefit vs Sunitinib. (First curated: 2020-06-11)

Changed Pembrolizumab in Colorectal adenocarcinoma with Tumour Mutational Burden High: 4

Comments changed: Phase 2 KEYNOTE-158 study. NCT02628067. Prospective biomarker analysis in 790 patients showed tTMB-high status (>=10 mutations per megabase) was associated with improved ORR to pembrolizumab (29% vs 6% in non-tTMB-high). However, tTMB could be a novel predictive biomarker for response to pembrolizumab in patients with advanced solid tumours, KEYNOTE-158 did not include MSS colorectal cancers.. (First curated: 2020-09-25)

Changed Toripalimab in Gastric cancer with Tumour Mutational Burden High: 4

Comments changed: Phase Ib/2 NCT02915432 trial. Toripalimab demonstrated an overall response rate of 12.1% and median overall survival of 4.8 months in chemo-refractory gastric cancer. The TMB-high group exhibited significantly superior overall survival of 14.6 months compared to 4.0 months, with an objective response rate of 33% versus 6% in the low TMB group at the 12 mutations/MB threshold.Exploratory analysis showed ORR 33 v 6% at TMB threshold of 12/MB. (First curated: 2020-11-13)

Changed Anti-PD-1 monoclonal antibody, Anti-PD-L1 monoclonal antibody, immune checkpoint blockade,PD-1 targeting, immune checkpoint blockade,PD-L1 targeting in Solid tumours with Tumour Mutational Burden High: 4

Comments changed: Pan-cancer analysis of 1,662 patients treated with immune checkpoint inhibitors (ICI) showed higher tumor mutational burden (TMB) associated with improved overall survival across multiple cancer types, although TMB cutpoints varied between cancer types.. (First curated: 2020-06-08)

Changed Olaparib in Breast cancer with XRCC2 Loss-of-function mutations: 4

Comments changed: Preclinical study. Synthetic lethal screening in MCF7 cells identified sensitivity to PARG inhibitor PDD00017273 in DNA damage-response deficient cells with BRCA1, BRCA2, PALB2, FAM175A, and BARD1 deficiencies, suggesting potential for single treatment therapy in HR deficient tumours.Cell line (MCF7) synthetic lethal screening using olaparib and specific PARG inhibitor PDD00017273. (First curated: 2021-06-09)

Changed Panitumumab, Cetuximab, Cetuximab + Irinotecan, Cetuximab + FOLFIRI, FOLFOX + Panitumumab in Colorectal adenocarcinoma with KRAS Oncogenic mutations: R1

Comments changed: RAS mutations, including KRAS and NRAS, were associated with resistance to anti-EGFR therapy, with patients having RAS wild-type tumors showing improved PFS and OS when treated with panitumumab-FOLFOX4 or cetuximab.. (First curated: 2020-04-16)

Changed Panitumumab, Cetuximab, Cetuximab + Irinotecan, Cetuximab + FOLFIRI, FOLFOX + Panitumumab in Colorectal adenocarcinoma with NRAS Oncogenic mutations: R1

Comments changed: RAS mutations, including KRAS and NRAS, were associated with resistance to anti-EGFR therapy, with patients having RAS wild-type tumors showing improved PFS and OS when treated with panitumumab-FOLFOX4 or cetuximab.. (First curated: 2020-04-16)

Changed Larotrectinib in Solid tumours with NTRK1 F589L, A608D, G595R, G667C, G667S: R1

Comments changed: Blacklisted by FDA approval. Preclinical study. Identified TRKA and TRKB kinase domain mutations (e.g., TRKA V573M, F589L/C, and TRKB Q596E/P, F617L/C/I) that confer resistance to pan-TRK inhibitor LOXO-101.. References changed: 10.1158/1538-7445.AM2016-LB-11830333516. (First curated: 2020-05-15)

Changed Entrectinib in Solid tumours with NTRK1 G595R, G667C: R1

Comments changed: Blacklisted by FDA approval. Review discussing NTRK fusion-positive cancers, detection methods, and treatment with TRK inhibitors, highlighting resistance mediated by NTRK kinase domain mutations and potential overcoming by second-generation TRK inhibitors.. (First curated: 2020-04-30)

Changed Larotrectinib in Solid tumours with NTRK2 Q596E, Q596P, G623S, F633L: R1

Comments changed: Blacklisted by FDA approval. Preclinical study. Identified TRKA and TRKB kinase domain mutations (e.g., TRKA V573M, F589L/C, and TRKB Q596E/P, F617L/C/I) that confer resistance to pan-TRK inhibitor LOXO-101.. (First curated: 2020-05-15)

Changed Entrectinib in Solid tumours with NTRK3 G623R: R1

Comments changed: Blacklisted by FDA approval. Review discussing NTRK fusion-positive cancers, detection methods, and treatment with TRK inhibitors, highlighting resistance mediated by NTRK kinase domain mutations and potential overcoming by second-generation TRK inhibitors.. (First curated: 2020-04-30)

Changed Larotrectinib in Solid tumours with NTRK3 G623R, G696A, F617L, F617L, F617C, F617I: R1

Comments changed: Blacklisted by FDA approval. Preclinical study. Identified TRKA and TRKB kinase domain mutations (e.g., TRKA V573M, F589L/C, and TRKB Q596E/P, F617L/C/I) that confer resistance to pan-TRK inhibitor LOXO-101.. References changed: 10.1158/1538-7445.AM2016-LB-11830333516. (First curated: 2020-05-15)

Changed LY3023414 in Endometrial cancer with AKT1 Oncogenic mutations: R2

Comments changed: Phase 2 study. NCT02684032. N=28. LY3023414 showed modest activity in patients with advanced endometrial cancer harboring PI3K pathway mutations, with ORR 16%, CBR 28%, median PFS 2.5 months, and median OS 9.2 months.N=28 with 25 Evaluable patients. ORR 16%. CBR 28%. Median PFS 2.5 months. Median OS 9.2 months. (First curated: 2021-12-17)

Changed Pembrolizumab, Atezolizumab, Nivolumab, Anti-PD-1 monoclonal antibody, Anti-PD-L1 monoclonal antibody in Non-small cell lung cancer with ALK Fusion: R2

Comments changed: IMMUNOTARGET registry. Retrospective study. N=551. Patients with advanced NSCLC and oncogenic driver alterations treated with ICI monotherapy. Objective response rate (ORR) varied by driver alteration: ALK=0%, EGFR=12%, KRAS=26%, BRAF=24%. Median PFS=2.8 months, OS=13.3 months. Notable lack of response in ALK fusion group.. (First curated: 2021-03-12)

Changed Lorlatinib in Non-small cell lung cancer with ALK L1198F and C1156Y: R2

Comments changed: Targeting ALK in ALK-rearranged malignancies is limited by emergence of drug resistance, with diverse mechanisms of resistance discovered, informing development of novel therapeutic strategies to overcome resistance.. (First curated: 2020-05-27)

Changed Venetoclax in Chronic lymphocytic leukaemia with BCL2 G101V, D103Y, A113G: R2

Comments changed: Retrospective case reports, Novel BCL2 mutations, including G101V, were identified in venetoclax-resistant CLL patients, conferring resistance by reducing the affinity of BCL2 for venetoclax and providing a potential biomarker for impending clinical relapse.. (First curated: 2020-04-25)

Changed SHP099, RMC-4550 in Triple-negative breast cancer with BRAF G464V, Class II mutations: R2

Comments changed: Preclinical study. SLLIP trial. NCT03248089. N=185. BRAF alterations detected in 22 patients (12%), with 82% being non-V600 mutations, and showed varied sensitivity to SHP2 inhibition in vitro. In cell line model for Class 2 mutation showed relative resistance to SHP2 inhibitors.Cell line model for Class II mutation showed relative resistance to SHP2 inhibitors.. (First curated: 2021-02-10)

Changed Cetuximab, Panitumumab in Colorectal adenocarcinoma with BRAF G469A, G469V, L485F, L525R, L597R, T599_V600TinsT, K601E, Class II mutations: R2

Comments changed: Retrospective study. Class 2 BRAF mutants had lower ORR compared to Class 3 (8% vs 50%) to anti-EGFR therapy, with 0% ORR in third-and-later lines treatment.Retrospective study. ORR 0% in class II BRAF mutants in third-and-later lines treatment.. (First curated: 2021-04-07)

Changed Divarasib in Colorectal adenocarcinoma, Solid tumours with BRAF G469A, L597Q, L597R, V600E, K601E: R2

Comments changed: Phase 1 trial. GO42144. NCT04449874. Divarasib. Confirmed response observed in 53.4% NSCLC and 29% colorectal cancer patients with KRAS G12C mutation, with median PFS of 13.1 and 5.6 months, respectively; serial ctDNA assessment identified genomic alterations associated with response and potential acquired and treatment-emergent resistance mechanisms.Phase 1/2 single arm trial. GO42144. Divarasib. NCT04449874. Acquired and treatment-emergent mutations. (First curated: 2023-08-24)

Changed Vemurafenib in Melanoma with BRAF K601E: R2

Comments changed: Case report. Lack of response to vemurafenib in melanoma carrying BRAF K601E mutation.Case report. Lack of response to melanoma. (First curated: 2021-11-16)

Changed Vemurafenib in Melanoma with BRAF L505H: R2

Comments changed: Case report. Class 2 BRAF mutation. Secondary BRAF(L505H) mutation acquired following Vemurafenib treatment, contributing to resistance in metastatic BRAF mutant melanoma patients.Case report. Secondary mutation acquired following Vemurafenib.. (First curated: 2021-02-10)

Changed Osimertinib in Non-small cell lung cancer with BRAF Oncogenic mutations, fusion: R2

Comments changed: Analysis of 155 EGFR-mutant lung cancer patients with acquired resistance to EGFR-TKI therapy identified EGFR T790M mutation as the most common mechanism (63%), followed by less frequent mechanisms including MET amplification (5%), HER2 amplification (13%), small cell transformation (3%), and BRAF mutations.Off-target mechanism. (First curated: 2020-06-10)

Changed Palbociclib in Pancreatic adenocarcinoma, Cholangiocarcinoma, Gallbladder cancer with CDKN2A Loss-of-function mutations, Oncogenic mutations: R2

Comments changed: TAPUR Study. N=20. Palbociclib monotherapy showed no objective response or stable disease at 16 weeks in patients with pancreatic and biliary cancers with CDKN2A loss or mutation, with median PFS of 7.2 and 7.3 weeks, and median OS of 12.4 and 11.1 weeks respectively.TAPUR. N=20. ORR and DCR 0%.. References changed: 3510071410.1200/PO.19.00124. (First curated: 2020-04-25)

Changed Vismodegib, Sonidegib in Basal cell carcinoma, Medulloblastoma with SMO D477G, E522K, G457S, S391N, D388N, N223D, L225R: R2

Tier changed: R24. Comments changed: Preclinical study. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation, showing activity against tumors with acquired resistance to Smoothened antagonists, including SMO(D477G) mutant.. (First curated: 2022-03-04)

12 June, 2025 (Version: 20250612AU)

New DB-1419 in Solid tumours with CD274 Protein expression: 4

Preclinical study. DB-1419, a bifunctional B7-H3xPD-L1 antibody-drug conjugate, demonstrated potent antitumor activity against multiple tumors with favorable pharmacokinetics and safety profiles, displaying efficient cellular internalization, direct cytotoxicity, antibody-dependent cellular cytotoxicity, and bystander effects. References: 40499141

New DB-1419 in Solid tumours with CD276 Protein expression: 4

Preclinical study. DB-1419, a bifunctional B7-H3xPD-L1 antibody-drug conjugate, demonstrated potent antitumor activity against multiple tumors with favorable pharmacokinetics and safety profiles, displaying efficient cellular internalization, direct cytotoxicity, antibody-dependent cellular cytotoxicity, and bystander effects. References: 40499141

New IBI3001 in Solid tumours with CD276 Protein expression: 4

Preclinical study. IBI3001, a B7-H3/EGFR bispecific ADC, demonstrated potent cytotoxicity in cancer cells with varying B7-H3 and EGFR expression across multiple solid tumors, and showed robust tumor growth inhibition in xenograft models. Note cytotoxicties were demonstrated across all expression levels. References: 10.1158/1538-7445.AM2024-LB055

New IBI3001 in Solid tumours with EGFR Protein expression: 4

Preclinical study. IBI3001, a B7-H3/EGFR bispecific ADC, demonstrated potent cytotoxicity in cancer cells with varying B7-H3 and EGFR expression across multiple solid tumors, and showed robust tumor growth inhibition in xenograft models. Note cytotoxicties were demonstrated across all expression levels. References: 10.1158/1538-7445.AM2024-LB055

New IBI334 in Solid tumours with EGFR Protein expression: 4

Preclinical study. IBI334, a novel ADCC-enhanced B7-H3/EGFR bispecific antibody, showed enhanced EGFR signal inhibition and potent efficacy in various xenograft models, with a large therapeutic window of >200 folds, indicating potential for safe and effective treatment of EGFR-driven solid tumors. References: 10.1158/1538-7445.AM2024-LB056

New VVD-442 in Solid tumours with ERBB2 Overexpression: 4

Preclinical study. Covalent binding to C242 in the PI3K p110 alpha RBD inhibits RAS-PI3K interaction, suppressing growth of RAS mutant and HER2 over-expressing tumors without inducing hyperglycemia. References: 10.1101/2024.12.17.629001

New BI-2493, BI-2865 in Solid tumours with HRAS Oncogenic mutations, Q95H: 4

Preclinical study. A non-covalent pan-KRAS inhibitor was discovered, which binds to the inactive state of KRAS, blocking nucleotide exchange and inhibiting downstream signalling, proliferation, and tumour growth in KRAS mutant cancer cells and mice models. References: 37258666

New VVD-442 in Solid tumours with KRAS G12C: 4

Preclinical study. Covalent binding to C242 in the PI3K p110 alpha RBD inhibits RAS-PI3K interaction, suppressing growth of RAS mutant and HER2 over-expressing tumors without inducing hyperglycemia. References: 10.1101/2024.12.17.629001

New ACBI3 in Solid tumours with KRAS G12S, G12A, G12C, G12V, G13C, G13D, G13V, Q61E, Q61H, Q61P, A146P, A146T, A146V: 4

Preclinical study. A single small-molecule degrader, ACBI3, was designed to target 13 of the 17 most prevalent oncogenic KRAS mutants, achieving potent and selective degradation, and inducing tumor regression in KRAS mutant xenograft mouse models. References: 39298590

New BI-2493, BI-2865 in Solid tumours with KRAS Oncogenic mutations, G12A, G12C, G12D, G12F, G12V, G12S, G13C, G13D, V14I, L19F, Q22K, D33E, Q61H, K117N, A146V, A146T: 4

Preclinical study. A non-covalent pan-KRAS inhibitor was discovered, which binds to the inactive state of KRAS, blocking nucleotide exchange and inhibiting downstream signalling, proliferation, and tumour growth in KRAS mutant cancer cells and mice models. References: 37258666

New BI-2493, BI-2865 in Solid tumours with NRAS Oncogenic mutations, L95H: 4

Preclinical study. A non-covalent pan-KRAS inhibitor was discovered, which binds to the inactive state of KRAS, blocking nucleotide exchange and inhibiting downstream signalling, proliferation, and tumour growth in KRAS mutant cancer cells and mice models. References: 37258666

New ACBI3 in Solid tumours with KRAS G12R, Q61L, Q61R, Q61K: R2

Preclinical study. A single small-molecule degrader, ACBI3, was designed to target 13 of the 17 most prevalent oncogenic KRAS mutants, achieving potent and selective degradation, and inducing tumor regression in KRAS mutant xenograft mouse models. References: 39298590

New BI-2493, BI-2865 in Solid tumours with KRAS G12R, Q61L, Q61R, Q61K, A59T: R2

Preclinical study. A non-covalent pan-KRAS inhibitor was discovered, which binds to the inactive state of KRAS, blocking nucleotide exchange and inhibiting downstream signalling, proliferation, and tumour growth in KRAS mutant cancer cells and mice models. References: 37258666

Changed Olaparib in Breast cancer with BRCA2 : 3

Alterations changed: Oncogenic mutations AND NOT Oncogenic mutations (germline). (First curated: 2020-05-30)

11 June, 2025 (Version: 20250611AU)

New Olaparib in Breast cancer with BRCA1+ERBB2 BRCA1:Oncogenic mutation and NOT ERBB2:Overexpression and NOT ERBB2:Amplification: R2

Phase 2 trial. NCT00679783. Single-arm trial. Olaparib showed objective response rate of 41% in BRCA-mutated ovarian cancer and 24% in non-BRCA-mutated ovarian cancer, but no responses in HER2-negative breast cancer. References: 21862407

New Olaparib in Ovarian cancer with BRCA1 Oncogenic mutations: 3

Phase 2 trial. NCT00679783. Single-arm trial. Olaparib showed objective response rate of 41% in BRCA-mutated ovarian cancer and 24% in non-BRCA-mutated ovarian cancer, but no responses in HER2-negative breast cancer. References: 21862407

New Olaparib in Ovarian cancer with BRCA2 Oncogenic mutations: 3

Phase 2 trial. NCT00679783. Single-arm trial. Olaparib showed objective response rate of 41% in BRCA-mutated ovarian cancer and 24% in non-BRCA-mutated ovarian cancer, but no responses in HER2-negative breast cancer. References: 21862407

Changed Olaparib in Breast cancer with BRCA1 : 3

Alterations changed: Oncogenic mutations AND NOT Oncogenic mutations (germline). (First curated: 2020-05-30)

10 June, 2025 (Version: 20250610AU)

New LY3214996 in Solid tumours with BRAF Oncogenic mutations: 4

Phase 1. NCT02857270. LY3214996, an ERK1/2 inhibitor, tumor PD inhibition in patients with advanced cancer, with tumor regression observed in 7 patients with BRAF/non-BRAF mutant cancers. References: 10.1200/JCO.2019.37.15_suppl.3001

New Ulixertinib in Solid tumours with BRAF Oncogenic mutations: 4

Phase 1 trial. NCT01781429. N=135. Ulixertinib, an ERK1/2 kinase inhibitor, showed an acceptable safety profile and early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid tumors with partial responses observed in 14% of evaluable patients. References: 29247021

New ADT-007 in Breast cancer with HRAS G12D: 4

Preclinical study. ADT-007, a pan-RAS inhibitor, blocks GTP activation of RAS effector interactions and showed antitumor activity and inducing antitumor immunity in GI cancer models with selective targeting of mutant or activated RAS cells. References: 39700396

New BAY1436032 in Low-grade glioma with IDH1 R132: 4

Phase I trial. NCT02746081. BAY1436032 showed clinical activity in a subset of heavily pretreated subjects with lower grade glioma (LGG), with an objective response rate of 11% and stable disease in 43%, and a 3-month PFS rate of 0.31, while no objective responses were observed in glioblastoma, intrahepatic cholangiocarcinoma, or other tumor types. References: 33622704

New ADT-007 in Solid tumours, Pancreatic adenocarcinoma, Lung adenocarcinoma, Colon adenocarcinoma, Breast adenocarcinoma, Low-grade serous ovarian cancer, Melanoma, Gastric cancer with KRAS G12C, G12D, G12S, G12V, G13D, P121H, Amplification: 4

Preclinical study. ADT-007, a pan-RAS inhibitor, blocks GTP activation of RAS effector interactions and showed antitumor activity and inducing antitumor immunity in GI cancer models with selective targeting of mutant or activated RAS cells. References: 39700396

New H231 in Colorectal adenocarcinoma with KRAS+NRAS NOT KRAS:exon 2 mutation and NOT KRAS:exon 3 mutation and NOT KRAS:exon 4 mutation and NOT NRAS:exon 2 mutation and NOT NRAS:exon 3 mutation and NOT NRAS:exon 4 mutation: 4

Preclinical study. ADCs targeting EGFR ligand epiregulin (EREG) demonstrate antitumor activity in colorectal cancer across RAS mutation status, offering a potential alternative to conventional EGFR-targeted therapy. References: 39693606

New ATX968 in Solid tumours with Microsatellite Instability High: 4

Preclinical study. Selective inhibition of DHX9 by a small-molecule inhibitor impairs proliferation of microsatellite instable-high and mismatch repair deficient cancers in vitro and xenograft models. References: 39589774

New ATX968 in Solid tumours with Mismatch repair Deficient: 4

Preclinical study. Selective inhibition of DHX9 by a small-molecule inhibitor impairs proliferation of microsatellite instable-high and mismatch repair deficient cancers in vitro and xenograft models. References: 39589774

New ADT-007 in Breast cancer, Melanoma with NRAS Q61K: 4

Preclinical study. ADT-007, a pan-RAS inhibitor, blocks GTP activation of RAS effector interactions and showed antitumor activity and inducing antitumor immunity in GI cancer models with selective targeting of mutant or activated RAS cells. References: 39700396

New Xaluritamig in Prostate cancer with STEAP1 Protein expression: 4

Phase 1 study. Xaluritamig, a STEAP1-targeted T-cell engager, showed responses (49% PSA50; 24% ORR) in patients with metastatic castration-resistant prostate cancer, with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Note relationship between STEAP1 expression and response was not prospectively assessed in this study. References: 37861461

New Olaparib in Breast cancer with BRCA1 Promoter methylation: R2

Phase 2 COMETA-Breast study. NCT03205761. Olaparib showed limited antitumor activity in pretreated advanced triple-negative breast cancer patients with BRCA1/2 promoter methylation, with an ORR of 9% and median PFS of 2 months. References: 10.1200/JCO.2023.41.16_suppl.1093

New Olaparib in Breast cancer with BRCA2 Promoter methylation: R2

Phase 2 COMETA-Breast study. NCT03205761. Olaparib showed limited antitumor activity in pretreated advanced triple-negative breast cancer patients with BRCA1/2 promoter methylation, with an ORR of 9% and median PFS of 2 months. References: 10.1200/JCO.2023.41.16_suppl.1093

New BAY1436032 in Acute myeloid leukaemia with IDH1 R132: R2

Phase 1 study. NCT03127735. N=27. BAY1436032, an IDH1 inhibitor, showed modest clinical activity in IDH1-mutant AML with an overall response rate of 15% (4/27; 1 CRp, 1 PR, 2 MLFS) and median treatment duration of 6 months among responders. References: 32733012

New BAY1436032 in Glioblastoma, Intrahepatic cholangiocarcinoma, Solid tumours except Low-grade glioma with IDH1 R132: R2

Phase I trial. NCT02746081. BAY1436032 showed clinical activity in a subset of heavily pretreated subjects with lower grade glioma (LGG), with an ORR of 11% and SD in 43%, and a 3-month PFS rate of 0.31, while no objective responses were observed in glioblastoma, intrahepatic cholangiocarcinoma, or other tumor types. References: 33622704

New Crizotinib in Non-small cell lung cancer with MET Y1230C (Y1248C): R2

Case report. MET Y1230C mutation (0.3% pre-treatment frequency) emerged as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping, co-occurring with METex14 alteration D1010H, and was detected in ctDNA at progression after 13 months of treatment. References: 27666659

New MRK003 in Triple-negative breast cancer with NOTCH2 Rearrangements: R2

Preclinical study. NOTCH1 mutations and high N1-ICD levels correlated with GSI sensitivity in TNBC and ACC, while NOTCH2 rearrangements were associated with GSI resistance in TNBC cell lines. References: 25104330

Removed RAF dimer inhibitor in Solid tumours with BRAF alterations L597, L597Q, K601, K601E: Tier 4   (First curated: 2020-04-16)

Removed Anti-PD-1 monoclonal antibody; Anti-PD-L1 monoclonal antibody in Solid tumours with MLH1 alterations Promoter methylation: Tier 4   (First curated: 2020-04-16)

Removed Anti-PD-1 monoclonal antibody; Anti-PD-L1 monoclonal antibody in Solid tumours with MSH2 alterations Promoter methylation: Tier 4   (First curated: 2020-04-16)

Removed Anti-PD-1 monoclonal antibody; Anti-PD-L1 monoclonal antibody in Solid tumours with MSH6 alterations Promoter methylation: Tier 4   (First curated: 2020-04-16)

Removed AG-270 in Solid tumours with MTAP alterations Deletion: Tier 4   (First curated: 2020-11-23)

Removed Ulixertinib; LY3214996; LTT462; Ravoxertinib in Solid tumours with NF1 alterations Oncogenic mutations: Tier 4   (First curated: 2020-04-16)

Removed NRR2Mab in Urothelial carcinoma with NOTCH2 alterations Gain-of-function mutations: Tier 4   (First curated: 2020-04-16)

Removed MRK003 + paclitaxel in Solid tumours with NOTCH2 alterations Rearrangements: Tier 4   (First curated: 2020-04-16)

Removed Anti-PD-1 monoclonal antibody; Anti-PD-L1 monoclonal antibody in Solid tumours with PMS2 alterations Promoter methylation: Tier 4   (First curated: 2020-04-16)

Changed Venetoclax + Rituximab in Chronic lymphocytic leukaemia with BCL2 Overexpression: 1

Comments changed: TGA approved. Phase 3 trial. NCT02005471. N=389. Venetoclax-rituximab demonstrates significantly improved 2-year progression-free survival (85% vs 36%) compared to bendamustine-rituximab in relapsed or refractory chronic lymphocytic leukemia, with BCL2 overexpression being a characteristic of CLL cells.. (First curated: 2020-06-15)

Changed Blinatumomab in Acute lymphoblastic leukaemia with CD19 Protein expression: 1

Comments changed: Phase 3 trial. TOWER. NCT02013167. N=405. Blinatumomab significantly improved overall survival (7.7 vs 4.0 months), remission rates (44% vs 25%), and event-free survival (31% vs 12%) in adults with relapsed or refractory B-cell precursor ALL, including both Ph-positive and Ph-negative subtypes. Note that surface antigen CD-19 is lineage-specific to B-cells and constitutively expressed on the majority of B-cell precursor ALL blasts and does not represent a biomarker selection criteria.. (First curated: 2020-06-15)

Changed Therapy in Breast cancer with ERBB2 Amplification, Overexpression: 1

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2020-04-16)

Changed Therapy in Diffuse large B-cell lymphoma with CD79B Protein expression: 1B

Therapy changed: Polatuzumab vedotin + Bendamustine + RituximabPolatuzumab vedotin-piiq + Bendamustine + Rituximab. (First curated: 2020-06-15)

Changed Trastuzumab deruxtecan in Non-small cell lung cancer, Endometrial cancer, Salivary gland cancer with ERBB2 Amplification: 3

Comments changed: Phase 2 basket trial. NCT02675829. N=88. Trastuzumab Emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%).Phase 2 basket trial. NCT02675829. N=88. Ado-trastuzumab emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%).. (First curated: 2025-06-09)

Changed Therapy in Salivary gland cancers with ERBB2 Amplification: 3

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2021-10-12)

Changed Therapy in Breast cancer with ERBB2 Amplification, Overexpression: 3

Therapy changed: Tucatinib + Trastuzumab EmtansineTucatinib + Ado-Trastuzumab Emtansine. (First curated: 2022-04-22)

Changed Therapy in Non-small cell lung cancer with ERBB2 Oncogenic mutations, V659E, A775_G776insYVMA (Y772_A775dup), P780_Y781insGSP (G778_P780dup), G778insCPG, G776delinsVC, exon 20 insertion: 3

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2020-05-04)

Changed Therapy in Gastroesophageal junction adenocarcinoma, Gastric Cancer with ERBB2 Overexpression: 3

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2020-07-21)

Changed Neratinib + Trastuzumab emtansine in Breast cancer with ERBB2 Overexpression, Amplification: 3

Comments changed: Phase 2. TBCRC022 Cohort 4. N=44. Neratinib + Trastuzumab Emtansine achieved 33.3%-35.3% CNS ORR in HER2+ breast cancer brain metastases, with median OS of 20.9-30.2 months across three cohorts.Phase 2. TBCRC022 Cohort 4. N=44. Neratinib + ado-trastuzumab emtansine achieved 33.3%-35.3% CNS ORR in HER2+ breast cancer brain metastases, with median OS of 20.9-30.2 months across three cohorts.. (First curated: 2025-01-13)

Changed RMC-4550 in Solid tumours with BRAF Class III mutations, G466V, G596R: 4

Comments changed: SHP2 inhibition by RMC-4550 is active in cancer models with class 3 BRAF mutants, NF1 loss, or KRASG12 mutations, suppressing RAS/MAPK signaling and cell growth by disrupting SOS1-mediated RAS-GTP loading.Cell line study demonstrating BRAF class III mutations are sensitive to SHP2 inhibition.. (First curated: 2022-02-04)

Changed Trastuzumab deruxtecan in Biliary tract cancer, Ovarian cancer with ERBB2 Amplification: 4

Comments changed: Phase 2 basket trial. NCT02675829. N=88. Trastuzumab Emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%).Phase 2 basket trial. NCT02675829. N=88. Ado-trastuzumab emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%).. (First curated: 2025-06-09)

Changed Therapy in Colorectal adenocarcinoma with ERBB2 ERBB2:amplification and KRAS:G12D: 4

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2021-03-17)

Changed Therapy in Breast cancer with ERBB2 L755S: 4

Therapy changed: Ado-Trastuzumab Emtansine, Poziotinib. (First curated: 2021-06-16)

Changed Therapy in Gastric cancer with ERBB2 MDK-ERBB2 fusion, Fusions: 4

Therapy changed: Trastuzumab, Trastuzumab EmtansineTrastuzumab, Ado-Trastuzumab Emtansine. (First curated: 2021-05-20)

Changed Therapy in Non-small cell lung cancer with ERBB2 V659E: 4

Therapy changed: Lapatinib, Afatinib, Trastuzumab EmtansineLapatinib, Afatinib, Ado-Trastuzumab Emtansine. (First curated: 2022-04-13)

Changed Therapy in Colorectal adenocarcinoma with ERBB2+KRAS ERBB2:amplification and KRAS:G12D: 4

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2021-03-17)

Changed Crizotinib in Non-small cell lung cancer with MET : 4

Alterations changed: D1028H (D1010H)Y1230C (Y1248C). Tier changed: 4R2. Comments changed: Case report. MET Y1230C mutation (0.3% pre-treatment frequency) emerged as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping, co-occurring with METex14 alteration D1010H, and was detected in ctDNA at progression after 13 months of treatment.Case report. Pre-treatment D1010H sensitizing to crizotinib.. (First curated: 2021-01-03)

Changed AG-270 in Solid tumours with MTAP Deletion: 4

Comments changed: Phase 1 trial. NCT03435250. N=40. AG-270/S095033, a MAT2A inhibitor, achieved 2 partial responses and 5 patients with stable disease ≥16 weeks in patients with advanced MTAP-deleted malignancies. First curated: 2020-11-23. (First curated: 2025-05-27)

Changed TetMYB in Solid tumours, Adenoid cystic carcinoma, Colorectal adenocarcinoma with MYB Alteration; Overexpression: 4

Comments changed: Phase1. MYPHISMO. NCT03287427. First-in-human trial evaluating the safety and efficacy of TetMYB vaccine in combination with anti-PD-1 antibody in patients with advanced solid cancers, including colorectal and adenoid cystic carcinoma.. (First curated: 2021-05-05)

Changed BET inhibitor in Solid tumours, Liquid cancers with MYC Amplification, Oncogenic mutations: 4

Comments changed: Review of bromodomain inhibitors, a new target class for drug development, highlighting the progress of BET inhibitors in clinical trials and discussing the potential of next-wave non-BET bromodomain inhibitors in oncology and non-oncology indications.. (First curated: 2020-04-16)

Changed BET inhibitor in Solid tumours, Liquid cancers with MYCN Amplification, Oncogenic mutations: 4

Comments changed: Preclinical studies demonstrated bromodomain inhibition as a therapeutic strategy in cancer, particularly for MYCN-amplified neuroblastoma, where BET bromodomain inhibitors downregulated the MYCN transcriptional program and impaired growth, inducing apoptosis, and conferred a significant survival advantage in in vivo models.. (First curated: 2020-04-16)

Changed eFT508 in Diffuse large B-cell lymphoma with MYD88 Gain-of-function mutations: 4

Comments changed: Preclinical study. MNK1/MNK2 inhibitor demonstrated anti-proliferative effects in DLBCL cell lines, reduced pro-inflammatory cytokine production, and showed anti-tumor activity in human lymphoma xenograft models.MNK inhibitor. (First curated: 2020-04-16)

Changed MRK003 in Solid tumours with NOTCH1 Oncogenic mutations, Overexpression: 4

Comments changed: Preclinical study. NOTCH1 mutations and expression levels of HES4 are identified as biomarkers predictive of response to gamma-secretase inhibitor (GSI) in triple-negative breast cancer and adenoid cystic carcinoma.. References changed: 25104330, 24667249. (First curated: 2020-04-16)

Changed MRK003 in Glioblastoma with NOTCH2 Gain-of-function mutations: 4

Comments changed: Pre-clinical study. NOTCH pathway blockade using gamma-secretase inhibitors depleted CD133-positive glioblastoma stem cells, inhibited neurosphere growth, and prolonged survival in xenograft models.Pre-clinical evidence. (First curated: 2020-04-16)

Changed MRK003 in Non-small cell lung cancer with NOTCH3 Overexpression: 4

Comments changed: Preclinical study. Gamma-secretase inhibitor MRK-003 inhibited Notch3 signaling, reduced proliferation, and induced apoptosis in lung cancer cell lines in vitro and in vivo.Pre-clinical evidence. (First curated: 2020-04-16)

Changed Exarafenib in Melanoma with NRAS Oncogenic mutations: 4

Comments changed: Phase 1/1b. NCT04913285. N=52. Exarafenib, a pan-RAF inhibitor, demonstrated preliminary clinical activity with 18% partial response and 47% stable disease in 34 patients across all dose levels with post-baseline tumor assessment.. (First curated: 2023-05-05)

Changed FOLFIRINOX in Pancreatic adenocarcinoma with RAD51C Oncogenic mutations (germline): 4

Comments changed: Case report. A patient with metastatic pancreatic adenocarcinoma and a germline RAD51C mutation showed a remarkable response to FOLFIRINOX, a platinum-containing chemotherapy regimen.. (First curated: 2020-07-02)

Changed Rucaparib, Niraparib in Ovarian cancer with RAD51C Promoter methylation: 4

Comments changed: Preclinical study. RAD51C promoter methylation loss causes PARP inhibitor resistance in high-grade serous ovarian carcinoma PDX models, where a single unmethylated copy of RAD51C is sufficient to drive resistance.. (First curated: 2023-01-18)

Changed RMC-4550 in Solid tumours with BRAF V600E, Class I mutations, Class II mutations, G469A: R2

Comments changed: SHP2 inhibition is active in cancers driven by class 3 BRAF mutants, NF1 loss, and certain KRASG12 mutants, which remain dependent on RAS nucleotide cycling, offering a potential therapeutic strategy for these currently intractable tumors.Cell line study.. (First curated: 2022-02-04)

Changed Palbociclib in Lung squamous cell carcinoma with CDK6 Amplification: R2

Comments changed: Phase 2, Lung-MAP S1400C trial, evaluated palbociclib in patients with cell cycle gene alterations, showing an ORR of 6%, with two partial responses observed in patients with CCND1 amplification, indicating limited efficacy as monotherapy in squamous NSCLC.Lung-MAP S1400C, ORR 6%. (First curated: 2020-11-10)

Changed Palbociclib in Gastrointestinal stromal tumour with CDKN2A Deletion: R2

Comments changed: Phase 2. NCT01907607. In patients with advanced GIST refractory to imatinib and sunitinib with CDKN2A loss, palbociclib showed no significant clinical activity with 86% of patients having progressive disease at 4 months and ORR 0%.Phase 2. NCT01907607. ORR 0%.. (First curated: 2022-09-28)

Changed Palbociclib in Pancreatic adenocarcinoma, Biliary tract cancer with CDKN2A Deletion, Oncogenic mutations: R2

Comments changed: TAPUR study. N=22 (12 pancreatic, 10 biliary cancer). ORR 0%. Median PFS 7.2 and 7.3 weeks, and median OS 12.4 and 11.1 weeks in pancreatic and biliary cohorts respectively, with CDKN2A loss or mutation treated with palbociclib.TAPUR. N=22. ORR 0%.. (First curated: 2022-10-16)

Changed Trastuzumab deruxtecan in Colorectal adenocarcinoma, Bladder cancer with ERBB2 Amplification and NOT overexpression: R2

Comments changed: Phase 2 basket trial. NCT02675829. N=88. Trastuzumab Emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%).Phase 2 basket trial. NCT02675829. N=88. Ado-trastuzumab emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%).. (First curated: 2025-06-09)

Changed Therapy in Colorectal adenocarcinoma with ERBB2 Amplification, Overexpression: R2

Therapy changed: Ado-Trastuzumab Emtansine + Pertuzumab. (First curated: 2021-03-17)

Changed Therapy in Solid tumours except Breast cancer, Gastric cancer, Gastroesophageal junction adenocarcinoma, Oesophageal adenocarcinoma with ERBB2 Amplification, Overexpression: R2

Therapy changed: Ado-Trastuzumab Emtansine. (First curated: 2022-08-26)

Changed Trastuzumab in Breast cancer with ERBB2 L755S, D769Y, V842I, K753E: R2

Comments changed: Somatic HER2 mutations, such as L755S, V842I, K753I, and D769Y, are associated with resistance to certain anti-HER2 therapies, including trastuzumab and lapatinib, while others like S310F, S310Y, R678Q, D769H, or I767M show activities, and specific mutations like L755S or D769Y may have activity from neratinib or afatinib in HER2-positive breast cancer.. (First curated: 2020-10-05)

Changed Therapy in Breast cancer with ERBB2 L755S, L755P: R2

Therapy changed: Ado-Trastuzumab Emtansine, Lapatinib + Trastuzumab, Trastuzumab, Lapatinib + Capecitabine, Lapatinib + Letrozole, Lapatinib + Paclitaxel, Trastuzumab + Paclitaxel, Trastuzumab + Pertuzumab + Paclitaxel, Trastuzumab + Capecitabine. (First curated: 2020-05-15)

Changed Lapatinib in Breast cancer with ERBB2 L755S, V842I, K753E: R2

Comments changed: Somatic HER2 mutations demonstrate varied therapeutic implications: L755S, V842I, K753I, and D769Y confer resistance to trastuzumab and lapatinib; S310F, S310Y, R678Q, D769H, and I767M are associated with favorable treatment outcomes; L755S and D769Y may respond to neratinib or afatinib.. (First curated: 2020-10-05)

Changed Lapatinib in Urothelial carcinoma with ERBB2 Overexpression: R2

Comments changed: Phase 3 trial. N=232. Maintenance lapatinib did not improve PFS (4.5 vs 5.1 months) or OS (12.6 vs 12.0 months) in HER1/HER2-positive metastatic urothelial bladder cancer patients after first-line chemotherapy, including in patients strongly positive for HER1/HER2.. (First curated: 2020-11-15)

Changed Therapy in Gastric cancer with ERBB2 ZNF207-ERBB2 fusion: R2

Therapy changed: Trastuzumab, Trastuzumab EmtansineTrastuzumab, Ado-Trastuzumab Emtansine. (First curated: 2021-05-20)

Changed Pictilisib in Solid tumours with ERBB3 Q809R: R2

Comments changed: Preclinical study. Oncogenic ERBB3 mutations identified in colon and gastric cancers, with mutant ERBB3 oncogenic activity dependent on ERBB2, suggesting potential resistance to ERBB-targeting therapies unless ERBB2 is also inhibited.. (First curated: 2022-05-18)

Changed Cetuximab in Head and neck squamous cell carcinoma with ERBB4 Oncogenic mutations: R2

Comments changed: Preclinical study. Afatinib showed antitumor activity against ESCC and HNSCC cell lines with activating oncogenic EGFR and HER4 mutations, suggesting potential for targeted therapy in patients with such mutations, particularly in HNSCC where HER4 mutations are relatively frequent, indicating a possible resistance mechanism.No response in this cohort. (First curated: 2020-04-23)

Changed GnRH agonist, Aromatase Inhibitor, Letrozole, Anastrozole, Exemestane, Tamoxifen in Breast cancer with ESR1 E380Q, V392I, S463P, V534E, P535H, L536R, L536Q, Y537S, Y537N, Y537C, D538G: R2

Comments changed: Review article discusses ESR1 mutations as a mechanism for acquired endocrine resistance in ER-positive breast cancer, occurring in approximately 20% of metastatic patients treated with endocrine therapies.. (First curated: 2020-04-26)

Changed Olaparib in Pancreatic adenocarcinoma with FANCD2 Oncogenic mutations, Oncogenic mutations (germline): R2

Comments changed: Two Phase 2 studies. N=46. Olaparib monotherapy showed limited antitumor activity in patients with pancreatic cancer with DDR-GAs, with a median PFS of 5.7 months and median OS of 13.6 months, suggesting a potential therapeutic opportunity for a subset of patients with PDAC harbouring DDR genetic alterations.Two Phase 2 studies of Olaparib in previously treatment pancreatic cancer. ORR 4% did not meet predefined threshold.. (First curated: 2021-03-16)

Changed Zoligratinib in Cholangiocarcinoma with FGFR2 L618F: R2

Comments changed: Preclinical and clinical study. FGFR2 extracellular domain in-frame deletions (EID) in intrahepatic cholangiocarcinoma are present in 2.8% of patients, conferring initial sensitivity to FGFR inhibitors. The L618F FGFR2 kinase domain mutation leads to acquired resistance, which can be overcome by futibatinib.. (First curated: 2022-09-28)

Changed Dovitinib in Cholangiocarcinoma with FGFR2 N549S, N549H: R2

Comments changed: Preclinical study. Comprehensive functional evaluation of 160 nonsynonymous FGFR mutations and ten fusion genes revealed varying transforming activity and sensitivity to seven FGFR TKIs, with several hotspot mutants showing relative resistance, and compound mutations affecting TKI-sensitivity.. (First curated: 2023-02-22)

Changed Infigratinib, AZD4547, Zoligratinib in Solid tumours with FGFR3 V443, V555M: R2

Comments changed: Phase 1/2 trial. BGJ398. N = 67. Patients with metastatic urothelial carcinoma bearing FGFR3 alterations. Overall response rate of 25.4% and disease control rate of 64.2% observed. Preclinical study identified gatekeeper mutation (FGFR3(V555M)) in FGFR3 as a mechanism of acquired resistance to FGFR inhibitors.. (First curated: 2020-05-22)

Changed Sotorasib in Solid tumours with KRAS V8L, G13D, V14L, K16T, A59S, Q61R, R68S, G77V, Y96D, Y96C, K117N, D119H, A146P: R2

Comments changed: Phase1/2 study. N=38. KRAS(G12C) mutant cancers treated with adagrasib or sotorasib. Putative mechanisms of resistance detected in 45% patients, including acquired KRAS alterations, bypass mechanisms, and histologic transformation to squamous-cell carcinoma. On-target resistance identified by deep mutational scanning and in vitro validated.. (First curated: 2021-06-25)

Changed Adagrasib in Solid tumours with KRAS V9F, G13D, V14L, K16T, A59S, Q61R, E62D, Y64N, R68S, M72L, G77V, H95D, H95Q, H95R, Y96D, Y96C, Q99K, K117N, D119H, A146P: R2

Comments changed: Phase 1/2 study. NCT03785249. N=38. Mechanisms of resistance to Adagrasib include acquired KRAS alterations (G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and KRAS(G12C) allele amplification) and bypass mechanisms involving MET amplification, NRAS, BRAF, MAP2K1, RET mutations, ALK, RET, BRAF, RAF1, FGFR3 fusions, and NF1, PTEN loss-of-function mutations. Histologic transformation to squamous-cell carcinoma was observed in 2 lung adenocarcinoma patients.On-target resistance identified by deep mutational scanning and in vitro validated.. (First curated: 2021-06-25)

Changed Pembrolizumab in Colorectal adenocarcinoma with KRAS+Microsatellite Instability KRAS:Oncogenic mutations AND Microsatellite Instability:High: R2

Comments changed: Phase 3 KEYNOTE-177 trial. NCT02563002. N=307. Pembrolizumab demonstrated superior progression-free survival (16.5 vs 8.2 months, HR 0.60) with reduced treatment-related adverse events (22% vs 66%) in MSI-H/dMMR metastatic colorectal cancer, with 83% of responders maintaining ongoing responses at 24 months. The KRAS subgroup did not show PFS benefit over chemotherapy.KRAS subgroup showed no PFS benefit over chemotherapy in KEYNOTE-177. (First curated: 2020-12-11)

Changed Pembrolizumab in Colorectal adenocarcinoma with KRAS+Mismatch repair KRAS:Oncogenic mutations AND Mismatch repair:deficient: R2

Comments changed: Phase 3 KEYNOTE-177 trial. NCT02563002. N=307. Pembrolizumab demonstrated superior progression-free survival (16.5 vs 8.2 months, HR 0.60) with reduced treatment-related adverse events (22% vs 66%) in MSI-H/dMMR metastatic colorectal cancer, with 83% of responders maintaining ongoing responses at 24 months. The KRAS subgroup did not show PFS benefit over chemotherapy.KRAS subgroup showed no PFS benefit over chemotherapy in KEYNOTE-177. (First curated: 2020-12-11)

Changed Duligotuzumab + FOLFIRI in Colorectal adenocarcinoma with KRAS+NRAS NOT KRAS:exon 2 mutation and NOT KRAS:exon 3 mutation and NOT KRAS:exon 4 mutation and NOT NRAS:exon 2 mutation and NOT NRAS:exon 3 mutation and NOT NRAS:exon 4 mutation: R2

Comments changed: Phase 2. NCT01652482. In RAS wild-type metastatic colorectal cancer, duligotuzumab plus FOLFIRI showed no improvement in PFS or OS compared with cetuximab and FOLFIRI, with a trend for lower ORR and different toxicity profiles.NCT01652482. Phase 2. In RAS wild-type metastatic colorectal cancer, there was no improvement of duligotuzumab plus FOLFIRI compared with cetuximab and FOLFIRI.. (First curated: 2021-05-18)

Changed Cetuximab in Breast cancer, Non-small cell lung cancer, Ovarian cancer with KRAS+NRAS+BRAF NOT KRAS:Oncogenic mutation and NOT NRAS:Oncogenic mutation and NOT BRAF:Oncogenic mutation: R2

Comments changed: Phase 2 TAPUR study. NCT02693535. N=49. Cetuximab showed no objective responses in breast cancer (N=10) and NSCLC (N=10), and no objective responses but 4 patients with stable disease for at least 16 weeks in ovarian cancer (N=29).NCT02693535. TAPUR. N=49 including breast, NSCLC, and ovarian cancers. ORR 0%.. (First curated: 2022-10-16)

Changed Rucaparib in Non-small cell lung cancer with Loss-of-heterozygosity score High: R2

Comments changed: Phase 2 Lung-MAP Sub-Study, S1900A. NCT03845296. N=64 (27 squamous; 37 non-squamous). Rucaparib showed limited efficacy in NSCLC patients with high genomic LOH and/or BRCA1/2 mutations, with an ORR of 7% (4% squamous; 9% non-squamous) and median PFS of 3.2 months (non-squamous) and 2.9 months (squamous). Genomic LOH does not predict activity.Phase 2 Lung-MAP Sub-Study, S1900A. ORR 7%. Genomic LOH does not predict activity.. (First curated: 2021-06-10)

Changed Dabrafenib + Trametinib, Trametinib in Colorectal adenocarcinoma with MAP2K1 F53L: R2

Comments changed: Paired pre-post treatment sequencing identified MAPK pathway alterations, including KRAS amplification, BRAF amplification, and MEK1 mutation, driving clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer.. (First curated: 2020-11-25)

Changed Cabozantinib in Solid tumours with MDM2 Amplification: R2

Comments changed: Preclinical study. MDM2 amplification identified as a potential mechanism of primary or acquired resistance to cabozantinib in RET-rearranged lung cancers, with MDM2 inhibitors showing effectiveness in suppressing tumor growth.Anti-RET activity. References changed: 10.1200/JCO.2016.34.15_suppl.906832083997. (First curated: 2020-11-17)

Changed Osimertinib in Non-small cell lung cancer with MET Amplification: R2

References changed: 27252416, 3793834827252416; 37938348. (First curated: 2020-03-12)

Changed Crizotinib in Non-small cell lung cancer with MET L1195V (L1213V), Y1230 (Y1248), D1228N (D1246N), D1228 (D1246), D1246 (D1228), Y1248 (Y1230), G1163 (G1181): R2

Comments changed: Evidence for Crizotinib and potential sequential use of type II MET inhibitors (cabozantinib, glesatinib, merestinib) in NSCLC patients with MET exon 14 skipping mutations after developing resistance to type I MET inhibitors.Strong evidence for Crizotinib. Capmatinib inferred. (First curated: 2020-05-15)

Changed Pembrolizumab in High-grade gliomas with Mismatch repair Deficient: R2

Comments changed: Single-agent pembrolizumab showed a DCR of 31% with no objective responses (ORR 0%) and four patients with stable disease in a prospective study of 13 recurrent high-grade gliomas with MMR protein loss.N=13. Single-agent PD-1 inhibitor showed no response in a prospective case series (ORR 0%) with 4 SD.. (First curated: 2022-06-20)

Changed Pembrolizumab in High-grade gliomas, Anaplastic astrocytoma, Glioblastoma with Mismatch repair Deficient: R2

Comments changed: Phase 2 trial. N=13. Median age 43 years. ORR 0%. DCR 31% (4 stable disease). TMB ranged 6.8-23.4 mutations/megabase. Pembrolizumab showed no apparent benefit in patients with recurrent HGG and MMR loss.N=13. ORR 0%. All patients were microsatellite stable.. (First curated: 2021-06-24)

Changed Durvalumab in Endometrial cancer with Mismatch repair Proficient, NOT Deficient: R2

Comments changed: Phase 2 trial. NCT03015129. Durvalumab showed promising activity in dMMR advanced endometrial carcinoma with ORR of 47% and median PFS of 8.3 months, but limited activity in pMMR advanced endometrial carcinoma with ORR of 3% and median PFS of 1.8 months.PHAEDRA. Phase 2. ORR in the pMMR cohort was 3% (1 of 35) with median PFS of 1.8 months.. (First curated: 2023-07-14)

Changed Pembrolizumab + Carboplatin + Pemetrexed in Non-small cell lung cancer with NRG1 Fusions: R2

Comments changed: Retrospective registry-based study. NRG1 fusion-positive lung cancers showed heterogeneity in molecular, pathological, and clinical characteristics, with low ORR to platinum-doublet chemotherapy (13%), taxane-based chemotherapy (14%), chemoimmunotherapy (0%), and single-agent immunotherapy (20%), while afatinib achieved an ORR of 25%.Retrospective registry-based study. Chemoimmunotherapy ORR 0%.. (First curated: 2021-06-08)

Changed Androgen receptor antagonist, GnRH agonist, CYP17A1 inhibitor, Enzalutamide, Apalutamide in Prostate cancer with RB1 Oncogenic mutations: R2

Comments changed: Review. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer were discussed, including restored AR signalling, AR bypass signalling, and complete AR independence, presenting new challenges for long-term disease control.. (First curated: 2020-04-26)

Changed Androgen receptor antagonist, GnRH agonist, CYP17A1 inhibitor, Enzalutamide, Apalutamide in Prostate cancer with TP53 Oncogenic mutations: R2

Comments changed: Preclinical study. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer were reviewed, including restored AR signalling, AR bypass signalling, and complete AR independence, presenting new challenges for long-term disease control.Off-target mechanism. (First curated: 2020-04-26)

09 June, 2025 (Version: 20250609AU)

New Selumetinib in Type 1 neurofibromatosis with NF1 Oncogenic mutations (germline): 1

Phase 3 KOMET trial. NCT04924608. N=145. Selumetinib significantly improved ORR (19.7% vs 5.4%) compared to placebo in adults with NF1 and symptomatic, inoperable plexiform neurofibroma. References: 10.1200/JCO.2025.43.16_suppl.3014

New Trastuzumab deruxtecan in Non-small cell lung cancer, Endometrial cancer, Salivary gland cancer with ERBB2 Amplification: 3

Phase 2 basket trial. NCT02675829. N=88. Ado-trastuzumab emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%). References: 10.1200/JCO.2025.43.16_suppl.3020

New JSKN003 in Gastroesophageal junction adenocarcinoma, Gastric Cancer, Colorectal adenocarcinoma with ERBB2 Overexpression: 3

Pooled analysis of JSKN003-101 and JSKN003-102 trials. NCT05494918, NCT05744427. N=40. JSKN003 showed activity in heavily pretreated patients with advanced HER2-overexpressing gastrointestinal tumors, with ORR of 67% and median PFS of 9.6 months. References: 10.1200/JCO.2025.43.16_suppl.3022

New GFH375 in Solid tumours, Non-small cell lung cancer, Pancreatic adenocarcinoma with KRAS G12D: 3

Phase 1/2 trial. NCT06500676. N=32. Single-agent GFH375, a KRAS G12D inhibitor that targets both GTP-bound and GDP-bound states of mutant KRASG12D protein, showed anti-tumor activity in patients with advanced solid tumors, with ORR of 27% and DCR of 86% across dose range. ORR 42% in 12 PDAC and 52% in PDAC at target dose range. References: 10.1200/JCO.2025.43.16_suppl.3013

New BC3195 in Non-small cell lung cancer with EGFR Oncogenic mutations: 4

Phase 1. NCT05957471, N=56, BC3195, an ADC targeting CDH3, showed preliminary activity in heavily pretreated patients with NSCLC, particularly in EGFR-mutant NSCLC with an ORR of 50% and mPFS > 6 months. References: 10.1200/JCO.2025.43.16_suppl.3019

New Trastuzumab deruxtecan in Biliary tract cancer, Ovarian cancer with ERBB2 Amplification: 4

Phase 2 basket trial. NCT02675829. N=88. Ado-trastuzumab emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%). References: 10.1200/JCO.2025.43.16_suppl.3020

New LY4170156 in Ovarian cancer, Peritoneal serous carcinoma, Fallopian tube carcinoma with FOLR1 Protein expression: 4

Phase 1a/b study. NCT06400472. LY4170156, an ADC targeting folate receptor alpha, showed a preliminary ORR of 38% (5/13) in HGSOC patients with varying FRα expression levels and prior mirvetuximab soravtansin treatment. References: 10.1200/JCO.2025.43.16_suppl.3023

New ADRX-0706 in Solid tumours with NECTIN4 Protein expression: 4

Phase 1 trial. NCT06036121. N=53. ADRX-0706, a Nectin-4 targeting antibody-drug conjugate (ADC), showed anti-tumor activity in 30 response-evaluable subjects treated at doses ≥8 mg/kg, with a confirmed complete response in a cervical cancer patient. The study reported an ORR of 17%, including 5 objective responses, and a DCR of 47%, with 9 patients experiencing stable disease. Nectin-4 expression is retrospective analysis criteria and not prospectively assessed. References: 10.1200/JCO.2025.43.16_suppl.3018

New BRY812 in Solid tumours with SLC39A6 Protein expression: 4

Phase 1 trial. NCT06038058. N=36. BRY812, an ADC targeting LIV-1, demonstrated an ORR of 24% (8/34) in breast cancer, with response rates increasing to 43% (6/14) in patients with high LIV-1 expression (PS2+). References: 10.1200/JCO.2025.43.16_suppl.3021

New BAT8008 in Solid tumours with TACSTD2 Protein expression: 4

Phase 1 study. NCT05620017. N=170. BAT8008 showed activity in advanced cervical cancer (ORR 36%, PFS 6.8 months) and oesophageal cancer (ORR 23%, PFS 5.3 months). References: 10.1200/JCO.2025.43.16_suppl.3024

New Trastuzumab deruxtecan in Colorectal adenocarcinoma, Bladder cancer with ERBB2 Amplification and NOT overexpression: R2

Phase 2 basket trial. NCT02675829. N=88. Ado-trastuzumab emtansine (TDM1) demonstrated variable activity in multiple HER2-amplified tumor types, with ORR in NSCLC (21.1%), endometrial cancer (21.7%), and salivary gland cancer (87.5%), while colorectal cancer had 0% ORR, and other HER2-amplified solid tumors had 8.7% ORR, including biliary (12.5%), ovarian (14.3%). References: 10.1200/JCO.2025.43.16_suppl.3020

New Tazemetostat in Epithelioid sarcoma, Atypical teratoid rhabdoid tumor with EZH2 Y666N: R2

Preclinical study. Identified molecular mechanisms of tazemetostat resistance in SMARCB1-deficient tumors, and developed a combination strategy using AURKB targeting to circumvent resistance. References: 38315003

New Tazemetostat in Epithelioid sarcoma, Atypical teratoid rhabdoid tumor with RB1 Deletion, Oncogenic mutations: R2

Preclinical study. Identified molecular mechanisms of tazemetostat resistance in SMARCB1-deficient tumors, and developed a combination strategy using AURKB targeting to circumvent resistance. References: 38315003

Changed Mirvetuximab soravtansine in Ovarian cancer with FOLR1 : 2

Alterations changed: Protein expression. (First curated: 2022-11-16)

Changed Repotrectinib with ROS1 Fusion: 3

Cancer type(s) changed: Solid tumours (First curated: 2022-01-21)

Changed AZD9833, Elacestrant, Tamoxifen in Breast cancer with ESR1 : 4

Alterations changed: F404L, D538G and F404L, E380Q and F404L. Comments changed: Novel ESR1 F404 mutations (F404L, F404I, and F404V) were acquired in 4% of patients in the plasmaMATCH Cohort A trial (NCT03182634, N=69). These mutations confer resistance to fulvestrant when combined with preexisting activating ESR1 mutations. In cell line models, F404L demonstrates sensitivity to tamoxifen and select SERDs. These mutations may be potentially targetable by oral ERalpha degraders in clinical development.plasmaMATCH. Treatment emergent mutation causing acquired resistance at the ligand binding domain. In cell line model, F404L is sensitive to tamoxifen and select SERDs.. (First curated: 2022-06-17)

Changed Fulvestrant in Breast cancer with ESR1 : R2

Alterations changed: F404L, F404I, F404V, D538G and F404L, E380Q and F404L. Comments changed: Novel ESR1 F404 mutations (F404L, F404I, and F404V) were acquired in 4% of patients in the plasmaMATCH Cohort A trial (NCT03182634, N=69). These mutations confer resistance to fulvestrant when combined with preexisting activating ESR1 mutations. In cell line models, F404L demonstrates sensitivity to tamoxifen and select SERDs. These mutations may be potentially targetable by oral ERalpha degraders in clinical development.plasmaMATCH. Treatment emergent mutation causing acquired resistance at the ligand binding domain.. References changed: 37982575, 10.1200/JCO.2022.40.16_suppl.1009. (First curated: 2022-06-17)

06 June, 2025 (Version: 20250606AU)

New ABBV-706 in High-grade well-differentiated neuroendocrine tumour, Neuroendocrine carcinoma, Solid tumour with SEZ6 Protein expression: 3

Phase 1. NCT05599984. ABBV-706, a SEZ6-targeting antibody-drug conjugate, showed preliminary efficacy in high-grade neuroendocrine neoplasms (NENs) with an overall objective response rate of 31% (20/64) and median progression-free survival of 6.8 months. References: 10.1200/JCO.2025.43.16_suppl.105

New SHR-1826 in Solid tumours with MET Overexpression, Amplification, Oncogenic mutation: 3

Phase 1 study. NCT06094556. N=116. SHR-1826, a c-MET-directed antibody-drug-conjugate, demonstrated a manageable safety profile and promising anti-cancer activity in heavily pretreated advanced solid tumors, particularly in NSCLC patients with an ORR of 40% and median PFS of 6.8 months. References: 10.1200/JCO.2025.43.16_suppl.106

New Sevabertinib in Non-small cell lung cancer with EGFR Exon 20 insertions, C797S: 4

Phase 1. NCT05099172. BAY2927088 is an oral TKI targeting EGFR and HER2 mutations that demonstrates strong potency and high selectivity for mutant versus wild-type EGFR, showing activities in NSCLC patients with EGFR exon 20 insertion mutations and EGFR C797S acquired resistance mutation. References: 10.1158/1538-7445.AM2023-CT126

New Sevabertinib in Non-small cell lung cancer with ERBB2 Exon 20 insertion mutation, A775_G776insYVMA (Y772_A775dup), G776delinsVC, S310F, S335C, L755S: 4

Preclinical study. BAY 2927088 showed strong antiproliferative activity against various HER2 mutations, including exon 20 insertion mutations (A775insYVMA, G776delinsVC) and point mutations (S310F, S335C, L755S), in isogenic Ba/F3 cell lines and patient-derived xenograft models. References: 10.1158/1538-7445.AM2023-4035

New DM002 in Solid tumours with MUC1 Protein expression: 4

Preclinical study. DM002 is a bispecific antibody-drug conjugate targeting HER3 and the juxtamembrane domain of MUC1, demonstrating endocytic and anti-tumor activity in patient-derived xenograft models of lung, breast, gastric, and pancreatic cancers. References: 10.1158/1538-7445.AM2023-LB214

Changed Sevabertinib in Non-small cell lung cancer with ERBB2 : 3

Alterations changed: Exon 20 insertion, Oncogenic mutations. (First curated: 2024-07-03)

Changed NVL-655 in Solid tumours, Non-small cell lung cancer with ALK : 4

Alterations changed: G1202R, T1151M, T1151insT, C1156Y, I1171N, I1171S, I1171T, F1174L, V1180L, L1196M, L1196Q, L1196Q, L1198F, G1202del, D1203N, S1206F, S1206Y, E1210K, G1269A, G1202R and T1151M, G1202R and F1174L, G1202R and L1196M, G1202R and L1198F, G1202R and G1269A, I1171N and L1198F, F1174L, F1174L, Exon 2–3 deletion, Exon 2-17 deletionG1202R, T1151M, T1151insT, C1156Y, I1171N, I1171S, I1171T, F1174L, V1180L, L1196M, L1196Q, L1196Q, L1198F, G1202del, D1203N, S1206F, S1206Y, E1210K, G1269A, G1202R and T1151M, G1202R and F1174L, G1202R and L1196M, G1202R and L1198F, G1202R and G1269A, — G1202R compound mutant, I1171N and L1198F, F1174L, F1174L, Exon 2–3 deletion, Exon 2-17 deletion. (First curated: 2025-04-30)

04 June, 2025 (Version: 20250604AU)

Changed GSK126 in Ovarian clear cell carcinoma with ARID1A Oncogenic mutations: 4

Comments changed: Preclinical study. EZH2 inhibition showed synthetic lethality in ARID1A-mutated ovarian cancer cells, with regression of ARID1A-mutated ovarian tumors in vivo.. (First curated: 2020-04-25)

Changed Molibresib, JQ1 in Ovarian clear cell carcinoma with ARID1A Oncogenic mutations: 4

Comments changed: Preclinical study. ARID1A mutation sensitises ovarian clear cell carcinomas to BET inhibitors, causing lethal interaction and inhibiting proliferation in cell lines, xenografts, and patient-derived xenograft models.. (First curated: 2020-04-16)

Changed M6620 in Solid tumours with ARID1A Oncogenic mutations: 4

Comments changed: Phase 1 trial of ATR inhibitor M6620, achieving 1 CR in a patient with ATM loss and ARID1A mutation, and 1 PR in a platinum-refractory and PARP inhibitor-resistant BRCA1 ovarian cancer patient when combined with carboplatin.1 CR from NCT02157792, with ATM loss. (First curated: 2010-10-05)

Changed M6620 in Solid tumours with ARID1A Oncogenic mutations: 4

Comments changed: Preclinical study. ARID1A deficiency sensitises tumour cells to ATR inhibitors, triggering premature mitotic entry, genomic instability, and apoptosis, representing a novel synthetic lethal therapy for ARID1A mutant tumours.Cell line study. (First curated: 2020-04-25)

Changed Olaparib, Veliparib, Rucaparib in Solid tumours with ARID1A Oncogenic mutations: 4

Comments changed: Preclinical study. ARID1A deficiency impairs DNA damage checkpoint, sensitising cells to PARP inhibitors, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.Pre-clinical only. (First curated: 2020-04-25)

Changed Nivolumab, Atezolizumab in Urothelial carcinoma with ARID1A Oncogenic mutations: 4

Comments changed: Retrospective biomarker study. ARID1A mutation and CXCL13 expression individually correlated with improved OS in mUCC patients receiving ICT, with combinatorial biomarker analysis suggesting further improved OS prediction.. (First curated: 2020-07-02)

Changed Olaparib, Rucaparib, Talazoparib in Solid tumours with ARID2 Loss-of-function mutations, Loss of protein expression: 4

Comments changed: Preclinical study. PBRM1 deficiency, occurring in 40% of clear cell renal cell carcinomas, confers synthetic lethality to DNA repair inhibitors, with PARP and ATR inhibitors showing promise in PBRM1-defective cancer models.. (First curated: 2022-11-28)

Changed Olaparib in Colorectal adenocarcinoma with ATM Loss-of-function mutations: 4

Comments changed: Preclinical study. ATM-deficient colorectal cancer cells are sensitive to PARP inhibitor olaparib, with enhanced sensitivity observed upon p53 depletion or ATM inhibition.. (First curated: 2020-04-25)

Changed Olaparib in Gallbladder cancer with ATM : 4

Alterations changed: Loss-of-function mutations, S1905Ifs*25. Comments changed: Case report. A patient with gallbladder carcinoma harboring an ATM-inactivating mutation (ATM S1905Ifs*25) responded to olaparib with a progression-free survival of 13 months.. (First curated: 2020-06-16)

Changed Olaparib in Prostate cancer with ATM Loss-of-function mutations: 4

Comments changed: Case reports.. (First curated: 2020-06-16)

Changed Adavosertib in Solid tumours with ATRX Loss-of-function mutations: 4

Comments changed: Preclinical study. ATRX-mutant cancers identified as selectively vulnerable to WEE1 inhibition through a genome-wide CRISPR-Cas9 screen, with AZD1775 showing robust inhibition of ATRX-deficient cell lines and xenografts.. (First curated: 2020-08-19)

Changed EPZ011989 in Mesothelioma with BAP1 Oncogenic mutations: 4

Comments changed: Preclinical study. Loss of BAP1 function leads to increased EZH2 expression, and BAP1-mutant cells are sensitive to EZH2 inhibition.Cell line study only. (First curated: 2020-04-16)

Changed Talazoparib in Prostate cancer with BRCA1 Oncogenic mutations: 4

Comments changed: TALAPRO-1. Phase 2. In BRCA1 mutants N=4. PR 2/4.TALAPRO-1. Phase 2. N=4. PR 2/4. (First curated: 2021-09-09)

Changed Neratinib, Fulvestrant + Neratinib in Breast cancer with ERBB2 T798I, L785F, D769Y: R2

Comments changed: Preclinical and clinical study. HER2 mutations define a targetable breast cancer subset. Concurrent activating HER2 or HER3 alterations and acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were associated with de novo and acquired resistance to neratinib.Gatekeeper mutation. (First curated: 2020-06-13)

Changed Trastuzumab, Ado-Trastuzumab Emtansine in Gastric cancer with ERBB2 ZNF207-ERBB2 fusion: R2

Comments changed: Preclinical study. HER2 fusions (ZNF207-HER2 and MDK-HER2) were identified as oncogenic drivers in gastric cancer, with ZNF207-HER2 fusion not responsive to trastuzumab due to impaired binding.. (First curated: 2021-05-20)

Changed AZD4547 in Solid tumours with FGFR1 Amplification: R2

Comments changed: Phase 2 NCI-MATCH trial. AZD4547 showed limited activity in tumors with FGFR aberrations, with confirmed partial responses in 8% of patients, primarily in those with FGFR1-3 point mutations or fusions.No response in these cohorts. (First curated: 2020-06-11)

Changed Ponatinib, Dovitinib, Infigratinib in Solid tumours with FGFR1 N564K: R2

Comments changed: Preclinical study. Biophysical characterization of drug-resistant mutants of fibroblast growth factor receptor 1 (FGFR1) showed that N546K and V561M mutants had varying affinities for different ATP-competitive inhibitors, with V561M mutant showing reduced affinity for PD173074 and N546K showing increased affinity for AMP-PNP.Molecular hinge. (First curated: 2020-05-22)

Changed Infigratinib, AZD4547, Zoligratinib in Solid tumours with FGFR1 V561M: R2

Comments changed: Preclinical study. Resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas is associated with either an activating V561M Gatekeeper mutation in the FGFR1 kinase domain or PTEN inactivation. Combined inhibition of FGFR and PI3K pathways shows additive effect in overcoming resistance.. (First curated: 2020-05-22)

Changed Fulvestrant + Ribociclib in Breast cancer with FGFR2 Amplification: R2

Comments changed: Preclinical study. FGFR1 amplification/alteration identified as a resistance mechanism to CDK4/6 inhibitors in ER+ breast cancer, with FGFR tyrosine kinase inhibitors (TKIs) abrogating this resistance and potentially improving treatment outcomes.. (First curated: 2020-04-15)

Changed AZD4547 in Solid tumours with FGFR2 Amplification: R2

Comments changed: Phase 2 NCI-MATCH trial. AZD4547 showed limited activity in tumors with FGFR aberrations, with confirmed partial responses in 8% of patients, primarily in those with FGFR1-3 point mutations or fusions.No response in these cohorts. (First curated: 2020-06-11)

Changed Infigratinib in Cholangiocarcinoma with FGFR2 E565A, L617M: R2

Comments changed: Preclinical study. FGFR2 kinase domain E565A and L617M are potential drivers of acquired resistance to infigratinib in FGFR2-fusion cholangiocarcinoma.. (First curated: 2020-11-03)

Changed Osimertinib, Gefitinib in Non-small cell lung cancer with FGFR2 Fusions, FGFR2-CCDC6 fusion, FGFR2-KIAA1598 fusion, FGFR2-TACC2 fusion: R2

Comments changed: FGFR2/3 fusions were identified as an acquired resistance mechanism in lung adenocarcinoma following EGFR TKI treatment. Combination of EGFR TKIs and FGFR TKIs showing clinical benefit.. (First curated: 2023-06-23)

Changed Trametinib in Melanoma with NF1 Oncogenic mutations, Loss-of-function mutations: 4

Tier changed: 4R2. Comments changed: Case report. A patient with NF1-mutated melanoma refractory to immunotherapy and chemotherapy responded to trametinib, a MEK inhibitor, with a DOR of 5 months, and showed increased CD8+ infiltration and PD-L1 expression during treatment.Case report. Duration of response 5 months.. (First curated: 2022-01-12)

Changed Binimetinib in Solid tumours except melanoma with NRAS G12, G13, Q61: R2

Comments changed: Phase 2 NCI-MATCH trial. NRAS subprotocol. Single-agent binimetinib showed limited efficacy with an ORR of 2%. Notably, a patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response, and patients with colorectal cancer bearing a NRAS codon 61 mutation had significantly longer OS and PFS compared to those with codon 12 or 13 mutations.NCI-MATCH. NRAS subprotocol. ORR 2% with a single responder.. (First curated: 2021-06-08)

Changed Ivosidenib in Acute myeloid leukaemia with NRAS Oncogenic mutations: R2

Comments changed: Phase 1 trial. NCT02074839. N=174. Multiple mechanisms of resistance to ivosidenib have been identified in IDH1-mutant relapsed/refractory AML. Primary resistance is associated with RTK pathway mutations, while acquired resistance involves second-site IDH1/IDH2 mutations that restore 2-HG production. NRAS mutations are associated with reduced response rates compared to wild-type NRAS.NRAS- reduced response rate compared with WT NRAS. (First curated: 2023-01-12)

Changed Larotrectinib in Solid tumours with NTRK1 Alterations AND NOT fusion: R2

Comments changed: Pooled analysis of larotrectinib trials. For non-fusion NTRK1/2/3 alterations, only one response was seen (of 73) with short duration of response.One PR (of 73) with short DOR.. (First curated: 2021-03-24)

Changed Larotrectinib in Solid tumours with NTRK2 Alterations AND NOT fusion: R2

Comments changed: Pooled analysis of larotrectinib trials. For non-fusion NTRK1/2/3 alterations, only one response was seen (of 73) with short duration of response.One PR (of 73) with short DOR.. (First curated: 2021-03-24)

Changed Larotrectinib in Solid tumours with NTRK3 Alterations AND NOT fusion: R2

Comments changed: Pooled analysis of larotrectinib trials. For non-fusion NTRK1/2/3 alterations, only one response was seen (of 73) with short duration of response.One PR (of 73) with short DOR.. (First curated: 2021-03-24)

Changed LY3023414 in Endometrial cancer with PTEN Loss-of-function mutations: R2

Comments changed: "Phase 2 study. N=28 with 25 evaluable patients. ORR 16%. CBR 28%. Median PFS 2.5 months. Median OS 9.2 months. LY3023414, a dual PI3K/mTOR inhibitor, showed modest activity in heavily pretreated advanced endometrial cancer with PI3K pathway mutations, but no correlation between molecular alterations and response was observed.. (First curated: 2021-12-17)

03 June, 2025 (Version: 20250603AU)

New Entrectinib in Non-small cell lung cancer with ALK F1245V: 3

Phase 1/2 ALKA-372-001 and STARTRK-1 trials. ALK F1245V mutant neuroblastoma achieved durable confirmed partial response lasting 8.3 months. References: 28183697, 10.1200/jco.2015.33.15_suppl.2517

New Uprosertib in Solid tumours with AKT2 Oncogenic mutations: 4

"Preclinical study. Selectivity profiling of Akt inhibitors GSK690693 and GSK2141795. References: 23795919

New Alectinib in Inflammatory myofibroblastic tumour with ALK Fusions: 4

Case report. A patient with inflammatory myofibroblastic tumor (IMT) harboring a novel SQSTM1-ALK fusion gene demonstrated a marked and durable response to alectinib, sustaining for 17 months without significant adverse events. References: 30790150

New Ceritinib in Inflammatory myofibroblastic tumour with ALK Fusions: 4

Case report. A patient with unresectable ALK-negative inflammatory myofibroblastic tumor (IMT) carrying a TFG-ROS1 fusion experienced partial response to ceritinib, a ROS1 inhibitor. References: 31805529

Removed Capmatinib in Non-small cell lung cancer with MET alterations Amplification: Tier 3   (First curated: 2020-05-14)

Changed Crizotinib in Anaplastic large cell lymphoma with ALK Fusions, EML4-ALK Fusion: 2

Comments changed: Not TGA approved. FDA approved. Phase 1b PROFILE 1013 study. NCT01121588. N=44. demonstrated crizotinib's durable activity in ALK-positive lymphomas (ORR 53%, 8 CRs, 1 PR, 2-year PFS 63%) and inflammatory myofibroblastic tumors (ORR 67%, 1 CR, 5 PRs, 2-year PFS 67%).Not TGA approved; FDA approved.. (First curated: 2020-04-25)

Changed Lenalidomide + Rituximab in Follicular lymphoma, Marginal zone lymphoma with CD20 Protein expression: 2

Comments changed: Phase 2 trial. N=45. Previously untreated MZL patients treated with lenalidomide and rituximab showed ORR of 93% with 70% CR/CRu. Median PFS was 59.8 months and 5-year OS was 96% at median follow-up of 75.1 months.. (First curated: 2020-06-15)

Changed Ensartinib in Non-small cell lung cancer with ALK C1156Y, C1156T, L1196M: 3

Comments changed: Review article discusses the mechanisms of resistance to ALK tyrosine kinase inhibitors.. (First curated: 2020-05-27)

Changed Entrectinib in Non-small cell lung cancer with ALK C1156Y, C1156T, L1196M: 3

Comments changed: Review article discusses the mechanisms of resistance to ALK tyrosine kinase inhibitors.. (First curated: 2020-05-27)

Changed Entrectinib in Non-small cell lung cancer with ALK : 3

Alterations changed: EML4-ALK Fusion, Fusions, VCL-ALK fusion, CAD-ALK fusion, F1245V. Comments changed: Phase 1/2 ALKA-372-001 and STARTRK-1 trials. Entrectinib demonstrated antitumor activity in TKI-naive patients with ALK fusions, achieving an ORR of 57% (4/7) with a median duration of response of 7.4 months.. References changed: 28183697, 10.1200/jco.2015.33.15_suppl.2517. (First curated: 2020-04-16)

Changed Brigatinib in Non-small cell lung cancer with ALK I1151ins, L1152P, L1152R, C1156Y, C1156T, F1174C, F1174L, F1174V, L1196M, S1206C, S1206Y, G1269A, G1269S: 3

Comments changed: Review article discusses the mechanisms of resistance to ALK tyrosine kinase inhibitors.. (First curated: 2020-05-27)

Changed Lorlatinib in Non-small cell lung cancer with ALK I1151ins, L1152P, L1152R, C1156Y, C1156T, I1171T, I1171N, I1171S, F1174C, F1174L, F1174V, L1196M, G1202R, S1206C, S1206Y, E1210K, G1269A, G1269S: 3

Comments changed: Review article discusses the mechanisms of resistance to ALK tyrosine kinase inhibitors.. (First curated: 2020-05-27)

Changed Ceritinib in Non-small cell lung cancer with ALK I1171T, I1171N, L1196M, S1206C, S1206Y, G1269A, G1269S: 3

Comments changed: Review article discusses the mechanisms of resistance to ALK tyrosine kinase inhibitors.. (First curated: 2020-05-27)

Changed Alectinib in Non-small cell lung cancer with ALK L1152P, L1152R, C1156Y, C1156T, F1174C, F1174L, F1174V, L1196M, S1206C, S1206Y, G1269A, G1269S: 3

Comments changed: Review article discusses the mechanisms of resistance to ALK tyrosine kinase inhibitors.. (First curated: 2020-05-27)

Changed Trametinib in Melanoma with BRAF G469R, A598_T599insV, AGAP3-BRAF fusion, L597Q, T470R: 3

Comments changed: Phase 2. NCT02296112. Trametinib in non-V600 BRAF mutation and BRAF fusions. ORR was 33% (3/9). Median PFS 7.3 months.Phase 2. NCT02296112. Trametinib in non-V600 BRAF fusions. ORR was 33% (3/9). Median PFS 7.3 months.. (First curated: 2022-09-07)

Changed Afatinib, Gefitinib, Erlotinib in Non-small cell lung cancer with EGFR A763_Y764insFQEA: 3

Tier changed: 32. Comments changed: Not explicitly TGA listed. Comprehensive molecular profiling can identify uncommon EGFR mutations such as kinase domain duplications and rearrangements that are responsive to EGFR inhibitors in lung adenocarcinomas.. (First curated: 2020-04-16)

Changed Capmatinib in Non-small cell lung cancer with MET Amplification: 3

References changed: 32877583, 10.1200/JCO.2019.37.15_suppl.9004, 10.1200/JCO.2020.38.15_suppl.9509. (First curated: 2020-05-06)

Changed Capivasertib in Solid tumours with AKT1 E17K: 4

Comments changed: Phase 1 Expansion cohort of AZD5363. Activity was seen in AKT1 E17K-mutant cancers (n=52) with median PFS of 5.5, 6.6, and 4.2 months in ER+ breast, gynecologic, and other solid tumors, respectively, and responses were associated with AKT1 E17K mutant allele imbalance and coincident PI3K pathway hotspot mutations.Phase 1 Expansion cohort data. (First curated: 2020-05-15)

Changed Therapy in Solid tumours with AKT2 Oncogenic mutations: 4

Therapy changed: CCT128930, Uprosertib. Comments changed: Preclinical study. CCT128930, a novel AKT inhibitor, exhibited antiproliferative activity, inhibited AKT substrates phosphorylation, and caused G1 arrest in PTEN-null U87MG cells, with antitumor activity observed in U87MG and BT474 human breast cancer xenografts.. References changed: 21191045, 23795919. (First curated: 2020-04-16)

Changed Crizotinib, Ceritinib, Brigatinib in Acute lymphoblastic leukaemia with ALK A348D, F856S: 4

Comments changed: Preclinical study. ALK mutations identified in leukemia patients were potently transforming and conferred sensitivity to ALK kinase inhibitors.. (First curated: 2020-05-25)

Changed Crizotinib, Alectinib in Solid tumours, Histiocytosis, Renal cell carcinoma with ALK Fusion: 4

Comments changed: Comprehensive genomic profiling of 114,200 clinical cases revealed ALK fusions in 0.8% of cases, with 22.9% of ALK fusions occurring in non-NSCLC tumors, which responded to anti-ALK targeted therapies.. (First curated: 2021-10-13)

Changed Brigatinib in Non-small cell lung cancer with ALK Fusion AND Amplification, L1196M, E1408V, T1151M: 4

Comments changed: Phase 1/2 and Phase 2 (ALTA) trials. Brigatinib showed substantial activity in crizotinib-resistant ALK+ NSCLC patients with ALK fusion-positive status (cORR 57%) and in those with secondary ALK mutations (cORR 50%), with complex mutation patterns associated with resistance in 25% of patients at end of treatment.. (First curated: 2022-06-15)

Changed Therapy in Inflammatory myofibroblastic tumour with ALK Fusions: 4

Therapy changed: Alectinib, Ceritinib. Comments changed: Case report. Dramatic response to alectinib observed in a patient with inflammatory myofibroblastic tumor harboring ALK fusion gene.. References changed: 28977547, 30790150, 31805529. (First curated: 2020-06-06)

Changed Alectinib in Breast Cancer with ALK STRN-ALK fusion: 4

Comments changed: Case report. A patient with STRN-ALK fusion-positive breast cancer responded to alectinib, with initial partial response followed by mixed response and eventual progression at 2 months, highlighting the potential benefit of comprehensive genomic profiling in identifying actionable targets in advanced breast cancer.. References changed: 3442322810.1200/PO.21.00142. (First curated: 2021-08-19)

Changed Ensartinib in Non-small cell lung cancer with ALK T1151, C1156Y, F1174C, F1174L, F1174V, G1269A, L1196M, S1206R: 4

Comments changed: Review. New generation anaplastic lymphoma kinase inhibitors in NSCLC, discussing the development of II and III generation TKIs to overcome acquired resistance to crizotinib and manage CNS localizations.. (First curated: 2020-06-13)

Changed Selumetinib in Low-grade serous ovarian cancer with BRAF Fusions: 4

Comments changed: Case report and genomic analysis. A patient with low-grade serous ovarian cancer experienced a complete and durable response to selumetinib, with tumour harbouring a 15-nucleotide deletion in MAP2K1 gene encoding MEK1, and 82% of 28 analysed tumours had ERK pathway-activating mutations, including BRAF fusions.Case report only. (First curated: 2020-05-15)

Changed Selumetinib in Low-grade serous ovarian cancer with MAP2K1 : 4

Alterations changed: Q56_V60del, Negative regulatory domain deletionOncogenic mutations. Comments changed: Case report and genomic analysis. A patient with low-grade serous ovarian cancer experienced a complete and durable response to selumetinib, with tumour harbouring a 15-nucleotide deletion in MAP2K1 gene encoding MEK1, and 82% of 28 analysed tumours had ERK pathway-activating mutations, including BRAF fusions.Case report and retrospective analysis of exceptional responder only. (First curated: 2020-05-20)

Changed Asciminib in Chronic myelogenous leukaemia with ABL1 A337V, P465S: R2

Comments changed: Preclinical and phase 1 studies showed that asciminib, an allosteric ABL1 inhibitor, targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant, and has distinct resistance mutations, including A337V and P465S, compared to catalytic-site ABL1 kinase inhibitors.. (First curated: 2020-05-21)

Changed Crizotinib in Non-small cell lung cancer with ALK Amplification: R2

Comments changed: Studies identified multiple mechanisms of resistance to ALK tyrosine kinase inhibitors, including secondary mutations in the ALK TK domain, ALK gene amplification, and aberrant activation of other kinases such as KIT and EGFR.. (First curated: 2020-04-25)

Changed Crizotinib in Neuroblastoma with ALK : R2

Alterations changed: F1174L, F1174V, AmplificationF1174L, Amplification. Comments changed: Phase 2 study. ADVL0912. Crizotinib showed limited activity in patients with ALK-aberrant relapsed/refractory neuroblastoma, with an ORR of 15%, and resistance was associated with specific ALK mutations such as F1174L and F1174V, and ALK amplification.. (First curated: 2021-03-04)

Changed Osimertinib in Non-small cell lung cancer with ALK Fusion: R2

Comments changed: Analysis of 155 EGFR-mutant lung cancer patients with acquired resistance to EGFR-TKI therapy revealed EGFR T790M mutation (63%), MET amplification (5%), HER2 amplification (13%), and small cell transformation (3%) as resistance mechanisms, including ALK fusion as an off-target resistance mechanism.Off-target mechanism. (First curated: 2020-06-10)

Changed Ceritinib in Non-small cell lung cancer with ALK I1151ins, L1152R, L1152P, C1156Y, C1156T, F1174C, F1174L, F1174V, G1202R, G1202del: R2

Comments changed: Targeting ALK TKIs is limited by resistance, with diverse mechanisms identified, informing novel therapeutic strategies, including development of inhibitors like JH-VIII-157-02 that overcome G1202R mutation.. References changed: 28050598, 28122866, 2656828928050598; 28122866; 26568289. (First curated: 2020-04-27)

Changed Crizotinib in Solid tumours with ALK L1196M, C1156Y: R2

Comments changed: Preclinical study. CH5424802, a selective ALK inhibitor, demonstrated antitumor activity against cancers with ALK gene alterations and inhibited the resistant gatekeeper mutant ALK L1196M.. (First curated: 2022-09-19)

Changed Crizotinib in Anaplastic large cell lymphoma with ALK NPM-ALK fusion: R2

Comments changed: Review articles. ALK-rearranged malignancies and mechanisms of resistance to ALK tyrosine kinase inhibitors... References changed: 28050598, 2812286628050598; 28122866. (First curated: 2020-04-27)

Changed Anti-androgen in Prostate cancer with AR Amplification: R2

Comments changed: Clinical cohort studies. Plasma DNA analysis demonstrates that androgen receptor (AR) gene aberrations, including copy number gain and point mutations (T878A, L702H, F876L, H874Y, T877A), are associated with resistance to abiraterone and enzalutamide in castration-resistant prostate cancer patients, predicting poor treatment outcomes and survival.. References changed: 25712683, 2653725825712683; 26537258. (First curated: 2020-04-25)

Changed Fulvestrant in Breast cancer with ARID1A Oncogenic mutations: R2

Comments changed: Preclinical study. ARID1A inactivation determines resistance to ER degrader fulvestrant by promoting a switch from ER-dependent luminal cells to ER-independent basal-like cells, mediated by loss of ARID1A-dependent SWI/SNF complex targeting to luminal lineage-determining transcription factors.. (First curated: 2020-06-15)

Changed Olaparib in Pancreatic adenocarcinoma with ARID1A Oncogenic mutations: R2

Comments changed: Two Phase 2 studies of Olaparib in previously treated pancreatic cancer with BRCAness; DDR-GAs subset (N=24) had higher median PFS (5.7 months) and OS (13.6 months); ARID1A (N=3) was among the DDR-GAs identified.Two Phase 2 studies of Olaparib in previously treatment pancreatic cancer. ORR 4% did not meet predefined threshold. ARID1A (N=3). (First curated: 2021-03-16)

Changed Olaparib in Breast cancer with ATM Oncogenic mutations: R2

Comments changed: Phase 2 TBCRC048 study. Olaparib showed efficacy in metastatic breast cancer with gPALB2 (ORR 82%, median PFS 13.3 months) and sBRCA1/2 (ORR 50%, median PFS 6.3 months) mutations, but not in ATM or CHEK2 mutations alone.TBCRC048. No responders. (First curated: 2020-05-30)

Changed Talazoparib in Lung squamous cell carcinoma with ATM Oncogenic mutations: R2

Comments changed: Lung-MAP Substudy S1400G. Phase 2. Talazoparib showed limited efficacy in homologous recombination repair-deficient squamous cell lung cancer with ORR of 4% in primary analysis population and 11% in full eligible population.Lung-MAP Substudy S1400G. ORR primary population 4%. (First curated: 2021-03-16)

Changed Olaparib in Prostate cancer with ATM Oncogenic mutations: R2

Comments changed: Retrospective study. Men with metastatic castration-resistant prostate cancer harboring ATM mutations had inferior outcomes to olaparib treatment compared to those with BRCA1/2 mutations, with 0% PSA response (0/6) versus 76% (13/17) and median PFS 2.4 months versus 12.3 months.Retrospective study. ORR 0%. (First curated: 2020-06-08)

Changed Olaparib in Prostate cancer with ATM Oncogenic mutations: R2

Comments changed: Updated: PROFOUND trial: No overall PFS difference in ATM subgroup, although benefits in patients previously treated with a taxane was noted (not sufficiently powered).Updated: PROFOUND trial: No overall PFS difference in , although benefits in patients previously treated with a taxane was noted (not sufficiently powered).. (First curated: 2020-12-11)

Changed Talazoparib in Lung squamous cell carcinoma with ATR Oncogenic mutations: R2

Comments changed: Lung-MAP Substudy S1400G. Phase 2. Talazoparib showed limited efficacy in homologous recombination repair-deficient squamous cell lung cancer with ORR of 4% in primary analysis population and 11% in full eligible population.Lung-MAP Substudy S1400G. ORR primary population 4%. (First curated: 2021-03-16)

Changed Olaparib, Talazoparib in Mesothelioma with BAP1 Loss-of-function mutations: R2

Comments changed: Preclinical study. Mesothelioma cells' sensitivity to PARP inhibitors is not dependent on BAP1 status, but is enhanced by temozolomide in cells with high Schlafen 11 and low O6-methylguanine-DNA methyltransferase expression, indicating a potential beneficial combination therapy for patients with specific tumor expression profiles.Preclinical data only. (First curated: 2020-07-02)

Changed Niraparib in Solid tumours with BAP1 Oncogenic mutations: R2

Comments changed: Phase 2 trial. NCT03207347. Niraparib showed limited activity in patients with BAP1 with ORR of (1/18) 6% but clinical benefit was observed in 78% of patients with confirmed mBAP1 tumor, suggesting potential utility in DDR pathway-deficient neoplasms with confirmed mBAP1.Phase 2. NCT03207347. ORR was 1 of 18 responder (6%).. References changed: 39626160, 10.1200/JCO.2022.40.16_suppl.3122. (First curated: 2022-06-04)

Changed Gefitinib, Erlotinib in Non-small cell lung cancer with BCL2L11 Deletion: R2

Comments changed: A common intronic deletion polymorphism in the BIM gene confers intrinsic resistance to tyrosine kinase inhibitors (TKIs) in CML and EGFR NSCLC by expressing BIM isoforms lacking the pro-apoptotic BH3 domain, leading to inferior responses to TKIs, but this resistance can be overcome with BH3-mimetic drugs.. (First curated: 2020-05-19)

Changed Larotrectinib in Low-grade spindle cell neoplasm, Solid tumour with BRAF BRAF-CREB3L2 rearrangement, amplification: R2

Comments changed: Case report. Off-target resistance mechanism identified in two pediatric patients with NTRK fusion-positive solid tumors treated with larotrectinib.. (First curated: 2023-09-11)

Changed Vemurafenib, Dabrafenib in Solid tumours with BRAF Class II mutations, K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, Fusions: R2

Comments changed: Preclinical study. Class 2 mutations shows insensitivity to Type 1 and half BRAF inhibitors.Class II mutations. (First curated: 2020-04-26)

Changed Vemurafenib in Non-small cell lung cancer with BRAF Oncogenic mutations AND NOT V600: R2

Comments changed: Phase 2. AcSé. NCT02304809. BRAF(V600) mutated NSCLC patients treated with Vemurafenib showed an ORR of 44.9% and median PFS of 5.2 months, while BRAF(nonV600) mutated patients had an ORR of 0%.Phase 2. AcSé. NCT02304809. ORR: 0%.. (First curated: 2021-11-10)

Changed Vemurafenib in Colorectal adenocarcinoma with BRAF V600: R2

Comments changed: Phase 2 VE-BASKET trial. NCT01524978. Vemurafenib showed varying response rates across different BRAF V600 mutation-positive nonmelanoma cancers, with anecdotal responses observed in colorectal cancer patients treated with vemurafenib and cetuximab but not as a single-agent.. (First curated: 2020-10-01)

Changed Lapatinib + Trastuzumab in Colorectal adenocarcinoma with BRAF V600E: R2

Comments changed: Phase 2 HERACLES trial. EudraCT 2012-002128-33. In treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer, dual-targeted therapy with trastuzumab and lapatinib achieved an objective response in 30% of patients. No response in a patient with BRAF V600E co-mutation.. (First curated: 2020-05-04)

Changed Trastuzumab + Pertuzumab in Colorectal adenocarcinoma with BRAF V600E: R2

Comments changed: Phase 2a MyPathway study. NCT02091141. N=57. Pertuzumab + Trastuzumab showed an objective response in 32% of patients with HER2-amplified metastatic colorectal cancer, with one patient achieving complete response and 17 partial responses, indicating a potential therapeutic opportunity. A single patient with BRAF V600E co-mutation had no response.. (First curated: 2020-05-04)

Changed Trastuzumab in Gastric cancer with BRAF V600E: R2

Comments changed: Biomarkers study, Resistance mechanism to Trastuzumab in HER2-positive metastatic gastric cancer, including EGFR/MET/KRAS/PI3K/PTEN mutations and amplifications, predicted poor PFS (2.6 vs 5.2 months) and OS (7.6 vs 16.1 months).Case-control study. (First curated: 2020-05-27)

Changed Sonidegib, Vismodegib in Solid tumours with BRAF V600E: R2

Comments changed: Preclinical study. RAS/MAPK pathway activation drives resistance to Smo inhibition and enhances metastatic behavior in Shh pathway-dependent tumors, with evidence of RAS/MAPK activation in secondary squamous cell cancers emerging from antecedent BCC tumors treated with Smo inhibitor.Off-target mechanism. (First curated: 2020-07-20)

Changed Selumetinib in Melanoma with BRAF V600E and Amplification: R2

Comments changed: Preclinical study. BRAF gene amplification promotes acquired resistance to MEK inhibitors in BRAF V600E mutant cancer cells by increasing phosphorylated MEK abundance, and combined MEK and BRAF inhibition overcomes this resistance mechanism.. (First curated: 2020-05-31)

02 June, 2025 (Version: 20250602AU)

New Erlotinib, Osimertinib in Non-small cell lung cancer with BRAF Fusion, AGK-BRAF fusion, PJA2-BRAF fusion: R2

Preclinical study and genomic analysis of patient samples. BRAF fusions (AGK-BRAF and PJA2-BRAF) were identified as an off-target mechanism of acquired resistance to EGFR TKI therapy in approximately 2% of EGFR-mutant lung cancer patients, and combined inhibition of EGFR and MEK or BRAF inhibition were shown to be potential therapeutic strategies. References: 30831205

New Adagrasib + Pembrolizumab in Non-small cell lung cancer with KRAS G12C: 2

Phase 2 KRYSTAL-7 study. NCT04613596. N=149. Adagrasib plus pembrolizumab showed an ORR of 44.3% and median OS of 18.3 months in patients with advanced/metastatic KRASG12C-mutated NSCLC, with varying efficacy across different PD-L1 expression levels. References: 10.1200/JCO.2025.43.16_suppl.8500

New Benmelstobart + Anlotinib in Non-small cell lung cancer with CD274 Protein expression: 2

Phase 3. NCT04964479. In PD-L1 positive NSCLC patients, benmelstobart + anlotinib significantly improved PFS (11.0 vs 7.1 months) and ORR (57.3% vs 39.6%) compared to pembrolizumab, particularly in subgroups with squamous cell carcinoma and PD-L1 expression ≥50%. References: 10.1200/JCO.2025.43.16_suppl.LBA8502

New Trastuzumab deruxtecan in Non-small cell lung cancer with ERBB2 Overexpression, Amplification: 2

Phase 3 DESTINY-Gastric04 trial. NCT04704934. In HER2+ (IHC 3+ or IHC 2+/ISH+) unresectable/metastatic GC/GEJA patients, T-DXd showed significant improvement in OS (14.7 vs 11.4 months), PFS (6.7 vs 5.6 months), and confirmed ORR (44% vs 29%) over Ramucirumab + Paclitaxel. References: 10.1200/JCO.2025.43.16_suppl.LBA4002

New Zipalertinib in Non-small cell lung cancer with EGFR Exon 20 insertion: 2

Phase 2b REZILIENT1 study. Zipalertinib achieved a confirmed ORR of 35% and median PFS of 9.5 months in non-small cell lung cancer patients harboring EGFR exon 20 insertion mutations following prior platinum-based chemotherapy with or without amivantamab. References: 10.1200/JCO-25-00763, 10.1200/JCO.2025.43.16_suppl.8503

New Camizestrant + Palbociclib, Camizestrant + Ribociclib, Camizestrant + Abemaciclib in Breast cancer with ESR1 Oncogenic mutations, D538G, Y537S, Y537N: 2

Phase 3 SERENA-6 trial. NCT04964934. In patients with ER-positive, HER2-negative advanced breast cancer with emerged ESR1 mutation, switching to camizestrant with continued CDK4/6 inhibitor resulted in significantly longer PFS (16.0 months vs 9.2 months) compared to continuing aromatase inhibitor plus CDK4/6 inhibitor. References: 10.1200/JCO.2025.43.17_suppl.LBA4

New Sevabertinib in Non-small cell lung cancer with ERBB2 Oncogenic mutations, Tyrosine kinase domain mutations: 2

Phase 1/2 SOHO-01 trial. In patients with advanced HER2-mutant NSCLC, Sevabertinib demonstrated an ORR of 59% in both pretreated patients naive to HER2-targeted therapy and treatment-naive patients. References: 10.1200/JCO.2025.43.16_suppl.8504

New Savolitinib + Osimertinib in Non-small cell lung cancer with EGFR+MET EGFR:Oncogenic mutations and MET:amplification: 2

Phase 3 SACHI study. In EGFR-mutant, MET-amplified advanced NSCLC patients progressing on EGFR-TKI, savolitinib + osimertinib significantly improved PFS versus chemotherapy (8.2 vs 4.5 months, HR=0.34). MET amplification was defined as copy number ≥5 or MET/CEP7 ratio ≥2.0. References: 10.1200/JCO.2025.43.17_suppl.LBA8505

New Patritumab deruxtecan in Non-small cell lung cancer with EGFR Exon 19 deletion, L858R, Exon 21 mutation: 3

Phase 3 HERTHENA-Lung02 trial. NCT05338970. N=586. Patritumab deruxtecan showed significant improvement in PFS (HR, 0.77) over platinum-based chemotherapy in EGFR-mutated NSCLC patients after disease progression on a 3rd-gen EGFR TKI, with median PFS 5.8 months vs 5.4 months. References: 10.1200/JCO.2025.43.16_suppl.8506

New Sacituzumab tirumotecan in Non-small cell lung cancer with EGFR Exon 19 deletion, L858R, Exon 21 mutation: 2

Phase 2/3 OptiTROP-Lung03 trial. NCT05631262. In EGFR-mutated NSCLC patients previously treated with EGFR TKI and platinum-based chemotherapy, sacituzumab tirumotecan demonstrated superior efficacy versus docetaxel with ORR of 45.1% vs 15.6%, PFS of 6.9 vs 2.8 months, and OS HR of 0.49. References: 10.1200/JCO.2025.43.16_suppl.8507

Removed EGFR inhibitor in Non-small cell lung cancer with BRAF+EGFR alterations EGFR:Oncogenic mutations and BRAF:fusion: Tier R2   (First curated: 2020-05-15)

Changed Therapy in Non-small cell lung cancer with ERBB2 Oncogenic mutations: 3

Therapy changed: SevabertinibBAY 2927088. Comments changed: Phase 1/2 SOHO-01 study. NCT05099172. N=34. Sevabertinib led to ORR of 70% (23/33) and DCR of 82% in HER2-mutant NSCLC patients. Median PFS was 8.1 months.Phase 1/2 SOHO-01 study. NCT05099172. N=34. BAY 2927088 led to ORR of 70% (23/33) and DCR of 82% in HER2-mutant NSCLC patients. Median PFS was 8.1 months.. (First curated: 2024-07-03)

Changed Encorafenib + Capamatinib in Colorectal adenocarcinoma with BRAF+MET BRAF:V600E AND MET:amplification: 4

Comments changed: Case report. BRAF V600E-mutated metastatic colorectal cancer developed secondary resistance to cetuximab, encorafenib, and binimetinib due to MET amplification, and tertiary resistance to capmatinib and encorafenib due to emergence of MET D1228N mutation and KRAS G12D.. (First curated: 2023-01-18)

Changed Encorafenib + Cetuximab in Colorectal adenocarcinoma with BRAF+KRAS BRAF:V600E AND KRAS:G12D, BRAF:V600E AND KRAS:Oncogenic mutations: R2

Comments changed: Case report. BRAF V600E-mutated metastatic colorectal cancer developed secondary resistance to cetuximab, encorafenib, and binimetinib due to MET amplification, and tertiary resistance to capmatinib and encorafenib due to emergence of MET D1228N mutation and KRAS G12D.. (First curated: 2023-01-18)

Changed Dabrafenib + Trametinib in Non-small cell lung cancer with BRAF+KRAS BRAF:V600E AND KRAS:Q61R: R2

Comments changed: Phase 2 MATCH-R trial. Acquired resistance mechanisms to BRAF/MEK inhibitors in BRAF(V600E) NSCLC identified, including MEK1 K57N, NRAS Q61R, KRAS Q61R mutations, and PTEN frameshift mutation, highlighting MAPK pathway involvement.. (First curated: 2021-04-06)

Changed Dabrafenib + Trametinib in Non-small cell lung cancer with BRAF+MAP2K1 BRAF:V600E AND MAP2K1:K57N: R2

Comments changed: Phase 2 MATCH-R trial. Acquired resistance mechanisms to BRAF/MEK inhibitors in BRAF(V600E) NSCLC identified, including MEK1 K57N, NRAS Q61R, KRAS Q61R mutations, and PTEN frameshift mutation, highlighting MAPK pathway involvement.. (First curated: 2021-04-06)

Changed Encorafenib + Cetuximab in Colorectal adenocarcinoma with BRAF+MET BRAF:V600E AND MET:amplification: R2

Comments changed: Case report. BRAF V600E-mutated metastatic colorectal cancer developed secondary resistance to cetuximab, encorafenib, and binimetinib due to MET amplification, and tertiary resistance to capmatinib and encorafenib due to emergence of MET D1228N mutation and KRAS G12D.. (First curated: 2023-01-18)

Changed Dabrafenib + Trametinib in Non-small cell lung cancer with BRAF+NRAS BRAF:V600E AND NRAS:Q61R: R2

Comments changed: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF(V600E) NSCLC identified, including MEK1 K57N, NRAS Q61R, KRAS Q61R, and PTEN frameshift mutations, highlighting the recurring involvement of the MAPK pathway.. (First curated: 2021-04-06)

Changed Dabrafenib + Trametinib in Non-small cell lung cancer with BRAF+PTEN BRAF:V600E AND PTEN:Oncogenic mutations: R2

Comments changed: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF(V600E) NSCLC identified, including MEK1 K57N, NRAS Q61R, KRAS Q61R, and PTEN frameshift mutations, highlighting the recurring involvement of the MAPK pathway.. (First curated: 2021-04-06)

Changed Veliparib in Pancreatic adenocarcinoma with BRCA2 Oncogenic mutations (germline): R2

Comments changed: Phase 2 trial. In patients with pancreas adenocarcinoma and germline BRCA/PALB2 mutation, cisplatin and gemcitabine with or without veliparib showed high response rates (74.1% and 65.2% respectively), with no significant difference between the two arms, suggesting resistance to PARP inhibitor veliparib when used in combination with DNA damaging agents.Single-agent has no confirmed response. (First curated: 2020-09-28)

Changed Palbociclib in Lung squamous cell carcinoma with CCND1 Amplification: R2

Comments changed: Phase 2, Lung-MAP S1400C trial, evaluated palbociclib in patients with cell cycle gene alterations, showing an ORR of 6%, with two partial responses observed in patients with CCND1 amplification, indicating limited efficacy as monotherapy in squamous NSCLC.Lung-MAP S1400C, ORR 6%. (First curated: 2020-11-10)

Changed Palbociclib in Lung squamous cell carcinoma with CCND2 Amplification: R2

Comments changed: Phase 2, Lung-MAP S1400C trial, evaluated palbociclib in patients with cell cycle gene alterations, showing an ORR of 6%, with two partial responses observed in patients with CCND1 amplification, indicating limited efficacy as monotherapy in squamous NSCLC.Lung-MAP S1400C, ORR 6%. (First curated: 2020-11-10)

Changed Palbociclib in Lung squamous cell carcinoma with CCND3 Amplification: R2

Comments changed: Phase 2, Lung-MAP S1400C trial, evaluated palbociclib in patients with cell cycle gene alterations, showing an ORR of 6%, with two partial responses observed in patients with CCND1 amplification, indicating limited efficacy as monotherapy in squamous NSCLC.Lung-MAP S1400C, ORR 6%. (First curated: 2020-11-10)

Changed Palbociclib in Glioblastoma with CDK4 Amplification: R2

Comments changed: Preclinical study. GBM xenograft cells with p16(INK4a) expression and either CDK4 amplification or RB mutation were resistant to PD0332991, a Cdk4/6 inhibitor, indicating that intact p16-Cdk4-Rb axis is a determinant of resistance to Cdk4/6 inhibition.. (First curated: 2022-06-24)

Changed Palbociclib in Lung squamous cell carcinoma with CDK4 Amplification: R2

Comments changed: Phase 2, Lung-MAP S1400C trial, evaluated palbociclib in patients with cell cycle gene alterations, showing an ORR of 6%, with two partial responses observed in patients with CCND1 amplification, indicating limited efficacy as monotherapy in squamous NSCLC.Lung-MAP S1400C, ORR 6%. (First curated: 2020-11-10)

Changed Larotrectinib in Low-grade glioma, Low-grade spindle cell neoplasm, Solid tumour with CDKN2A Deletion: R2

Comments changed: Case reports. Off-target resistance mechanism identified in two pediatric patients with NTRK fusion-positive solid tumors treated with larotrectinib.. (First curated: 2023-09-11)

Changed Trastuzumab in Gastric cancer with EGFR Amplification: R2

Comments changed: Case-control study. AMNESIA panel alterations, including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications, were more frequent in HER2-positive metastatic gastric cancer patients resistant to trastuzumab, and absence of these alterations was associated with longer median PFS (5.2 vs 2.6 months) and OS (16.1 vs 7.6 months).. (First curated: 2020-05-27)

Changed Cetuximab in Glioblastoma with EGFR Amplification: R2

Comments changed: Phase 2 trial of cetuximab in recurrent high-grade glioma showed limited activity, with 5.5% partial response rate and median PFS of 1.9 months, and no significant correlation was found between response and EGFR amplification, indicating potential resistance mechanism unrelated to EGFR gene copy number.. (First curated: 2020-06-25)

Changed Dacomitinib in Glioblastoma with EGFR Amplification: R2

Comments changed: Phase 2 trial of dacomitinib in recurrent glioblastoma with EGFR amplification showed limited single-agent activity, with a median PFS of 2.7 months and PFS6 of 10.6%.PFS6 10%. (First curated: 2020-06-11)

Changed Gefitinib in Glioblastoma with EGFR Amplification: R2

Comments changed: Phase 2 trial evaluated gefitinib in newly diagnosed glioblastoma patients, showing no significant improvement in OS or PFS, with no correlation between EGFR status and clinical outcome, indicating potential resistance to gefitinib.No survival benefit. (First curated: 2020-06-11)

Changed Larotrectinib in Low-grade glioma with EGFR Amplification: R2

Comments changed: Case reports. Off-target resistance mechanism identified in two pediatric patients with NTRK fusion-positive solid tumors treated with larotrectinib.. (First curated: 2023-09-11)

Changed Erlotinib in Colorectal adenocarcinoma with EGFR EGFR-SEPT14 Fusion: R2

Comments changed: Case report. A patient with colorectal adenocarcinoma harboring a rare EGFR-SEPT14 fusion achieved a partial response to erlotinib, but subsequently developed resistance with the emergence of EGFRvIII mutation.. (First curated: 2020-09-03)

Changed Vandetanib in Solid tumours with RET S904F: R2

Comments changed: Preclinical and clinical studies. Resistance mechanisms to RET inhibitors in RET-dependent cancers, including a secondary RET mutation S904F in the activation loop conferring resistance to vandetanib, and highlighted the need for next-generation RET inhibitors to overcome resistance.. (First curated: 2020-11-17)

01 June, 2025 (Version: 20250601AU)

New Obrixtamig in Extrapulmonary neuroendocrine carcinoma with DLL3 High expression: 3

Phase 1 trial. NCT04429087. Obrixtamig showed greater efficacy in patients with extrapulmonary neuroendocrine carcinomas with high DLL3 expression (ORR: 40.0%, median DoR: 7.9 months) compared to those with low DLL3 expression (ORR: 3.3%). DLL3-high is defined as >50% TC. References: 10.1200/JCO.2025.43.16_suppl.3004

New BNT142 in Ovarian cancer, Solid tumours with CLDN6 Protein expression: 4

Phase 1/2 BNT142-01 trial. NCT05262530. N=65. BNT142 showed promising anti-tumor activity with 7 partial responses in ovarian cancer and a disease control rate of 58% across all dose levels in CLDN6+ advanced solid tumors. CLDN6 positivity is defined as ≥ membrane positivity in 10% of cell. No clear relationship beween CLDN6 expression level versus response seen. References: 10.1200/JCO.2025.43.16_suppl.2501

New 212Pb-VMT-alpha-NET in Neuroendocrine tumour with SSTR2 Protein expression: 4

Phase 1/2a study. NCT05636618. [212Pb]VMT-α-NET. 3/7 patients achieving partial responses at 185 MBq dose level in SSTR2-expressing neuroendocrine tumors. DOTATATE-positive. References: 10.1200/JCO.2025.43.16_suppl.3005

New Trametinib in Melanoma with BRAF K601, K601E: R2

Phase 2 NCI-MATCH trial. NCT02465060 (Subprotocol R). N=32. Trametinib showed limited activity with 3% ORR and 34% clinical benefit rate in patients with BRAF non-V600 mutations or fusions, with median PFS of 1.8 months and median OS of 5.7 months. References: 31924734

Removed Cobimetinib; Trametinib in Non-small cell lung cancer with MAP2K1 alterations Oncogenic mutations: Tier 4   (First curated: 2020-06-11)

Removed RO5045337 in Liposarcoma with MDM2 alterations Amplification: Tier 4   (First curated: 2020-04-16)

Removed AZD4547 in Lung squamous cell carcinoma with FGFR3 alterations Alteration: Tier R2   (First curated: 2020-11-10)

Removed Ponatinib in Solid tumours with NRAS alterations Q61K: Tier R2   (First curated: 2020-11-17)

Changed Vandetanib in Non-small cell lung cancer with RET Fusions: 3

Comments changed: Phase 2 trial. N=18. Vandetanib showed an ORR of 18% and DCR of 65% in pretreated NSCLC patients with RET rearrangement, with a median PFS of 4.5 months and OS of 11.6 months.Not TGA approved. ORR 18%. OncoKB LOE 2. (First curated: 2020-04-27)

Changed Sorafenib in Non-small cell lung cancer with ARAF S214C: 4

Comments changed: Case report and preclinical study. ARAF S214C mutation identified in a lung adenocarcinoma patient with a near-complete response to sorafenib, was shown to be oncogenic and sorafenib-sensitive in cellular transformation assays.Single case report. OncoKB LOE 3. (First curated: 2020-06-02)

Changed Trametinib in Melanoma with BRAF K601, K601E: 4

Comments changed: Phase 2 trial of Trametinib in patients with metastatic BRAF-mutant melanoma. N=97. In BRAF-inhibitor naive patients (cohort B, N=57), ORR was 25% (1 CR, 13 PR), median PFS 4.0 months, and median OS 14.2 months. One patient with BRAF K601E mutation had a confirmed PR with PFS of 32 weeks.Case reports only; OncoKB LOE 3. References changed: 23248257; 31924734. (First curated: 2020-05-15)

Changed Cobimetinib, Trametinib with MAP2K1 Oncogenic mutations: 4

Cancer type(s) changed: Melanoma, Non-small cell lung cancer Comments changed: Trametinib showed activities in treating cell lines or patients with MEK1 mutations across various malignancies, suggesting MEK1 mutations as potential indications for trametinib therapy, although resistance was observed with varying responses to different MEK1 mutations.OncoKB LOE 3. (First curated: 2020-04-16)

Changed Therapy in Solid tumours with MAP2K1 Oncogenic mutations: 4

Therapy changed: UlixertinibMEK inhibitor, ERK inhibitor. Comments changed: Preclinical study. ERK inhibitor ulixertinib showed therapeutic potential against BRAF mutant, BRAF-MEK inhibitor resistant, or RAS mutant tumors with clinical activity against various tumor types in a first-in-human dose-escalation study.. (First curated: 2020-05-15)

Changed Trametinib in Glioblastoma, Type 1 neurofibromatosis with NF1 Oncogenic mutations: 4

Comments changed: Case report. Treatment-refractory neurofibromatosis-associated glioblastoma experienced clinical and radiological benefit from the MEK inhibitor, trametinib.OncoKB LOE 3, case report only. (First curated: 2020-04-16)

Changed GDC-0077 in Breast cancer with PIK3CA Oncogenic mutations: 4

Comments changed: Phase 1a dose escalation study. NCT03006172. N=20. GDC-0077, a p110α-selective and mutant-degrading PI3K inhibitor, showed manageable safety profile, linear PK, and preliminary anti-tumor activity with 25% partial response rate and 45% clinical benefit rate in patients with PIK3CA-mutant solid tumors.Phase 1. NCT03006172. First-in-human ORR confirmed PR in 4 pts (20%). Clinical benefit rate was 45%; OncoKB LOE 3. (First curated: 2020-04-16)

Changed Capmatinib, Crizotinib in Non-small cell lung cancer with EGFR Amplification: R2

Comments changed: Preclinical and clinical genomic analysis identified on-target MET kinase domain mutations and off-target mechanisms including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF as drivers of resistance to MET TKIs in MET exon 14-mutant NSCLC.Off-target resistance. (First curated: 2020-05-31)

Changed Capmatinib in Non-small cell lung cancer with ERBB3 Amplification: R2

Comments changed: Preclinical and clinical genomic analysis identified on-target MET kinase domain mutations and off-target mechanisms including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF as drivers of resistance to MET TKIs in MET exon 14-mutant NSCLC.Off-target resistance. (First curated: 2020-05-31)

Changed Lapatinib in Breast cancer with ERBB3 F94L, G284R, D297Y, T355I, E1261A: R2

Comments changed: Preclinical study. HER3 mutations (e.g., T355I, F94L, G284R, D297Y, E1261A) were found to be activating and confer resistance to lapatinib in ER+ and HER2+ breast cancer cells, with HER3(T355I) inducing cell proliferation via HER4/HER1-dependent ERK1/2 and cyclinD1 mediated pathways.In ER-positive HER2-positive cell line. (First curated: 2020-09-15)

Changed Fulvestrant in Breast cancer with ESR1 ESR1-YAP1 fusion, ESR1-PCDH11X fusion, ESR1-SOX9 fusion, ESR1-ARNT2 fusion: R2

Comments changed: Preclinical study. Functionally active ESR1 gene fusions and activating ESR1 LBD point mutations drives endocrine treatment failure and resistance in metastatic breast cancer.. (First curated: 2022-12-07)

Changed Tamoxifen, Letrozole, Fulvestrant in Breast cancer with ESR1 Fusion, ESR1-YAP1 fusion, ESR1-PCDH11X fusion: R2

Comments changed: Preclinical study. ESR1 gene fusions (e.g., ESR1-e6>YAP1 and ESR1-e6>PCDH11X) confer estrogen-independent growth, anti-estrogen resistance, and metastatic progression in ER-positive breast cancer, although remaining sensitive to CDK4/6 inhibitors.. (First curated: 2022-12-07)

Changed Pembrolizumab in Melanoma with FBXW7 Loss-of-function mutations, R505: R2

Comments changed: Preclinical studies. Inactivation of Fbxw7 impairs dsRNA sensing and confers resistance to PD-1 blockade through downregulation of viral sensing pathways, including decreased expression of MDA5 and RIG1, and diminished type I IFN and MHC-I expression.. (First curated: 2020-12-03)

Changed AZD4547 in Lung squamous cell carcinoma with FGFR1 Alteration: R2

Comments changed: Phase 2 Lung-MAP S1400D substudy. AZD4547 targeting FGFR alteration showed minimal activity with ORR (1/27) 7% and median PFS of 2.7 months in previously treated FGFR-altered squamous NSCLC.. (First curated: 2020-11-10)

Changed Fulvestrant + Palbociclib, Fulvestrant + Ribociclib in Breast cancer with FGFR1 Amplification: R2

Comments changed: FGFR1 amplification mediates endocrine resistance in ER+ breast cancer by conferring broad resistance to ER, PI3K, and CDK4/6 inhibitors, but retains sensitivity to mTOR inhibitors, suggesting a potential therapeutic role for mTOR inhibitors in ER+/FGFR1+ MBC.. (First curated: 2020-04-15)

Changed AZD4547 in Lung squamous cell carcinoma with FGFR1 Amplification: R2

Comments changed: Phase 2 Lung-MAP S1400D substudy. AZD4547 targeting FGFR alteration showed minimal activity with ORR (1/27) 7% and median PFS of 2.7 months in previously treated FGFR-altered squamous NSCLC.SWOG S1400D; Minimal response (1/27). (First curated: 2020-06-11)

Changed AZD4547 in Lung squamous cell carcinoma with FGFR3 Amplification, Fusion, S249C: R2

Comments changed: Phase 2 Lung-MAP S1400D substudy. AZD4547 targeting FGFR alteration showed minimal activity with ORR (1/27) 7% and median PFS of 2.7 months in previously treated FGFR-altered squamous NSCLC.SWOG S1400D; Minimal response (1/27). References changed: 31195180, 33125909. (First curated: 2020-06-11)

Changed Nilotinib in Melanoma with KIT Amplification: R2

Comments changed: Phase 2 UN10-06 trial. Nilotinib in metastatic melanoma with KIT gene aberrations showed durable response in a subset of patients with specific KIT mutations in exons 11 and 17, although the primary endpoint of response rate was not met. In the KIT amplification only subgroup, 1/15 patients responded (ORR 6%) with a duration of response of 5 weeks. Gene co-mutation status was not available.Phase 2 UN10-06 trial. In KIT amplification only subgroup, only 1/15 response with with DOR of 5 weeks only (ORR 6%). Gene co-mutation status was not available in the case.. (First curated: 2020-12-31)

Changed Imatinib, Sunitinib, Regorafenib in Gastrointestinal stromal tumour with KIT D816V: R2

Comments changed: Preclinical studies and case reports. Type II c-Kit inhibitors such as BLU-285 inhibit activation loop mutants including KIT D816V and PDGFRA D842V mutations, demonstrating activity in phase 1 studies in patients with KIT/PDGFRA-driven cancers.Preclinical studies and case reports. Type II c-Kit inhibitors are sensitive to KIT D816 and PDGFR842V mutations. (First curated: 2020-04-23)

Changed Axitinib in Gastrointestinal stromal tumour with KIT D816V, D816H, D816: R2

Comments changed: Preclinical study. Axitinib showed potent activity against various cKIT primary and secondary mutations, including imatinib-resistant mutations T670I and V654A, in GIST preclinical models and patient-derived primary cells, but lacked activity in D816.. (First curated: 2020-06-27)

Changed Sunitinib in Gastrointestinal stromal tumour with KIT K642E, D816V, D820A, D816: R2

Comments changed: Preclinical and biomarker studies. Investigations into KIT mutations and resistance mechanisms revealed that midostaurin and avapritinib exhibit distinct resistance profiles, with T670I gatekeeper mutation conferring avapritinib resistance, and that ripretinib, a switch-control kinase inhibitor, broadly inhibits KIT and PDGFRA mutants, while rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST.Primary GIST resistance. (First curated: 2020-05-15)

Changed Sunitinib in Gastrointestinal stromal tumour with KIT R796G, C809G, D816F, D816G, D816H, D816V, D816, D820A, D820E, D820G, D820N, D820V, D820Y, N822H, N822I, N822K, N822T, N822Y, Y823D, A829P, S840N: R2

Comments changed: Preclinical studies investigated secondary resistance mechanisms in KIT-mutant GIST, identifying distinct resistance profiles for ATP-competitive inhibitors midostaurin and avapritinib, and demonstrating the potential of combining TKIs with complementary activity against resistant mutations to suppress growth of polyclonal imatinib-resistance.. (First curated: 2020-05-15)

Changed Imatinib in Melanoma with KIT : R2

Alterations changed: A829P, T670I. Comments changed: Preclinical study. Secondary c-Kit mutations (A829P and T670I) confer acquired resistance to RTK inhibitors (imatinib and nilotinib) in c-Kit mutant melanoma cells, but alternative RTK inhibitors (dasatinib and sunitinib) or combined inhibition of MAPK and PI3K pathways may overcome this resistance.Not TGA approved.. (First curated: 2020-05-15)

Changed Regorafenib in Gastrointestinal stromal tumour with KIT V654A, D816V, D816: R2

Comments changed: Preclinical studies. Secondary kinase domain mutations in KIT as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in GIST, with distinct resistance profiles observed for midostaurin and avapritinib, and ripretinib showing broad spectrum inhibition of oncogenic and drug-resistant KIT and PDGFRA variants.Secondary resistance. (First curated: 2020-05-15)

Changed Imatinib in Gastrointestinal stromal tumour with KIT V654A, N655S, T670I, N680K, F681L, C809G, D816G, D816H, D816V, D816, D820G, D820E, D820N, D820V, D820Y, N822H, N822I, N822K, N822T, N822Y, Y823D, A829P, S840N: R2

Comments changed: Preclinical studies. Secondary kinase domain mutations in KIT as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in GIST, with distinct resistance profiles observed for midostaurin and avapritinib, and ripretinib showing broad spectrum inhibition of oncogenic and drug-resistant KIT and PDGFRA variants.Secondary resistance. (First curated: 2020-05-15)

Changed Avapritinib in Gastrointestinal stromal tumour with KIT V654A, N655S, T670I, N822T, S840N: R2

Comments changed: Preclinical studies. Secondary kinase domain mutations in KIT as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in GIST, with distinct resistance profiles observed for midostaurin and avapritinib, and ripretinib showing broad spectrum inhibition of oncogenic and drug-resistant KIT and PDGFRA variants.Secondary resistance. (First curated: 2020-05-15)

Changed Crizotinib in Non-small cell lung cancer with MET F1007fs (F1025fs): R2

Comments changed: Case report. Novel MET Exon 14 skipping treatment-naive lung adenocarcinoma presented primary resistance to crizotinib.Case report. Primary resistance to crizotinib. (First curated: 2021-01-03)

Changed Vandetanib, Cabozantinib in Solid tumours with RET V804L, V804M: R2

Comments changed: Preclinical study. RET(V804L) and RET(G810A) gatekeeper mutations confer resistance to RET inhibitors, but can be overcome by next-generation inhibitors such as ponatinib and lenvatinib. (First curated: 2020-11-17)

Changed Crizotinib in Non-small cell lung cancer with ROS1 E1395G, L1947R, G1971E, S1986Y, S1986F, L2026M, G2032R, D2033N, S2060G, V2098U, L2155S: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Cabozantinib in Non-small cell lung cancer with ROS1 F2004C, F2075V, D2113G: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Lorlatinib in Non-small cell lung cancer with ROS1 G2032R: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Crizotinib, Entrectinib, Loratinib in Solid tumours with ROS1 G2032R: R2

Comments changed: Preclinical study. ROS1 fusions and secondary resistance mutationsof earlier-generation TKIs.. (First curated: 2023-04-14)

Changed Ensartinib in Non-small cell lung cancer with ROS1 G2032R, D2033N: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Ceritinib in Non-small cell lung cancer with ROS1 L1951R, G2032R, D2033N, G2101A, L2155S: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Brigatinib in Non-small cell lung cancer with ROS1 L1951R, L2026M, G2032R, D2033N: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed AZD3463 in Non-small cell lung cancer with ROS1 L2026M, G2032R: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Entrectinib in Non-small cell lung cancer with ROS1 L2026M, G2032R, D2033N: R2

Comments changed: Preclinical studies. Secondary resistance mutation in ROS1-rearranged NSCLC was observed, and profiling studies revealed structural features distinguishing ROS1 kinase domains.. (First curated: 2020-04-25)

Changed Vismodegib, Sonidegib in Basal cell carcinoma, Solid tumours with SMO D473G, D473Y, D473H, G497W, V321M, W281L, Q477E, A327P, C390R, D506N, E181K, E481G, G453D, K519R, K564E, L221P, L353F, N476K, P513L, P698T, P739L, P739S, R168H, R199Q, T336I, T349I, T349P, T534I, T548I, T640A, V386A, V404M, V414A, A459V, D384N, E518K, I408V, N219D, S387N, T241M, V281C: R2

Comments changed: Preclinical and clinical studies demonstrated hedgehog signaling inhibitors' activity in various solid and hematological cancers, including pancreatic cancer, medulloblastoma, and leukemia, with SMO mutations identified as a key resistance mechanism in basal cell carcinoma.On-target resistance. (First curated: 2020-04-25)

Changed Vismodegib in Medulloblastoma with SMO D473H: R2

Comments changed: Preclinical study. Genomic analysis of basal cell carcinoma tumor biopsies revealed On-target resistance to vismodegib associated with Hedgehog pathway reactivation through SMO mutation and SUFU and GLI2 copy number changes.. (First curated: 2020-04-25)

Changed Vismodegib in Basal cell carcinoma with SUFU Loss-of-function mutations: R2

Comments changed: Preclinical study. Genomic analysis of basal cell carcinoma tumor biopsies revealed vismodegib resistance associated with Hedgehog pathway reactivation through SMO mutation and SUFU and GLI2 copy number changes, suggesting combination therapies targeting multiple levels of the Hedgehog pathway may overcome resistance.Xenografts models of Sufu tumors showed resistance to SMO inhibition.. (First curated: 2021-02-28)

31 May, 2025 (Version: 20250531AU)

New Encorafenib + Cetuximab + mFOLFOX6 in Colorectal adenocarcinoma with BRAF V600E: 2

Phase3 BREAKWATER trial. NCT04607421. N=637. Encorafenib + cetuximab + mFOLFOX6 demonstrated significant improvement in PFS (12.8 vs 7.1 months) and OS (30.3 vs 15.1 months) compared to standard of care in BRAF V600E-mutant metastatic colorectal cancer. References: 10.1200/JCO.2025.43.16_suppl.LBA3500

New Olaparib, Talazoparib, Niraparib, Rucaparib in Uterine leiomyosarcoma with BRCA2 Oncogenic mutation, Deletion: 3

Retrospective analysis of 35 patients with BRCA-altered uterine sarcoma. N=13 treated with PARPis in recurrent/metastatic setting. ORR was 46% (1 CR, 5 PR). CBR was 62%. Median PFS was 13.2 months. Median PFS ratio compared to previous systemic therapy was 1.9. 60% ORR observed in patients with BRCA2 homozygous deletions. References: 40117531

New DB-1310 in Non-small cell lung cancer with EGFR Exon 19 deletion, L858R: 3

Phase 1/2a trial. DB-1310, a HER3-targeted ADC, showed antitumor activity in heavily pretreated EGFRm NSCLC, with unconfirmed ORR of 44% (20/46) and median PFS of 7.0 months. References: 10.1200/JCO.2025.43.16_suppl.3000

New Datopotamab Deruxtecan in Non-small cell lung cancer with EGFR Exon 19 deletion, T790M, L858R, G719, L861Q, Exon 20 insertion mutations: 3

Phase 2 TROPION-Lung05 trial. NCT04484142. N=137. Dato-DXd showed an ORR of 35.8% in heavily pretreated NSCLC with actionable genomic alterations, with median DOR of 7.0 months. References: 39761483

New Patritumab deruxtecan in Non-small cell lung cancer with EGFR Exon 19 deletion,L858R: 3

Phase 2 HERTHENA-Lung01 trial. NCT04619004. N=225. Patritumab Deruxtecan (HER3-DXd) showed a confirmed ORR of 29.8% with median DOR of 6.4 months, median PFS of 5.5 months, and median OS of 11.9 months in patients with EGFR-mutated NSCLC previously treated with EGFR TKI and platinum-based chemotherapy. References: 37689979

New Izalontamab brengitecan in Non-small cell lung cancer with EGFR Oncogenic mutation and NOT Exon 19 deletion and NOT L858R, Exon 20 insertion: 3

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic EGFR mutations, with ORR of 69% and mPFS of 7.0 months. References: 10.1200/JCO.2025.43.16_suppl.3001

New Izalontamab brengitecan in Non-small cell lung cancer with ERBB2 Oncogenic mutation: 3

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic EGFR mutations, with ORR of 53%, DCR 100%, and mPFS of 7.5 months. References: 10.1200/JCO.2025.43.16_suppl.3001

New TQB2102 in Colorectal adenocarcinoma with ERBB2 Overexpression: 3

Phase1 trial. TQB2102. N=181. TQB2102, a bispecific anti-HER2 antibody-drug conjugate, was well-tolerated with no dose-limiting toxicities and showed promising anti-tumor activity with an ORR of 41.2% in patients with advanced solid tumors, including HER2-positive (ORR 52%), HER2-low metastatic breast cancer (ORR 47%), HER2 overexpressed colorectal cancer (ORR 44%), HER2-positive gastric cancer (ORR 40%). References: 10.1200/JCO.2025.43.16_suppl.3002

New TQB2102 in Gastric cancer with ERBB2 Overexpression: 3

Phase1 trial. TQB2102. N=181. TQB2102, a bispecific anti-HER2 antibody-drug conjugate, was well-tolerated with no dose-limiting toxicities and showed promising anti-tumor activity with an ORR of 41.2% in patients with advanced solid tumors, including HER2-positive (ORR 52%), HER2-low metastatic breast cancer (ORR 47%), HER2 overexpressed colorectal cancer (ORR 44%), HER2-positive gastric cancer (ORR 40%). References: 10.1200/JCO.2025.43.16_suppl.3002

New TQB2102 in Solid tumours with ERBB2 Overexpression: 3

Phase1 trial. TQB2102. N=181. TQB2102, a bispecific anti-HER2 antibody-drug conjugate, was well-tolerated with no dose-limiting toxicities and showed promising anti-tumor activity with an ORR of 41.2% in patients with advanced solid tumors, including HER2-positive (ORR 52%), HER2-low metastatic breast cancer (ORR 47%), HER2 overexpressed colorectal cancer (ORR 44%), HER2-positive gastric cancer (ORR 40%). References: 10.1200/JCO.2025.43.16_suppl.3002

New TQB2102 in Breast cancer with ERBB2 Overexpression, Protein expression, Low-protein expression: 3

Phase1 trial. TQB2102. N=181. TQB2102, a bispecific anti-HER2 antibody-drug conjugate, was well-tolerated with no dose-limiting toxicities and showed promising anti-tumor activity with an ORR of 41.2% in patients with advanced solid tumors, including HER2-positive (ORR 52%), HER2-low metastatic breast cancer (ORR 47%), HER2 overexpressed colorectal cancer (ORR 44%), HER2-positive gastric cancer (ORR 40%). References: 10.1200/JCO.2025.43.16_suppl.3002

New MK-1084, MK-1084 + Cetuximab in Colorectal adenocarcinoma with KRAS G12C: 3

Phase 1 KANDLELIT-001 trial. NCT05067283. MK-1084, a KRAS G12C inhibitor, showed antitumor activity in patients with advanced KRAS G12C-mutated CRC, with ORR of 36% as monotherapy, 50% with cetuximab, and 14% with cetuximab + mFOLFOX6. References: 10.1200/JCO.2025.43.16_suppl.3508

New Olomorasib + Cetuximab in Colorectal adenocarcinoma with KRAS G12C: 3

Phase 1/2 study. NCT04956640. N=93. Olomorasib + cetuximab showed an ORR of 42% and mPFS of 7.5 months in patients with KRAS G12C-mutant CRC, with a favorable safety profile and optimal dose of olomorasib determined as 100 mg BID. References: 10.1200/JCO.2025.43.16_suppl.3507

New Sotorasib + Panitumumab in Colorectal adenocarcinoma with KRAS G12C: 3

Phase 1b CodeBreaK 101 trial. NCT04185883. N=40. Sotorasib + panitumumab + FOLFIRI showed promising efficacy in pretreated KRAS G12C-mutated mCRC with ORR of 57.5%, median PFS of 8.2 months, and median OS of 17.9 months. References: 10.1200/JCO.2025.43.16_suppl.3506

New Izalontamab brengitecan in Non-small cell lung cancer with KRAS Oncogenic mutation, G12C: 3

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic KRAS/MET alterations, with ORR of 40% and mPFS of 7.0 months. References: 10.1200/JCO.2025.43.16_suppl.3001

New Izalontamab brengitecan in Non-small cell lung cancer with MET Exon 14 deletion, Exon 14 splicing mutation,: 3

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic KRAS/MET alterations, with ORR of 40% and mPFS of 7.0 months. References: 10.1200/JCO.2025.43.16_suppl.3001

New Izalontamab brengitecan in Non-small cell lung cancer with ALK Fusion: 4

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic ALK/ROS1/RET fusions, with ORR of 35% and mPFS of 4.5 months. References: 10.1200/JCO.2025.43.16_suppl.3001

New Olaparib + Temozolomide in Uterine leiomyosarcoma with RAD51 Loss of protein expression: 4

Phase 2 study. NCI Protocol 10250. N=22. Olaparib + temozolomide showed an ORR of 27% and mPFS of 6.9 months in advanced uterine leiomyosarcoma. 50% of tumors were homologous recombination-deficient by RAD51 assay, with prolonged mPFS (11.2 vs 5.4 months) in RAD51-deficient tumors. The RAD51 status is determined using a IHC based foci formation assay. References: 37467452

New Izalontamab brengitecan in Non-small cell lung cancer with RET Fusion: 4

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic ALK/ROS1/RET fusions, with ORR of 35% and mPFS of 4.5 months. References: 10.1200/JCO.2025.43.16_suppl.3001

New Izalontamab brengitecan in Non-small cell lung cancer with ROS1 Fusion: 4

Phase Ib study. N=68. iza-bren, an EGFR x HER3 bispecific ADC, showed promising activity in NSCLC patients with driver mutations outside of classic ALK/ROS1/RET fusions, with ORR of 35% and mPFS of 4.5 months. References: 10.1200/JCO.2025.43.16_suppl.3001

Changed Therapy in Solid tumours with EGFR+ERBB3 EGFR:Protein expression AND ERBB3:Protein expression: 3

Therapy changed: Izalontamab brengitecan. (First curated: 2024-09-13)

Changed Therapy in Urothelial carcinoma with EGFR+ERBB3 EGFR:Protein expression AND ERBB3:Protein expression: 3

Therapy changed: Izalontamab brengitecan. (First curated: 2024-09-13)

28 May, 2025 (Version: 20250528AU)

New Vemurafenib + Cobimetinib in Solid tumours, Non-small cell lung cancer with BRAF V600E: 3

Phase 2 trial. MoST substudy 12. ACTRN12620000861954. N=64. VEM+COB achieved ORR of 50% in refractory BRAF V600-mutated solid tumours and 42% in 1L NSCLC, with median PFS of 7.9 months and OS of 15.9 months in solid tumour group, and 6-mo PFS rates of 68% and 67% in solid and 1L NSCLC groups respectively. References: 10.1016/j.annonc.2024.08.690

New Osimertinib + Crizotinib in Non-small cell lung cancer with EGFR+MET EGFR:T790M and MET:amplification: 4

Case report. EGFR-mutant NSCLC patient with emergent MET amplification after disease progression on erlotinib had a sustained partial response to combination osimertinib and crizotinib, with MET amplification persisting as a resistance mechanism at CNS progression. References: 30881166

New GQ1001 in Solid tumour with ERBB2 Overexpression, Amplification: 4

Phase Ia study. NCT04450732. GQ1001, a HER2-targeting ADC, showed promising antitumor activity in HER2-positive advanced solid tumors, with 6 out of 15 evaluable subjects achieving confirmed partial response at doses ≥ 7.2 mg/kg, and a median progression-free survival of 4.8 months. References: 10.1158/1538-7445.AM2023-CT178

New Palazestrant in Breast cancer with ESR1 Protein expression, Oncogenic mutations: 4

Phase 1b/2 study. NCT0526610. N=33. Palazestrant + Palbociclib were well tolerated with 55% grade 3 and 9% grade 4 neutropenia. 4 partial responses (2 confirmed) out of 19 response-evaluable patients with a CBR of 42% across all patients and 67% in patients with ESR1 mutations. References: 10.1158/1538-7445.SABCS23-PS15-04

New Palazestrant in Breast cancer with ESR1 Protein expression, Oncogenic mutations, Y537S, D538G: 4

Preclinical study. Palazestrant (OP-1250), a novel oral complete estrogen receptor antagonist, demonstrated superior efficacy and pharmacokinetic properties compared to fulvestrant, elacestrant, and tamoxifen in ER-positive breast cancer models, including wild-type and ESR1-mutant xenografts and intracranial implants. Updated: 2025-05-28. References: 38102750

New BGB-B2033 in Hepatocellular carcinoma with GPC3 Protein expression: 4

Preclinical study. BGB-B2033, a 4-1BB/GPC3 bispecific antibody, exhibits potent antitumor activity in GPC3-expressing tumor models. References: 10.1158/1538-7445.AM2025-6009

New MT-303 in Hepatocellular carcinoma with GPC3 Protein expression: 4

Preclinical study. MT-303, an LNP-formulated GPC3-specific CAR mRNA, demonstrated improved expression and anti-tumor activity in a hepatocellular carcinoma xenograft model (HepG2). References: 10.1136/jitc-2024-SITC2024.1125

New Talazoparib in Pancreatic adenocarcinoma with PALB2 Loss-of-function mutations: 4

Phase 1 trial. NCT01286987. Talazoparib demonstrated antitumour activity in a single case of PALB2 mutation amongst 13 pancreatic cancer patients who showed partial responses. References: 28242752

New Osimertinib in Non-small cell lung cancer with EGFR L718V, L718Q, L792: R2

Novel secondary EGFR mutations L718 and L792 confer osimertinib resistance in NSCLC patients, with L718Q conferring the greatest resistance, and parallel or downstream oncogene alterations also contributing to resistance. References: 29506987

New Osimertinib + Crizotinib in Non-small cell lung cancer with EGFR+MET EGFR:Exon 19 deletion and MET:Exon 14 skipping mutation, EGFR:L858R and MET:Exon 14 skipping mutation: R2

Preclinical study. Acquired MET exon 14 alteration drives secondary resistance to EGFR tyrosine kinase inhibitor in EGFR-mutated lung cancer. References: 31157314

New Trastuzumab in Extramammary Paget’s disease with ERBB3 A232V: R2

Case report. A patient with ERBB2(S310F) mutated metastatic extramammary Paget's disease initially responded to trastuzumab and carboplatin, but developed resistance with additional genomic alterations including ERBB3(A232V) and PIK3CA(G106V) mutations and MET and CDK6 amplification. References: 31803359

New AZD4547 in Solid tumours with FGFR1 Amplification, Oncogenic mutations: R2

Phase 2 NCI-MATCH trial (arm W). Patients with tumors harboring FGFR aberrations treated with AZD4547 showed confirmed partial responses in 8% of patients, limited to those with FGFR1-3 point mutations or fusions, with a higher response rate of 22% in patients with FGFR fusions. References: 32463741, 10.1200/JCO.2018.36.15_suppl.2503

New Trametinib in Melanoma with MAP2K2 Q60P: R2

Preclinical study. Concurrent MEK2-Q60P mutation and BRAF amplification/V600E were identified in melanoma cells resistant to BRAF and MEK inhibitors, conferring sustained MAPK activation and on-target resistance, which was addressed by a triple combination of dabrafenib, trametinib, and GSK2126458. References: 24055054

New Trastuzumab in Extramammary Paget’s disease with MET Amplification: R2

Case report. A patient with ERBB2(S310F) mutated metastatic extramammary Paget's disease initially responded to trastuzumab and carboplatin, but developed resistance with additional genomic alterations including ERBB3(A232V) and PIK3CA(G106V) mutations and MET and CDK6 amplification. References: 31803359

New Larotrectinib in Solid tumours with NTRK1 High mRNA expression: R2

Phase 2 trial. ACTRN12619001147178. Larotrectinib showed limited efficacy in tumors with NTRK overexpression (ORR 0%). References: 39720993

New Larotrectinib in Solid tumours with NTRK2 High mRNA expression: R2

Phase 2 trial. ACTRN12619001147178. Larotrectinib showed limited efficacy in tumors with NTRK overexpression (ORR 0%). References: 39720993

New Larotrectinib in Solid tumours with NTRK3 High mRNA expression: R2

Phase 2 trial. ACTRN12619001147178. Larotrectinib showed limited efficacy in tumors with NTRK overexpression (ORR 0%). References: 39720993

Removed Erdafitinib in Non-small cell lung cancer with FGFR2 alterations FGFR2-BICC1 fusion: Tier 4   (First curated: 2022-02-16)

Removed GSK3368715 in Solid tumours with MTAP alterations Deletion: Tier 4   (First curated: 2020-04-16)

Removed Sorafenib in Gastrointestinal stromal tumour with KIT alterations D816H, D816V: Tier R2   (First curated: 2022-01-25)

Removed Lapatinib + Trastuzumab in Colorectal adenocarcinoma with KRAS alterations Oncogenic mutations: Tier R2   (First curated: 2020-05-04)

Removed Trastuzumab in Breast cancer with MET alterations Overexpression: Tier R2   (First curated: 2020-05-15)

Changed Binimetinib + Encorafenib in Melanoma with BRAF V600E, V600K: 1

Comments changed: TGA approved. PBS reimbursed. Phase 3 COLUMBUS trial. NCT01909453. Median overall survival was significantly longer with encorafenib plus binimetinib (33.6 months) compared to vemurafenib (16.9 months) in patients with BRAF(V600)-mutant melanoma.TGA approved. PBS reimbursed. COLUMBUS trial.. (First curated: 2020-05-15)

Changed Dostarlimab in Endometrial cancer with Mismatch repair Deficient: 1

Tier changed: 12. Comments changed: TGA approved. PBS reimbursed. FDA approved. Phase 1 trial. GARNET. NCT02715284. N=71. Dostarlimab demonstrated an objective response rate of 42.3-43% (30 patients) with 12.7-13% complete response and 29.6% partial response in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) endometrial cancer as assessed by IHC, PCR, or NGS. Duration of response was 96.4% at 6 months and 76.8% at 12 months with an acceptable safety profile.GARNET trial: dMMR as assessed by IHC or MSI-H by PCR or NGS. ORR 43% with 13% CR. Duration of response at 6 months: 96%. FDA approved.. (First curated: 2021-04-23)

Changed Dostarlimab + Carboplatin + Paclitaxel in Endometrial cancer with Mismatch repair Deficient: 1

Tier changed: 12. Comments changed: TGA approved. PBS reimbursed. Phase 3 RUBY trial. NCT03981796. N=494. Dostarlimab plus carboplatin-paclitaxel significantly improved PFS over placebo. In the dMMR/MSI-H population, PFS at 24 months was 61% with dostarlimab and 16% with placebo. OS at 24 months was 83% with dostarlimab and 59% with placebo.. (First curated: 2023-12-16)

Changed Lu-177 vipivotide tetraxetan in Prostate cancer with PSMA Protein expression: 1B

Comments changed: TGA approved. FDA approved 2022-03-24. Phase 3 VISION trial. NCT03511664. N=831. Lutetium-177-PSMA-617 plus standard care significantly prolonged PFS (8.7 vs 3.4 months, HR 0.40) and OS (15.3 vs 11.3 months, HR 0.62) in patients with PSMA-positive (Gallium-68 positive) metastatic castration-resistant prostate cancer.TGA approaved. FDA approved 2022-03-24. Phase 3 VISION trial. NCT03511664. N=831. Lutetium-177-PSMA-617 plus standard care significantly prolonged PFS (8.7 vs 3.4 months, HR 0.40) and OS (15.3 vs 11.3 months, HR 0.62) in patients with PSMA-positive (Gallium-68 positive) metastatic castration-resistant prostate cancer.. (First curated: 2021-06-21)

Changed Capivasertib + Fulvestrant in Breast cancer with AKT1 Oncogenic mutation: 2

Comments changed: Not TGA approved. FDA approved. Phase 3. CAPItello-291 trial. NCT04305496. N=708. Capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant 7.2 vs 3.6 months in the overall population, and 7.3 v 3.1 months in patients with AKT pathway alterations). ORR was 40% (placebo 35%). 69% had received previous CDK4/6 inhibitor therapy.Not TGA approaved. FDA approved. Phase 3. CAPItello-291 trial. NCT04305496. N=708. Capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant 7.2 vs 3.6 months in the overall population, and 7.3 v 3.1 months in patients with AKT pathway alterations). ORR was 40% (placebo 35%). 69% had received previous CDK4/6 inhibitor therapy.. (First curated: 2023-11-29)

Changed Sorafenib in Gastrointestinal stromal tumour with KIT Oncogenic mutations, V654A, T670I, D820A, D820E, D820G, D820N, D820V, D820Y, N822H, N822I, N822K, N822T, N822Y, Y823D, A829P: 2

Comments changed: Not TGA approved. Not FDA approved. NCCN recommended 2A. Preclinical study. Sorafenib inhibits various KIT and PDGFRA mutant kinases associated with imatinib-resistant or sunitinib-resistant gastrointestinal stromal tumors (GIST), except for substitutions at KIT codon D816 and PDGFRA codon 842.Not TGA approved; Not FDA approved. NCCN recommended 2A. (First curated: 2020-05-16)

Changed Ibrutinib in Waldenstroms macroglobulinaemia with MYD88 Oncogenic mutations, L265P: 2

Comments changed: Phase 2 study. NCT01614821. N=63. Ibrutinib demonstrated high activity in pretreated Waldenstrom's macroglobulinemia patients with an overall response rate of 91% and major response rate of 73%. Patients with MYD88(L265P)CXCR4(WT) mutations achieved the highest response rates at 100% overall response and 91% major response.. (First curated: 2020-08-26)

Changed Pimitespib in Gastrointestinal stromal tumour with PDGFRA Oncogenic mutations: 2

Comments changed: Phase 3. CHAPTER-GIST-301. Phase 3 CHAPTER-GIST-301 trial. N=86. Pimitespib significantly improved PFS (2.8 months vs 1.4 months) and cross-over-adjusted OS (13.8 vs 9.6 months) compared with placebo in patients with advanced GIST refractory to standard TKIs. Single-agent Pimitespib was effective in treat-refractory GIST patients after imatinib, sunitinib, and regorafenib failure, including those with secondary KIT resistance.. (First curated: 2021-07-02)

Changed Capivasertib + Fulvestrant in Breast cancer with PIK3CA Oncogenic mutation: 2

Comments changed: Not TGA approved. FDA approved. Phase 3. CAPItello-291 trial. NCT04305496. N=708. Capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant 7.2 vs 3.6 months in the overall population, and 7.3 v 3.1 months in patients with AKT pathway alterations). ORR was 40% (placebo 35%). 69% had received previous CDK4/6 inhibitor therapy.Not TGA approaved. FDA approved. Phase 3. CAPItello-291 trial. NCT04305496. N=708. Capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant 7.2 vs 3.6 months in the overall population, and 7.3 v 3.1 months in patients with AKT pathway alterations). ORR was 40% (placebo 35%). 69% had received previous CDK4/6 inhibitor therapy.. (First curated: 2023-11-29)

Changed Capivasertib + Fulvestrant in Breast cancer with PTEN Loss-of-function mutations, deletion: 2

Comments changed: Not TGA approved. FDA approved. Phase 3. CAPItello-291 trial. NCT04305496. N=708. Capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant 7.2 vs 3.6 months in the overall population, and 7.3 v 3.1 months in patients with AKT pathway alterations). ORR was 40% (placebo 35%). 69% had received previous CDK4/6 inhibitor therapy.Not TGA approaved. FDA approved. Phase 3. CAPItello-291 trial. NCT04305496. N=708. Capivasertib plus fulvestrant significantly improved PFS over placebo plus fulvestrant 7.2 vs 3.6 months in the overall population, and 7.3 v 3.1 months in patients with AKT pathway alterations). ORR was 40% (placebo 35%). 69% had received previous CDK4/6 inhibitor therapy.. (First curated: 2023-11-29)

Changed Dasatinib in Acute lymphoblastic leukaemia, Chronic myelogenous leukaemia with ABL1 E255K, E255V, F359C, F359I, F359V, Y253H, A337V, P465S: 3

Tier changed: 32. (First curated: 2020-05-21)

Changed Bosutinib in Acute lymphoblastic leukaemia, Chronic myelogenous leukaemia with ABL1 E255K, E255V,F317C, F317I, F317L, F317V, F359C, F359I, F359V, T315A, Y253H, A337V, P465S: 3

Tier changed: 32. Comments changed: Phase 3 BFORE trial. NCT02130557. Bosutinib demonstrated significantly higher MMR rate at 12 months (47.2% vs 36.9%) and CCyR rate by 12 months (77.2% vs 66.4%) compared to imatinib in patients with newly diagnosed chronic-phase CML.BCR-ABL1 fusion required, and not TGA approved by biomarker. OncoKB LOE 1. (First curated: 2020-05-21)

Changed Nilotinib in Acute lymphoblastic leukaemia, Chronic myelogenous leukaemia with ABL1 F317C, F317I, F317L, F317V, T315A, V299L, A337V, P465S: 3

Tier changed: 32. Comments changed: Phase 3 trial. NCT00471497. N=846. Nilotinib (300mg or 400mg twice daily) showed higher major molecular response rates (44% and 43% vs 22%) and complete cytogenetic response rates (80% and 78% vs 65%) compared to imatinib (400mg once daily) in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML.BCR-ABL1 fusion required, and not TGA approved by biomarker. OncoKB LOE 1. (First curated: 2020-05-21)

Changed Imatinib in Acute lymphoblastic leukaemia, Chronic myelogenous leukaemia with ABL1 V299L, A337V, P465S: 3

Tier changed: 32. Comments changed: Randomised study. N=1106. Imatinib showed superior major cytogenetic response (87.1% vs 34.7%), complete cytogenetic response (76.2% vs 14.5%), and freedom from progression to accelerated-phase or blast-crisis CML (96.7% vs 91.5%) compared to interferon alfa plus low-dose cytarabine in newly diagnosed chronic-phase CML. BCR-ABL1 fusion required, and not TGA approved by biomarker.BCR-ABL1 fusion required, and not TGA approved by biomarker. Adapted from APAR.. (First curated: 2020-05-21)

Changed Ponatinib in Acute lymphoblastic leukaemia, Chronic myelogenous leukaemia with ABL1 Y253H, E255K, E255V, V299L, F317L, F317C, F317I, F317V, F359C, F359V, F359I, A337V, P465S: 3

Tier changed: 32. (First curated: 2020-05-21)

Changed Durvalumab + Olaparib in Breast cancer with BRCA1 Oncogenic mutations (germline): 3

Comments changed: Phase 1/2 MEDIOLA trial. NCT02734004. N=34. Olaparib + durvalumab demonstrated antitumour activity in breast cancer patients (TNBC and non-TNBC) with maximum two prior treatment lines. In germline BRCA-mutated metastatic breast cancer, ORR was 63% with 80% disease control rate at 12 weeks and 50% at 28 weeks. PD-L1 status (1% threshold) was not significant.MEDIOLA breast cancer cohort, including both TNBC and non-TNBC. Maximum of two lines of prior treatments. ORR 63%. DCR 28 weeks: 50%. Note: PD-L1 (at 1%) status NS.. (First curated: 2020-09-21)

Changed Afatinib in Non-small cell lung cancer with ERBB2 A775_G776insYVMA (Y772_A775dup), M774dup: 3

Comments changed: Global named patient use program. N=28. Heavily pretreated ERBB2 mutation-positive NSCLC. Afatinib showed activity with ORR of 19% (3/16) with DCR of 69% (11/16). Subgroup with p.A775_G776insYVMA insertion in exon 20 (N=10) had median TTF of 9.6 months, ORR of 33%, and DCR of 100%.Global named used program. Heavily pretreated NSCLC with ERBB2 mutation. N=28. ORR of 19% (3/16) with DCR of 69% (11/16). (First curated: 2022-09-07)

Changed Poziotinib in Solid tumours, Non-small cell lung cancer with ERBB2 A775_G776insYVMA (Y772_A775dup), P780_Y781insGSP (G778_P780dup): 3

Comments changed: Phase 2 trial. NCT03066206. N=50. Poziotinib showed an ORR of 32% and median PFS of 5.5 months in EGFR exon 20-mutant NSCLC patients, with sensitivity influenced by insertion location (ORR: 46% near-loop vs 0% far-loop).Phase 2. ORR 43% (5/12) and DCR 83%. NCT03066206.. References changed: 3582039731588020. (First curated: 2020-06-15)

Changed Poziotinib in Non-small cell lung cancer with ERBB2 A775_G776insYVMA (Y772_A775dup), P780_Y781insGSP (G778_P780dup), G776delinsVC, Exon 20 insertion, Exon 20 mutation: 3

Comments changed: Phase 2 trial. N=30. Poziotinib showed antitumor activity in patients with HER2 exon 20 mutant NSCLC with a confirmed ORR of 27%, median PFS of 5.5 months, and median OS of 15 months, despite 90% having received prior platinum-based chemotherapy.N=30. NSCLC subsequent to platinum-based chemotherapy. ORR 27%. Median DOR 5.0 months. Median PFS 5.5 months. Median OS 15 months.. (First curated: 2021-09-23)

Changed Margetuximab + Pembrolizumab in Gastric cancer, Gastroesophageal junction adenocarcinoma, Oesophageal adenocarcinoma with ERBB2 Amplification: 3

Comments changed: Phase 1b/2 CP-MGAH22-05 trial. NCT02689284. N=95. Margetuximab plus pembrolizumab showed acceptable safety and tolerability with an ORR of 18% (17/92) in patients with previously treated HER2-positive gastro-oesophageal adenocarcinoma.CP-MGAH22–05. (First curated: 2020-07-03)

Changed Carboplatin + Paclitaxel + Trastuzumab in Uterine serous carcinoma with ERBB2 Amplification: 3

Comments changed: Phase 2 trial. N=61. Median PFS was significantly longer with carboplatin-paclitaxel-trastuzumab (12.6 months) versus carboplatin-paclitaxel (8.0 months) in patients with HER2-positive advanced or recurrent uterine serous carcinoma.Not TGA approved; NCCN 2A; OncoKB LOE 2. (First curated: 2020-04-16)

Changed Trastuzumab + Pertuzumab in Salivary gland cancers with ERBB2 Amplification, Overexpression, L755F, D679H, G766V: 3

Comments changed: Phase 2a MyPathway trial. NCT02091141. N=19. Objective response rate (ORR) was 63% (12/19) in patients with advanced salivary gland carcinoma treated with targeted therapies matched to specific molecular alterations, including pertuzumab + trastuzumab for HER2 alterations, vismodegib for PTCH-1/SMO mutation, vemurafenib for BRAF V600 mutation, and atezolizumab for high tumor mutational burden.Phase 2A Basket. MyPathway. (First curated: 2020-07-03)

Changed Ado-Trastuzumab Emtansine in Non-small cell lung cancer with ERBB2 Oncogenic mutations, V659E, A775_G776insYVMA (Y772_A775dup), P780_Y781insGSP (G778_P780dup), G778insCPG, G776delinsVC, exon 20 insertion: 3

Comments changed: Phase 2 trials. Trastuzumab emtansine (T-DM1) showed activity in patients with HER2-overexpressing (IHC 3+) NSCLC and HER2-mutant lung cancers, with overall response rates of 20% and 44% respectively, with responses associated with HER2 gene amplification in the HER2-overexpressing cohort.Not TGA approved. OncoKB LOE 2.. (First curated: 2020-05-04)

Changed Trastuzumab deruxtecan in Breast cancer with ERBB2 : 3

Alterations changed: Protein expression and NOT amplificationprotein expression and NOT amplification. Tier changed: 34. Comments changed: Phase 1b study. NCT02564900. DESTINY-Breast04. N=54. Trastuzumab deruxtecan showed an ORR of 37.0% with median DOR of 10.4 months in patients with HER2-low-expressing advanced breast cancer.. (First curated: 2020-10-05)

Changed Erdafitinib in Cholangiocarcinoma with FGFR2 Fusions: 3

Comments changed: Phase 2a study. LUC2001. NCT02699606. Erdafitinib showed encouraging efficacy in Asian advanced cholangiocarcinoma patients with FGFR alterations, with an ORR of 50% (60% in FGFR2-alteration positive patients) and median PFS of 5.6 months (12.4 months in FGFR2-alteration positive patients).. (First curated: 2020-06-11)

Changed Rogaratinib in Urothelial carcinoma with FGFR3 High mRNA expression: 3

Comments changed: Randomised Phase 2. FORT-1. NCT03410693. In the FGFR1/3 mRNA positive population (N=87), rogaratinib demonstrated an ORR of 21% (18/87) and median OS of 8.3 months, which was not superior to chemotherapy.NCT03410693. Randomised Phase 2. FORT-1. FGFR1/3 mRNA positive population. N=87 in the Rogaratinib group. ORR was 21% (18/87), and median OS was 8.3 months. However, neither ORR or OS was superior to chemotherapy group.. (First curated: 2022-10-20)

Changed Sorafenib in Acute myeloid leukaemia with FLT3 Internal tandem duplication: 3

Comments changed: Phase 2 SORMAIN trial. DRKS00000591. N=83. Sorafenib maintenance therapy significantly improved RFS (HR, 0.39) and 24-month RFS probability (85.0% vs 53.3%) compared to placebo in FLT3-ITD-positive AML patients after allogeneic HCT.SORMAIN trial. Maintenance treatment. 24 months RFS 53.3% vs 85% placebo. (First curated: 2020-10-05)

Changed Sorafenib in Acute myeloid leukaemia with FLT3 Internal tandem duplication: 3

Comments changed: Phase 2. N=13. Sorafenib treatment in FLT3-ITD AML patients showed initial response with clearance of bone marrow myeloblasts in 12 patients, but subsequent nonresponsiveness emerged due to expansion of LICs bearing D835 mutation.. (First curated: 2020-04-16)

Changed Ivosidenib + Azacitidine in Acute myeloid leukaemia with IDH1 Oncogenic mutations: 3

Comments changed: Phase Ib trial. NCT02677922. N=23. Ivosidenib plus azacitidine in newly diagnosed mIDH1 AML patients ineligible for intensive induction chemotherapy demonstrated an ORR of 78%, CR rate of 61%, 12-month OS of 82%, and was well tolerated.N=23. ORR 78%. CR 61%. OS at 12 months 82%. (First curated: 2021-02-02)

Changed Imatinib in Melanoma with KIT Oncogenic mutations and NOT Amplification: 3

Comments changed: Phase 2 trial. N=25. Imatinib showed a ORR of 29% in metastatic mucosal, acral, or CSD melanoma with KIT amplifications and/or mutations, with higher response rate in KIT mutated (54%) versus KIT amplified only (0%).ORR 54% in KIT mutation. (First curated: 2020-04-15)

Changed Adagrasib in Non-small cell lung cancer, Colorectal adenocarcinoma, Solid tumours with KRAS G12C: 3

Comments changed: Phase 1/2 KRYSTAL-1 trial. NCT03785249. N=79. Adagrasib demonstrated an ORR of 45% and disease control rate of 96% in patients with advanced/metastatic NSCLC harboring KRAS G12C mutation, with a median time on treatment of 8.2 months.KRYSTAL-1. Combined Phase 1&2. ORR 45% (NSCLC), 17% (CRC). (First curated: 2020-11-03)

Changed Adagrasib in Solid tumours, Pancreatic adenocarcinoma, Appendiceal carcinoma, Cholangiocarcinoma, Endometrial carcinoma with KRAS G12C: 3

Comments changed: Phase 1/2. KRYSTAL-1. N=57. NCT03785249. Adagrasib 600mg BD demonstrated an ORR of 35% (20/57), with 33% in PDAC subgroup and 42% in BTC. DCR was 86%. Median DOR was 5.3 months and median PFS was 7.4 months.Not TGA approved. Not FDA approved. Phase 1/2. KRYSTAL-1. N=57. NCT03785249. Adagrasib 600mg BD. ORR was 35% (20/57). DCR was 86%. Median DOR was 5.3 months. ORR was 33% in PDAC subgroup and 42% in BTC. Median PFS was 7.4 months.. (First curated: 2023-04-21)

Changed Savolitinib in Papillary renal cell carcinoma with MET Oncogenic mutations, Amplification: 3

Comments changed: Phase 3 SAVOIR trial. NCT03091192. N=60. Savolitinib showed numerically greater PFS (7.0 months vs 5.6 months), OS, and ORR compared to sunitinib in patients with MET-driven papillary renal cell carcinoma, with fewer grade 3 or higher AEs (42% vs 81%). Statistical significance for the primary endpoint was not demonstrated in the phase 3 SAVOIR trial due to poor recruitment.Type 1 papillary renal cell carcinoma. Note: statistical significance for the primary endpoint, PFS, was not demonstrated in the phase 3 SAVOIR trial due to poor recruitment.. (First curated: 2020-05-30)

Changed Repotrectinib with ROS1 Fusion: 3

Cancer type(s) changed: Solid tumours References changed: 10.1200/JCO.2019.37.15_suppl.9011. (First curated: 2022-01-21)

Changed Repotrectinib with ROS1 Fusion, G2032R: 3

Cancer type(s) changed: Non-small cell lung cancer, Solid tumours (First curated: 2020-06-23)

Changed Ceritinib in Non-small cell lung cancer with ROS1 Fusions: 3

Comments changed: Phase 2 trial. Ceritinib demonstrated clinical activity in patients with ROS1-rearranged NSCLC, with ORR of 62%, median PFS of 9.3 months, and median OS of 24 months, in patients with ROS1-rearranged NSCLC who develop resistance to crizotinib.Positive phase 2 trial.. (First curated: 2020-05-06)

Changed Uprosertib in Breast cancer with AKT3 Oncogenic mutations: 4

Comments changed: Preclinical study. Novel AKT inhibitors (GSK2110183 and GSK2141795) showed anti-tumor effects in mouse tumor models, with enhanced efficacy when combined with MEK inhibitor (GSK2110212; trametinib) in KRAS-driven pancreatic cancer models.. (First curated: 2020-04-16)

Changed Alectinib in Non-small cell lung cancer with ALK VKORC1L1-ALK fusion, T1151K: 4

Comments changed: Case report. A lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation showed a response to alectinib, demonstrating its clinical activity against the T1151K mutation.. (First curated: 2022-03-09)

Changed Mivebresib in Prostate cancer with AR AR-V7, F877L, L702H: 4

Comments changed: Preclinical study. BET inhibitor ABBV-075 inhibited transcription activation downstream of AR and TMPRSS2:ETS fusion proteins, showing antiproliferative activity in models with resistance to second-generation antiandrogens and AR splice variant AR-V7 and gain-of-function mutations, F877L and L702H.Preclinical evidence only. (First curated: 2020-04-23)

Changed Therapy in Glioma with AR Protein expression: 4

Therapy changed: EnzalutamideCYP17A1 inhibitor. Comments changed: Preclinical study. Androgen receptor (AR) was amplified in 27% of glioblastoma specimens from men and 38.2% from women, with overexpression of AR-RNA and AR-protein in 93% and 56% of samples, respectively; AR antagonists induced concentration-dependent death in glioblastoma cell lines, and enzalutamide reduced tumor volume by 72% in human glioma xenografts.Weak evidence. (First curated: 2020-04-16)

Changed Therapy in Solid tumours with BRAF Fusions: 4

Therapy changed: FORE8394, RAF dimer inhibitorPLX8394, RAF dimer inhibitor. (First curated: 2020-04-16)

Changed LY3009120 in Solid tumours with BRAF L485_P490del: 4

Comments changed: Class II BRAF mutations. Preclinical study. Oncogenic BRAF in-frame deletion in the alpha-C helix identified in various cancers were found to be sensitive to RAF dimer inhibitor LY3009120, which showed tumor growth regression in tumor models, whereas vemurafenib was inactive.Class II mutations. BRAF in-frame deletion in the alpha-C helix favour dimerization and is sensitive to LY3009120 but resistant to Vemurafenib. (First curated: 2021-10-19)

Changed Sorafenib in Solid tumours with BRAF L485_P490delinsF, L485_P490delinsY: 4

Comments changed: Preclinical study. BRAFΔβ3-αC in-frame deletion mutants reveals differences in sensitivity with RAF inhibitors.Preclinical study. BRAFΔβ3-αC in-frame deletion mutants reveals differences in sensitivitywith RAF inhibitors.. (First curated: 2024-07-31)

Changed Trametinib in Melanoma with BRAF L597, L597Q: 4

Comments changed: Retrospective analysis of 5 patients with non-V600 BRAF mutation (K601E and L597Q) metastatic melanoma showed 3 patients achieved partial response to trametinib, with manageable toxicity and reduced phospho-ERK signalling in paired biopsies.Single case report. (First curated: 2020-04-16)

Changed Therapy in Solid tumours with BRAF L597, L597Q, K601, K601E: 4

Therapy changed: FORE8394PLX8394. (First curated: 2020-06-09)

Changed Dabrafenib + Trametinib in Melanoma with BRAF T599_V600insT: 4

Comments changed: Case reports. BRAF T599dup-mutated melanoma patients showed response to BRAF and MEK inhibitors.Case series.. (First curated: 2023-12-22)

Changed Vemurafenib + Cobimetinib in Pancreatic adenocarcinoma with BRAF T599_V600insT: 4

Comments changed: Retrospective case series of 81 patients with RAF family-mutated pancreatic cancer showed varied responses to targeted and standard therapies across different RAF mutational subgroups: BRAF V600/Exon 15, BRAF or RAF1 fusions, and Exon 11 mutations. One case with T599 duplication had 20 weeks duration of therapy.Case report. Duration of therapy was 20 week. (First curated: 2022-02-08)

Changed Therapy in Solid tumours with BRAF V600E: 4

Therapy changed: FORE8394PLX8394. Comments changed: Preclinical study. RAF inhibitor FORE8394 disrupts BRAF dimers and selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants and BRAF V600 monomers.Preclinical study. RAF inhibitor PLX8394 disrupts BRAF dimers and selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants and BRAF V600 monomers.. (First curated: 2020-06-09)

Changed Abemaciclib, Palbociclib in Non-small cell lung cancer with CDKN2A Loss of protein expression: 4

Comments changed: Phase 2 clinical trial and preclinical study. Palbociclib showed stable disease in 50% of p16-null NSCLC patients with median OS of 16.6 months, and preclinical data showed synergy with mTOR inhibition, particularly in tumors carrying RAS mutations.Cytostatic. (First curated: 2020-04-23)

Changed Osimertinib in Non-small cell lung cancer with EGFR Kinase domain duplication: 4

Comments changed: Case reports. Two NSCLC patients with EGFR kinase domain duplication (KDD) mutation, one of whom achieved stable disease with osimertinib after resistance to afatinib, highlighting osimertinib as a potential effective therapy following resistance to first- and second-generation EGFR-TKIs.. (First curated: 2021-12-06)

Changed Afatinib in Non-small cell lung cancer with EGFR L747P, L747S: 4

Comments changed: Preclinical and clinical study. Afatinib showed improved PFS (11.97 months) and ORR (80%) in patients with lung adenocarcinoma harboring uncommon EGFR p.L747P and p.L747S mutations, with no patients acquiring p.T790M resistance after afatinib failure.Retrospective sample. (First curated: 2020-06-08)

Changed Afatinib, Osimertinib in Non-small cell lung cancer with EGFR L747S, D761Y, T854A: 4

Comments changed: Preclinical study. Irreversible EGFR-TKIs showed efficacy against uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A.Cell line study. (First curated: 2020-04-16)

Changed Gefitinib in Non-small cell lung cancer with EGFR : 4

Alterations changed: L833V, H835L. Comments changed: Case report. A lung adenocarcinoma patient with a heterozygous complex mutation of L833V and H835L in the EGFR gene showed a good response to gefitinib treatment.. (First curated: 2020-06-11)

Changed Afatinib, Osimertinib in Non-small cell lung cancer with EGFR T751_I759delinsS: 4

Comments changed: Case report. Lung adenocarcinoma patient with rare EGFR T751_I759delinsS mutation showed initial good response to afatinib and subsequent response to osimertinib after developing resistance to afatinib, highlighting potential treatment options for patients with rare EGFR mutations.. (First curated: 2021-11-10)

Changed Erlotinib + Osimertinib in Non-small cell lung cancer with EGFR T790M and C797S and T790M-C797S trans-allelic conformation: 4

Comments changed: Case report. Lung adenocarcinoma with EGFR 19Del/T790M/in trans-C797S mutations demonstrated durable clinical response to combined first- and third-generation EGFR tyrosine kinase inhibitor therapy.. (First curated: 2020-05-15)

Changed AMG-596 in Glioma, Glioblastoma with EGFR vIII: 4

Comments changed: Preclinical study. EGFRvIII-targeted bispecific T-cell engager shows therapeutic activity in glioblastoma by redirecting T cells to eliminate EGFRvIII-expressing GBM cells.. (First curated: 2020-04-16)

Changed Erlotinib, Lapatinib in Glioblastoma with EGFR vIII, EGFR-SEPT14 fusion: 4

Comments changed: Preclinical study. Integrated analysis of genomic alterations in glioblastoma revealed LZTR1 mutations with loss of heterozygosity, CTNND2 loss-of-function mutations associated with mesenchymal phenotype, and EGFR fusions (e.g., EGFR-SEPT14) that activate STAT3 signaling and confer sensitivity to EGFR inhibition.Xenograft model.. (First curated: 2023-04-05)

Changed Dabrafenib + Trametinib + Osimertinib in Non-small cell lung cancer with EGFR+BRAF EGFR:Oncogenic mutations and BRAF:V600E: 4

Comments changed: Case report. A patient with EGFR-mutant/BRAF V600E lung adenocarcinoma showed impressive radiological and ctDNA response to combination therapy with dabrafenib, trametinib, and osimertinib, suggesting potential efficacy in patients with acquired BRAF V600E resistance mutation.. (First curated: 2021-05-28)

Changed MK-2206 + Gemcitabine in Solid tumours with EGFR+ERRFI1 EGFR:low expression AND ERRFI1:Oncogenic mutations: 4

Comments changed: Cell line study. ERRFI1 differentially regulates EGFR and AKT pathways in a context-dependent manner, promoting cell growth and chemotherapy desensitization in EGFR-low cells while inhibiting growth in EGFR-high cells. AKT inhibitors sensitize cells to chemotherapy.Cell line study of effect of EFFRI1. AKT inhibitor sensitises cell to chemotherapy. (First curated: 2020-11-17)

Changed Therapy in Non-small cell lung cancer with EGFR+MET EGFR:Oncogenic mutations and MET:amplification and NOT EGFR:T790M: 4

Therapy changed: Gefitinib + CapmatinibGefitinib + Savolitinib. Comments changed: Phase Ib/II study. Capmatinib plus gefitinib showed clinical activity in patients with EGFR-mutated, MET-dysregulated NSCLC who progressed on EGFR-TKI, particularly in those with high MET-amplified tumors (ORR 47% with MET gene copy number ≥ 6), addressing a predominant EGFR-TKI resistance mechanism.. (First curated: 2020-06-23)

Changed Osimertinib + Crizotinib in Non-small cell lung cancer with EGFR+MET EGFR:T790M and MET:amplification: 4

Comments changed: Case report. MET amplification emerged as a resistance mechanism after T790M positivity in EGFR-mutant NSCLC, and was effectively targeted with a combination of crizotinib and osimertinib, showing tolerability and efficacy.Case reports. References changed: 28274743, 30881166, 31157314. (First curated: 2020-06-29)

Changed Osimertinib + Pralsetinib in Non-small cell lung cancer with EGFR+RET EGFR:Oncogenic mutations and RET:fusion: 4

Comments changed: Preclinical study and case reports. RET fusions, such as CCDC6-RET, were identified as a mechanism of acquired resistance to osimertinib in EGFR-mutant NSCLC, and combined EGFR and RET inhibition with osimertinib and BLU-667 showed effectiveness in treating patients with RET-mediated resistance.Two case reports. (First curated: 2020-10-05)

Changed Osimertinib + Crizotinib in Non-small cell lung cancer with EGFR+ROS1 EGFR:Oncogenic mutations and ROS1:fusion: 4

Comments changed: Preclinical study. GOPC-ROS1 rearrangement identified as an acquired resistance mechanism to osimertinib, with observed response to crizotinib combined treatments in lung adenocarcinoma.Case report. (First curated: 2020-10-05)

Changed Lapatinib + Trastuzumab in Breast cancer with ERBB2 D769Y, R896C: 4

Comments changed: Preclinical study. Activating HER2 mutations identified in 25 breast cancer patients lacking HER2 gene amplification were functionally characterized, showing sensitivity to neratinib, an irreversible HER2 inhibitor, but variable response to lapatinib.. (First curated: 2022-03-30)

Changed Afatinib in Non-small cell lung cancer with ERBB2 Exon 16 skipping mutation: 4

Comments changed: Preclinical study. HER2 ex16 deletion, a novel HER2 splice variant, was identified as a potential osimertinib resistance mechanism in EGFR L858R/T790M-positive NSCLC, and its resistance was synergistically reversed by combining osimertinib with afatinib.. (First curated: 2021-03-11)

Changed Neratinib in Breast cancer with ERBB2 G309A, V777L, D769H, V842I, L755S, L755_759del: 4

Comments changed: Preclinical study. HER2 somatic mutations identified in 25 breast cancer patients without HER2 gene amplification, with 7 activating mutations sensitive to neratinib, suggesting potential benefit of HER2-targeted therapy.. (First curated: 2022-03-30)

Changed Trastuzumab, Ado-Trastuzumab Emtansine in Gastric cancer with ERBB2 MDK-ERBB2 fusion, Fusions: 4

Comments changed: Biomarker analysis. Whole-transcriptome sequencing identified 3 novel HER2 fusions (ZNF207-HER2, MDK-HER2, and NOS2-HER2) in 14% of 21 HER2-amplified gastric cancer samples. Trastuzumab showed activity in MDK-HER2 but not ZNF207-HER2 expressing xenografts due to differential binding.. (First curated: 2021-05-20)

Changed Afatinib in Lung adenocarcinoma with ERBB2 Oncogenic mutations: 4

Comments changed: Phase 2 study. In Cohort 3, one unconfirmed response from seven patients (5 SD). Note individual and concomitant mutations not reported.One unconfirmed response from seven patients (5 SD). Individual and concomitant mutations not reported.. (First curated: 2020-04-16)

Changed Margetuximab in Solid tumours with ERBB2 Overexpression: 4

Comments changed: Phase 1 study. NCT01148849. N=66. Margetuximab showed single-agent activity in patients with HER2-positive advanced solid tumors, with 12% (7/60) confirmed partial responses and 50% (30/60) stable disease, including durable responses in breast cancer patients.. (First curated: 2020-12-18)

Changed GQ1001 in Solid tumour with ERBB2 Overexpression, Amplification: 4

Comments changed: Preclinical study. GQ1001, a next-generation HER2-targeting ADC, demonstrated robust anti-tumor activity in HER2-positive models, including those resistant to anti-HER2 TKIs and/or mAbs, with enhanced linker stability and reduced off-target toxicity.. (First curated: 2023-12-06)

Changed Afatinib, Neratinib, Poziotinib in Acute myeloid leukaemia with ERBB2 : 4

Alterations changed: R188C, P489L, L1157R. Comments changed: Preclinical study. ERBB2 mutations (R188C, P489L, and L1157R) identified in leukaemia patients are oncogenic and sensitive to irreversible pan-HER inhibitors, such as afatinib, neratinib, and poziotinib, with nanomolar IC50 values, and to trastuzumab, particularly for extracellular domain mutants. Updated: 2025-05-28. (First curated: 2023-01-11)

Changed Lapatinib + Capecitabine in Extramammary Paget’s disease with ERBB2 S310F: 4

Comments changed: Case report. A patient with metastatic extramammary Paget's disease associated with adnexal adenocarcinoma harbouring ERBB2 S310F mutation responded to anti-HER2 drugs.. (First curated: 2020-06-09)

Changed Trastuzumab + Carboplatin in Extramammary Paget’s disease with ERBB2 S310F: 4

Comments changed: Case report. A patient with ERBB2(S310F) mutated metastatic extramammary Paget's disease initially responded to trastuzumab and carboplatin, but developed resistance with additional genomic alterations including ERBB3(A232V) and PIK3CA(G106V) mutations and MET and CDK6 amplification.. (First curated: 2020-06-09)

Changed Pyrotinib in Breast cancer with ERBB2 : 4

Alterations changed: S310F, S310Y, L403V, L755S, D769Y, A775_Y776insYVMA (Y772_A775dup), V777L, T862AS310F, S310Y, L403V, L755S, D769Y, A775_Y776insYVMA, V777L, T862A. Comments changed: Phase 2 trial. NCT03412383. Pyrotinib monotherapy achieved an ORR of 40% and CBR of 60% in HER2 amplification-negative, mutation-positive metastatic breast cancer patients, with a median PFS of 4.9 months. Responses or prolonged SD were seen in S310F, L755S, D769Y, V777L, T862A, and A775_Y776insYVMA (Y772_A775dup).. (First curated: 2021-07-06)

Changed Lapatinib, Afatinib in Urothelial carcinoma with ERBB2 S310F, S653C, D277H and S310F: 4

Comments changed: Preclinical study. ERBB2 mutations were found in 15% of urothelial bladder cancer cell lines, and these mutations enhanced ErbB2 activation and predicted a response to lapatinib, with 93% reversal of mutant-induced growth patterns.. (First curated: 2020-09-15)

Changed Trastuzumab, Pertuzumab, Afatinib, Neratinib, Lapatinib in Solid tumours with ERBB2 V659E, G660D, G660R, R678Q, V697L, Q709, Transmembrane domain mutation, Juxtamembrane domain mutation: 4

Comments changed: Preclinical study. Activating HER2 transmembrane and juxtamembrane domain mutations (G660D, R678Q, E693K, Q709L) identified in patient tumors were found to be sensitive to anti-HER2 antibodies and small-molecule kinase inhibitors, with a germline G660D mutant lung cancer patient showing clinical response to HER2 blockade.. (First curated: 2021-06-23)

Changed H3Mab-17 in Colorectal adenocarcinoma with ERBB3 Overexpression: 4

Comments changed: Preclinical study. Anti-HER3 monoclonal antibody H(3)Mab-17 showed antitumor activity, inducing ADCC and CDC against Caco-2 cells and significantly reducing tumor growth in a Caco-2 xenograft model.. (First curated: 2021-07-28)

Changed Palbociclib in Breast cancer with ESR1 Fusion, ESR1-YAP1 fusion, ESR1-PCDH11X fusion: 4

Comments changed: Preclinical study. ESR1 gene fusions in ER-positive breast cancer confer estrogen-independent growth, anti-estrogen resistance, and metastatic progression, but remain sensitive to CDK4/6 inhibitors.. (First curated: 2022-12-07)

Changed AZD9496 in Breast cancer with ESR1 Protein expression: 4

Comments changed: Phase 1 trial. AZD9496, an oral selective estrogen receptor degrader, showed evidence of prolonged disease stabilization in heavily pretreated ER(+)/HER2(-) advanced breast cancer patients, with a partial response in one patient and stable disease at 12 months in four patients.. (First curated: 2020-04-16)

Changed Cisplatin in Solid tumours with FANCA S1088F: 4

Comments changed: Preclinical study. Germline FANCA S1088F mutation disrupts FANC protein complex, resulting in increased sensitivity to DNA damaging agents, suggesting potential predictive biomarker for prostate cancer treatment response.Case report. (First curated: 2020-04-16)

Changed Therapy in Head and neck squamous cell carcinoma with FANCC Loss of protein expression: 4

Therapy changed: OlaparibPARP inhibitor. Comments changed: Preclinical study. Fanconi anemia head and neck cancers acquired relative interstrand crosslinker resistance and PARP inhibitor sensitivity, with increased PARP-mediated DNA damage sensing and repair in Fanconi anemia-deficient cells.Preclinical data only. (First curated: 2020-04-16)

Changed Therapy in Pancreatic adenocarcinoma with FANCG Oncogenic mutations: 4

Therapy changed: ATM inhibitor, KU-55933. Comments changed: Preclinical study. FA pathway-deficient tumor cells are sensitive to ATM inhibition, suggesting a potential therapeutic strategy for tumors with FA pathway dysfunction, particularly in cancers with FA pathway deficiency such as certain breast, ovarian, pancreatic, and hematological tumors.Preclinical data only. (First curated: 2020-04-16)

Changed PRN1371 in Hepatocellular carcinoma with FGF19 Amplification: 4

Comments changed: FGF19-FGFR4 signaling pathway is a potential target for HCC treatment, with various FGFR4/pan-FGFR inhibitors in different clinical trial phases, offering future perspectives for improving efficacy in relation to aberrant FGF19-FGFR4 expression.Cell line study. (First curated: 2020-04-16)

Changed Erdafitinib in Solid tumours with FGFR1 Amplification, Fusion, Oncogenic mutations and NOT V561: 4

Comments changed: Phase 1 study. NCT01703481. Erdafitinib showed clinical activity in advanced solid tumors with FGFR mutations or fusions, particularly in urothelial carcinoma (ORR 46.2%) and cholangiocarcinoma (ORR 27.3%), with median response durations of 5.6 and 11.4 months, respectively.NCT01703481, ORR 46.2%. (First curated: 2020-06-11)

Changed AZD4547 in Solid tumours with FGFR1 : 4

Alterations changed: FusionsAmplification, Fusion, Oncogenic mutations. Comments changed: Phase 2 NCI-MATCH trial (arm W). Patients with tumors harboring FGFR aberrations treated with AZD4547 showed confirmed partial responses in 8% of patients, limited to those with FGFR1-3 point mutations or fusions, with a higher response rate of 22% in patients with FGFR fusions.No response in these cohorts. References changed: 32463741, 10.1200/JCO.2018.36.15_suppl.2503, 10.1200/jco.2014.32.15_suppl.803510.1200/JCO.2018.36.15_suppl.2503, 10.1200/jco.2014.32.15_suppl.8035, 32463741. (First curated: 2020-06-11)

Changed Erdafitinib in Non-small cell lung cancer with FGFR2 FGFR2-BICC1 fusion: 4

Comments changed: Case report showing partial response to erdafitinib. Updated: 2022-02-16. References changed: 35050756, 10.1200/PO.20.00110. (First curated: 2021-04-06)

Changed Lirafugratinib in Cholangiocarcinoma with FGFR2 FGFR2-TTC28 fusion, FGFR2-OPTN fusion, K310R, V564F, V564L, M537I, N549D, N549K, N549H, V564I, E565A, L617V, K641N, K659M: 4

Comments changed: Preclinical study. RLY-4008, a highly selective FGFR2 inhibitor, showed activity across various FGFR2 alterations and resistance mutations, inducing regression in xenograft models with FGFR2 resistance mutations while sparing FGFR1 and FGFR4, suggesting broad therapeutic potential in FGFR2-driven cancers.. (First curated: 2024-09-25)

Changed AZD4547 in Solid tumours with FGFR3 Fusions: 4

Comments changed: Phase 2 NCI-MATCH trial (arm W). Patients with tumors harboring FGFR aberrations treated with AZD4547 showed confirmed partial responses in 8% of patients, limited to those with FGFR1-3 point mutations or fusions, with a higher response rate of 22% in patients with FGFR fusions.Response in small numbers (2/9). References changed: 10.1200/JCO.2018.36.15_suppl.2503, 32463741. (First curated: 2020-06-11)

Changed TYRA-300 in Solid tumours with FGFR3 Fusions, FGFR3-TACC3 fusion, V555M, V555L, V555G, V555K, K650M, K650E, Oncogenic mutations, S249C, R248C, Y373C, G370C: 4

Comments changed: Preclinical study. TYRA-300 is a potent FGFR3-selective inhibitor targeting FGFR3 alterations in urothelial cancers and achondroplasia. It was designed to be effective against activating FGFR3 mutations and gatekeeper resistance mutations (V555L/M). Preclinical studies demonstrate significant FGFR3 isoform selectivity, potentially limiting toxicities observed with pan-FGFR inhibitors.. References changed: 10.1016/j.annonc.2022.07.591, 32463741. (First curated: 2022-10-13)

Changed Ponatinib, Dovitinib in Cholangiocarcinoma with FGFR3 N540K, V555M, L608V: 4

Comments changed: Preclinical study and case series. Polyclonal secondary FGFR2 mutations in the kinase domain were identified in cfDNA and biopsies of FGFR2 fusion-positive cholangiocarcinoma patients, driving acquired resistance to FGFR inhibitor BGJ398, and were surmountable by distinct FGFR inhibitors.. (First curated: 2023-02-22)

Changed Trametinib in Non-small cell lung cancer with GNAS R201C, R201H: 4

Comments changed: Case report. A NSCLC patient with osimertinib resistance harboring GNAS R201C and R201H mutations showed stable disease when treated with trametinib.. (First curated: 2023-12-14)

Changed Trametinib in Appendiceal cancer with GNAS R201H: 4

Comments changed: Case report. A patient with appendiceal adenocarcinoma and a GNAS R201H mutation experienced clinical benefit from trametinib, with a decrease in tumor markers and improvement in quality of life.. (First curated: 2023-12-14)

Changed Cisplatin in Breast cancer with Homologous Recombination Deficiency Score High: 4

Comments changed: Preclinical and clinical study. Homologous recombination deficiency (HRD) score, defined as HRD score ≥42 or BRCA1/2 mutation, predicts response to platinum-containing neoadjuvant chemotherapy in triple-negative breast cancer patients, including those with BRCA1/2 nonmutated tumors with high HRD scores.. (First curated: 2020-04-16)

Changed HB-201, HB-201 + HB-202 in HPV16-positive cancers with HPV genotype HPV16-positive: 4

Comments changed: Phase 1/2 study. NCT04180215. HB-201 monotherapy demonstrated preliminary antitumor activity in 16 HPV16+ cancer patients (predominantly HNSCC) with 2 partial responses and 6 stable disease outcomes. Alternating HB-201 and HB-202 therapy achieved stable disease in 2 of 2 patients.. (First curated: 2021-06-21)

Changed Selumetinib, Cobimetinib, PD0325901 in Solid tumours with HRAS Oncogenic mutations: 4

Comments changed: Preclinical study. Mutant HRAS cancer cell lines showed sensitivity to MEK inhibitors (AZD6244, MEK162, and PD0325901) and mTOR inhibition, with synergistic effects observed with combined MEK and mTOR inhibition, suggesting a potential therapeutic target for HRAS mutant tumors.Cell line study. (First curated: 2020-04-16)

Changed Olutasidenib in Glioma with IDH1 R132: 4

Comments changed: Phase Ib/II trial. Olutasidenib demonstrated preliminary clinical activity in patients with relapsed/refractory IDH1-mutant glioma, with 8% achieving partial response and 32% having stable disease, in those harbouring IDH1 R132 mutations.. References changed: 35639513, 10.1200/JCO.2020.38.15_suppl.2505. (First curated: 2020-05-30)

Changed Therapy in Gastrointestinal stromal tumour with KIT Exon 11 mutation, Exon 11 deletion, K642E, D816E, D816F, D816H, D816I, D816V, D816Y, D820E, D820Y, Y823D, A829P: 4

Therapy changed: BezuclastinibPLX9486. (First curated: 2023-06-27)

Changed Sorafenib in Gastrointestinal stromal tumour with KIT V560D, A502_Y503dup, V654A, T670I, D820A, D820E, D820G, D820Y, N822H, N822K, Y823D, A829P: 4

Comments changed: Preclinical study. Sorafenib inhibits various KIT and PDGFRA mutant kinases associated with imatinib-resistant or sunitinib-resistant gastrointestinal stromal tumors (GIST), except for substitutions at KIT codon D816 and PDGFRA codon 842.. (First curated: 2022-01-25)

Changed Therapy in Melanoma with MAP2K2 Q60P: 4

Therapy changed: Dabrafenib + Trametinib + Omipalisib. Tier changed: 4R2. Comments changed: Preclinical study. Concurrent MEK2-Q60P mutation and BRAF amplification/V600E were identified in melanoma cells resistant to BRAF and MEK inhibitors, conferring sustained MAPK activation and on-target resistance, which was addressed by a triple combination of dabrafenib, trametinib, and GSK2126458.. (First curated: 2020-05-31)

Changed Anetumab Ravtansine with MSLN Protein expression, Overexpression: 4

Cancer type(s) changed: Solid tumours, Mesothelioma, Ovarian cancer Comments changed: Phase 1 study. Anetumab ravtansine showed clinical activity in patients with high mesothelin expression, with 1 complete response and 11 partial responses among 148 patients with various solid tumors, including mesothelioma and ovarian cancer.. (First curated: 2020-06-28)

Changed Everolimus in Urothelial carcinoma with MTOR E2014K, E2419K: 4

Comments changed: Phase 2 study. Everolimus showed biological activity in a subset of patients with advanced urothelial carcinoma, with 2 partial responses and 12 minor regressions, suggesting a potential role for mTOR pathway inhibition, although no clear association was observed between mTOR pathway marker expression and response.. (First curated: 2020-04-16)

Changed Temsirolimus in Renal cell carcinoma with MTOR L1460P, L2209V, L2427Q: 4

Comments changed: Retrospective observational study. Mutations in MTOR, TSC1, or TSC2 were associated with response to rapalogs in metastatic renal cell carcinoma patients, with higher frequency of mutations in responders (28%) compared to nonresponders (11%).OncoKB LOE 3; Retrospective association only. (First curated: 2020-04-16)

Changed Temsirolimus in Breast cancer with MTOR Oncogenic mutations: 4

Comments changed: Phase 2 study. Temsirolimus showed antitumor activity with an ORR of 9.2% in heavily pretreated patients with locally advanced or metastatic breast cancer, with similar efficacy observed at both 75mg and 250mg doses.. (First curated: 2020-04-16)

Changed Everolimus in Renal cell carcinoma with MTOR Q2223K: 4

Comments changed: Retrospective observational study. Mutations in MTOR, TSC1, or TSC2 were associated with response to rapalogs in metastatic renal cell carcinoma patients, with higher frequency of mutations in responders (28%) compared to nonresponders (11%).OncoKB LOE 3; Retrospective association only. (First curated: 2020-04-16)

Changed Sapanisertib + Metformin in Solid tumours with MTORC1 Oncogenic mutations: 4

Comments changed: Phase 1 trial. NCT03017833. N=30. Sapanisertib + metformin showed anti-tumor activity in patients with mTOR/AKT/PI3K pathway alterations, including 4 patients achieving partial response, 3 of whom had PTEN mutations and 1 had AKT and mTOR mutation.. (First curated: 2021-06-18)

Changed CX-5461 in Neuroblastoma with MYC Amplification, Overexpression: 4

Comments changed: Preclinical study. CX-5461 down-regulates MYCN protein and suppresses neuroblastoma tumor growth, particularly in MYCN-amplified tumors. Xenograft models using the KELLY cell line demonstrate orthotopic tumor growth suppression following CX-5461-induced MYCN downregulation.Xenograft model established on KELLY cell line CX-5461 leads to MYCN downregulation and suppress orthotopic tumour growth.. (First curated: 2021-03-06)

Changed CX-5461 in Small-cell lung cancer with MYCL Overexpression: 4

Comments changed: Preclinical study. MYCL amplification in SCLC promotes tumor-forming capacity and ribosomal biogenesis, and deletion of Mycl suppresses SCLC, suggesting RNA Pol I inhibition as a potential therapeutic target, which showed significant tumor inhibition in an autochthonous Rb/p53-deleted mouse SCLC model.. (First curated: 2021-06-12)

Changed Enfortumab Vedotin in Solid tumours with NECTIN4 Protein expression: 4

Comments changed: Phase 1 EV-101 study. Enfortumab vedotin showed antitumor activity in Nectin-4-positive metastatic urothelial carcinoma patients, with an ORR of 43% and median OS of 12.3 months, indicating sensitivity to the drug in heavily pretreated patients.. (First curated: 2022-06-11)

Changed Trametinib in Glioblastoma with NF1 Oncogenic mutations (germline): 4

Comments changed: Case report. A 24-year-old male with neurofibromatosis type I-associated glioblastoma showed clinical and radiological benefit from the MEK inhibitor, trametinib.. (First curated: 2020-05-14)

Changed RMC-4550 in Solid tumours with NF1 Oncogenic mutations, Loss-of-function mutations, N184fs, Q1336*: 4

Comments changed: Preclinical study. SHP2 phosphatase inhibitor RMC-4550 was effective in human cancer models with RAS-GTP-dependent oncogenic BRAF (class 3 BRAF mutants), NF1 loss, or nucleotide-cycling oncogenic RAS (KRAS(G12C)), by disrupting SOS1-mediated RAS-GTP loading and decreasing oncogenic RAS/RAF/MEK/ERK signalling.Cell line study.. (First curated: 2022-02-04)

Changed Mirdametinib + JQ1 in Malignant peripheral nerve sheath tumor with NF1+SUZ12 NF1:Loss-of-function mutations AND SUZ12:Loss-of-function mutations: 4

Comments changed: Preclinical study. Loss of PRC2 component SUZ12 sensitizes cancers with NF1 mutations to BRD4-based therapies by amplifying Ras-driven transcription.. (First curated: 2020-11-26)

Changed Everolimus + Docetaxel in Urothelial carcinoma with NF2 Loss-of-function mutations: 4

Comments changed: Case report. Exceptional response observed in urothelial carcinoma bearing an NF2 mutation when treated with everolimus in combination with taxane.. (First curated: 2020-10-08)

Changed VT104 in Mesothelioma with NF2 Oncogenic mutation, Deletion: 4

Comments changed: Preclinical study. Small molecule inhibitors of TEAD auto-palmitoylation selectively inhibit proliferation and tumor growth of NF2-deficient mesothelioma, providing a potential therapeutic strategy for targeting the Hippo-YAP pathway in YAP-driven cancers.. (First curated: 2023-06-28)

Changed SCH772984 in Solid tumours with NRAS Oncogenic mutations: 4

Comments changed: Preclinical study. SCH772984, a novel ERK1/2 inhibitor, showed activity in models with BRAF, NRAS, or KRAS mutations and effectively inhibited MAPK signaling in BRAF or MEK inhibitor-resistant models.. (First curated: 2022-01-15)

Changed Zenocutuzumab in Solid tumours with NRG1 Fusion: 4

Comments changed: Case series and preclinical study. MCLA-128, a bispecific HER2/3 antibody, showed clinical responses in patients with NRG1 fusion-positive cancers, including pancreatic ductal adenocarcinoma and non-small cell lung cancer, by inhibiting ligand-driven activation of the HER3 pathway.. (First curated: 2020-05-31)

Changed Zenocutuzumab in Solid tumours with NRG1 Fusion, CD74-NRG1 fusion, CLU-NRG1 fusion, ATP1B1-NRG1 fusion, SLC3A2-NRG1 fusion, APP-NRG1 fusion: 4

Comments changed: Preclinical and case series study. Zenocutuzumab, a HER2xHER3 bispecific antibody, showed effectiveness in NRG1 fusion-positive cancer models and patients. In a cohort of 3 patients with NRG1 fusion-positive metastatic cancer, 2 achieved rapid and durable responses: 2 pancreatic cancer patients with ATP1B1-NRG1 fusion and 1 non-small cell lung cancer patient with CD74-NRG1 fusion.N=3. 2/3 patients with NRG1 fusion-positive metastatic cancer achieved rapid responses, including 2 with ATP1B1-NRG1 pancreatic cancer and 1 with CD74-NRG1 non-small cell lung cancer.. (First curated: 2024-12-06)

Changed Seribantumab in Breast cancer, Non-small cell lung cancer, Ovarian cancer, Solid tumours with NRG1 Fusion, DOC4-NRG1 fusion, SLC3A2-NRG1 fusion, CD74-NRG1 fusion: 4

Comments changed: Preclinical study. Seribantumab effectively inhibits growth of patient-derived and isogenic cell line and xenograft models with oncogenic NRG1 fusions in breast, lung, and ovarian cancers, inducing tumor regression by blocking activation of ERBB family members and downstream signaling.Seribantumab inhibits in vitro and in vivo of NRG1 fusion in breast, lung, and ovarian patient-derived cancer models.. (First curated: 2022-05-17)

Changed Lumretuzumab + Erlotinib in Non-small cell lung cancer with NRG1 Fusion; SLC3A2-NRG1 fusion: 4

Comments changed: Case reports. Two patients with invasive mucinous lung adenocarcinoma harboring NRG1 fusion achieved at least 16 weeks of progression-free survival when treated with lumretuzumab, an anti-HER3 antibody, in combination with erlotinib.Case report of invasive mucinous adenocarcinoma of lung. NRG fusion. (First curated: 2021-03-31)

Changed Afatinib in Non-small cell lung cancer with NRG1 Fusions: 4

Comments changed: Registry study. NRG1 fusion-positive lung cancers showed varied clinicopathologic features and responded poorly to chemotherapy (ORR 13-14%) and immunotherapy (ORR 0-20%), but afatinib achieved an ORR of 25% regardless of fusion type. CD74-NRG1 and non-CD74-NRG1 have similar ORR (22% and 27% respectively).Retrospective registry-based study. Afatinib ORR 25%. CD74-NRG1 and non-CD74-NRG1 have similar ORR (22% and 27% respectively).. (First curated: 2021-06-08)

Changed Afatinib in Pancreatic adenocarcinoma with NRG1 Fusions, ATP1B1-NRG1 fusion: 4

Comments changed: Preclinical study and case series. NRG1 gene fusions were identified in KRAS wild-type pancreatic ductal adenocarcinoma. Two patients with NRG1 fusion-positive tumors treated with afatinib demonstrated significant and rapid response.. (First curated: 2021-06-25)

Changed Zenocutuzumab in Breast cancer with NRG1 SLC3A2-NRG1 fusion: 4

Comments changed: Case report. Sustained tumor regression observed with Zenocutuzumab, a bispecific antibody targeting HER2/HER3 signaling, in NRG1 fusion-positive, estrogen receptor-positive breast cancer.. (First curated: 2023-04-20)

Changed Larotrectinib in Oesophageal squamous cell carcinoma with NTRK1 Amplification: 4

Comments changed: Case report. A patient with metastatic esophageal carcinoma harboring NTRK1 gene amplification showed significant tumor shrinkage and decrease in tumor markers after treatment with larotrectinib, suggesting potential efficacy of larotrectinib in cases with NTRK gene amplification.Single case report showing partial response to larotrectinib with DOR 3.7 month.. (First curated: 2021-03-24)

Changed ICP-723 in Solid tumours with NTRK1 Fusion: 4

Comments changed: Phase 1/2 trial. NCT04685226. ICP-723, a next-generation pan-TRK inhibitor, showed encouraging efficacy in patients with NTRK gene fusion positive tumors with an ORR of 66.7% (4 PR) and DCR of 100%, including intracranial activity in a patient with brain metastasis, and demonstrated activity against various tumor types.Phase 1. NCT04685226. Four of 6 responders with NTRK fusion. (First curated: 2022-06-04)

Changed Taletrectinib in Solid tumours with NTRK1 Fusion: 4

Comments changed: Preclinical study. DS-6051b induces growth inhibition in NTRK-rearranged cancers in vitro and in vivo.. (First curated: 2020-04-30)

Changed ICP-723 in Solid tumours with NTRK2 Fusion: 4

Comments changed: Phase 1/2 trial. NCT04685226. ICP-723, a next-generation pan-TRK inhibitor, showed encouraging efficacy in patients with NTRK gene fusion positive tumors with an ORR of 66.7% (4 PR) and DCR of 100%, including intracranial activity in a patient with brain metastasis, and demonstrated activity against various tumor types.Phase 1. NCT04685226. Four of 6 responders with NTRK fusion. (First curated: 2022-06-04)

Changed Taletrectinib in Solid tumours with NTRK2 Fusion: 4

Comments changed: Preclinical study. DS-6051b induces growth inhibition in NTRK-rearranged cancers in vitro and in vivo.. (First curated: 2020-04-30)

Changed Larotrectinib in Ependymoma with NTRK2 KANK1-NTRK2 fusion: 4

Comments changed: Case report. Recurrent disseminated ependymoma harboring a KANK1-NTRK2 fusion experienced a durable response to larotrectinib, a TRK inhibitor, with significant clinical and radiographic improvement, highlighting the importance of integrated genomic profiling in pediatric CNS tumors with NTRK fusions.. References changed: 3465109510.1200/PO.20.00375. (First curated: 2021-08-19)

Changed ICP-723 in Solid tumours with NTRK3 Fusion: 4

Comments changed: Phase 1/2 trial. NCT04685226. ICP-723, a next-generation pan-TRK inhibitor, showed encouraging efficacy in patients with NTRK gene fusion positive tumors with an ORR of 66.7% (4 PR) and DCR of 100%, including intracranial activity in a patient with brain metastasis, and demonstrated activity against various tumor types.Phase 1. NCT04685226. Four of 6 responders with NTRK fusion. (First curated: 2022-06-04)

Changed Taletrectinib in Solid tumours with NTRK3 Fusion: 4

Comments changed: Preclinical study. DS-6051b induces growth inhibition in NTRK-rearranged cancers in vitro and in vivo.. (First curated: 2020-04-30)

Changed Therapy in Pancreatic adenocarcinoma with PALB2 Loss-of-function mutations: 4

Therapy changed: Cisplatin + Gemcitabine, Cisplatin + Gemcitabine + VeliparibPARP inhibitor. Comments changed: Phase 2 trial. Significant responses observed in patients with pancreas adenocarcinoma and germline BRCA/PALB2 mutation, with Response Rate (RR) of 74.1% and 65.2% in patients treated with cisplatin and gemcitabine with or without veliparib, respectively.. References changed: 28242752, 31976786, 31806540, NCT01682772. (First curated: 2020-04-25)

Changed Therapy in Prostate cancer with PALB2 Oncogenic mutations: 4

Therapy changed: RucaparibPARP inhibitor. Comments changed: Phase 2 TRITON2 trial. NCT02952534. Responses to Rucaparib observed in patients with PALB2 alterations, among other DDR-associated genes, but limited responses seen in patients with ATM, CDK12, or CHEK2 alterations.. (First curated: 2020-04-25)

Changed Talazoparib in Prostate cancer with PALB2 Oncogenic mutations: 4

Comments changed: Phase 2 TALAPRO-1 trial. NCT03148795. Talazoparib demonstrated antitumour activity in metastatic castration-resistant prostate cancer with DDR-HRR gene alterations, achieving an objective response rate of 29.8% (31/104) in patients with measurable soft-tissue disease. In the PALB2 subgroup (N=4), 1 confirmed partial response was observed.TALAPRO-1. Phase 2. N=4. 1 PR.. (First curated: 2021-09-09)

Changed FOLFIRINOX in Pancreatic adenocarcinoma with PALB2 Oncogenic mutations (germline): 4

Comments changed: Retrospective observational study. Patients with PALB2 mutation (n=4), along with BRCA1 and BRCA2 mutants, had a high ORR (58%) and prolonged rwPFS (10.1 months) when treated with platinum-based chemotherapy.Retrospective cohort study. Only 4 patients.. (First curated: 2020-04-25)

Changed Olaparib, Rucaparib, Talazoparib in Solid tumours with PBRM1 Loss-of-function mutations, Loss of protein expression: 4

Comments changed: Preclinical study. PBRM1 deficiency is synthetic lethal with DNA repair inhibitors, with PARP and ATR inhibitors showing efficacy in PBRM1-defective cancer cells, particularly in clear cell renal cell carcinomas, due to elevated replication stress, micronuclei, and R-loops.. (First curated: 2022-11-28)

Changed Anti-PD-1 monoclonal antibody in Solid tumours with PDCD1LG2 Amplification: 4

Comments changed: Case report. A patient with metastatic colon cancer and amplification of CD274 (PD-L1) and PDCD1LG2 (PD-L2) showed a durable response to nivolumab, but acquired resistance developed through outgrowth of cells lacking these amplifications, suggesting that combination therapies targeting both amplified and non-amplified cell populations might be more effective.. References changed: 3513517410.1200/PO.18.00017. (First curated: 2020-04-16)

Changed Ripretinib in Gastrointestinal stromal tumour with PDGFRA D842V: 4

Comments changed: Preclinical study. Ripretinib, a switch-control kinase inhibitor, demonstrated efficacy against a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants, particularly activation loop mutations, in cancer models.. (First curated: 2020-05-15)

Changed Imatinib, Sorafenib, Sunitinib in Gastrointestinal stromal tumour with PDGFRA V561D, D842_H845del: 4

Comments changed: Preclinical study. Sorafenib inhibits various KIT and PDGFRA mutant kinases associated with imatinib-resistant or sunitinib-resistant gastrointestinal stromal tumors (GIST), except for substitutions at KIT codon D816 and PDGFRA codon 842.. (First curated: 2022-01-25)

Changed Imatinib in Gastrointestinal stromal tumour with PDGFRA : 4

Alterations changed: V561D, N659K, D842Y, D842_I843delinsIM, D842_H845del, I843_H846del, Exon 18 deletion, Exon 12 mutation, Exon 14 mutationD842V. Comments changed: Preclinical study. Various PDGFRA mutations showed different in vitro sensitivity to imatinib, with exon 12 and 14 mutations being imatinib-sensitive, while most exon 18 mutations, particularly D842V, were imatinib-resistant, except for D842Y, D846Y, N848K, Y849K, and HDSN845-848P.Cell line study.. (First curated: 2022-01-25)

Changed Imatinib, Sunitinib in Gastrointestinal stromal tumour with PDGFRA W559_R560del: 4

Comments changed: Case report. A patient with gastrointestinal stromal tumor harboring a rare exon 12 PDGFRA mutation showed a dramatic response to sunitinib after relapsing on imatinib, suggesting sunitinib as a potential treatment option for this rare molecular subtype.. (First curated: 2023-01-18)

Changed Alpelisib in Solid tumours with PIK3CA Oncogenic mutations: 4

Comments changed: Phase Ia study. NCT01219699. Alpelisib showed preliminary activity in PIK3CA-altered solid tumors with ORR 6%, CBR 58%, and median PFS of 5.5 months in estrogen receptor-positive breast cancer.ORR 6%. CBR 58%.. (First curated: 2020-04-16)

Changed Ipatasertib in Solid tumours with PIK3CA : 4

Alterations changed: Kinase domain mutationsOncogenic mutations. Comments changed: Preclinical study. GDC-0068, a selective Akt inhibitor, showed antitumor activity in human cancer cells with markers of Akt activation, including PTEN loss and PIK3CA kinase domain mutations, and enhanced antitumor activity of chemotherapeutic agents.. (First curated: 2020-04-16)

Changed Pembrolizumab in Colorectal adenocarcinoma with POLE P286R: 4

Comments changed: Case report. A patient with POLE-mutated colorectal cancer and ultra-high tumor mutation burden experienced a complete and sustained response to pembrolizumab.Complete response. (First curated: 2020-11-15)

Changed Olaparib in Diffuse Intrinsic Pontine Glioma with PPM1D Loss-of-function mutations: 4

Comments changed: Preclinical study. PPM1D-mutant DIPG cells showed sensitization to PARP inhibitor Olaparib when targeted with PPM1D inhibitor GSK2830371, impairing homologous recombination-mediated DNA repair.. (First curated: 2022-04-04)

Changed Ipatasertib in Solid tumours with PTEN Loss-of-function mutations: 4

Comments changed: Preclinical study. GDC-0068, a selective Akt inhibitor, showed antitumor activity in human cancer cells and xenograft models, with sensitivity correlated to PTEN loss and high-basal phospho-Akt levels.. (First curated: 2020-04-16)

Changed Sapanisertib + Metformin in Solid tumours with PTEN Loss-of-function mutations: 4

Comments changed: Phase 1 study. NCT03017833. Sapanisertib + metformin showed anti-tumor activity in patients with advanced solid tumors harbouring PTEN mutations and AKT/mTOR pathway alterations, with 4/30 patients achieving partial response, mostly with PTEN mutations.. (First curated: 2021-06-18)

Changed Trametinib in Histiocytosis with PTPN11 Oncogenic mutations, E72K: 4

Comments changed: Case report. Multifocal histiocytic sarcoma patient showed response to MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib.. (First curated: 2020-04-16)

Changed Olaparib, Rucaparib in Ovarian cancer with RAD50 Oncogenic mutations; Deletions: 4

Comments changed: Preclinical study. RAD50 copy number deletion is associated with BRCAness and improved response to PARP inhibitors in BRCA wild-type ovarian cancer, with decreased RAD50 expression leading to enhanced sensitivity to cisplatin and olaparib.Cell line study. (First curated: 2020-10-20)

Changed Olaparib in Solid tumours with RAD51C Oncogenic mutations: 4

Comments changed: Preclinical study. RAD51C-deficient cancer cells showed increased sensitivity to olaparib, with enhanced G2-M cell-cycle arrest and apoptosis, and RAD51C deficiency may be considered a biomarker for predicting olaparib's antitumor effects.. (First curated: 2020-04-25)

Changed Cobimetinib in Melanoma with RAF1 Fusion; GOLGA4-RAF1 fusion: 4

Comments changed: Case report. A metastatic melanoma patient with a GOLGA4-RAF1 fusion and resistance to anti-CTLA4/anti-PD1 combination immunotherapy showed a profound response to MEK inhibitor therapy, indicating the potential of thorough molecular characterization to identify therapeutic targets in treatment-resistant cancers harbouring specific mutations.. (First curated: 2021-01-12)

Changed Trametinib in Non-small cell lung cancer with RASA1 Loss-of-function mutations; Oncogenic mutations: 4

Comments changed: Preclinical study. RASA1 and NF1 co-mutations define a distinct subset of NSCLC, associated with sensitivity to MEK inhibition, particularly with concurrent loss-of-function mutations.. (First curated: 2021-04-28)

Changed LY3295668 in Solid tumours with RB1 Oncogenic mutations, Loss-of-function mutations, loss of protein expression: 4

Comments changed: Preclinical study. Loss-of-function mutations in RB1 gene are common in several treatment-refractory cancers. AURKA inhibitor LY3295668 showed cytotoxic effects in RB1-deficient cancer cells and led to durable regression of RB1(mut) tumor xenografts.. (First curated: 2020-10-26)

Changed Taletrectinib in Non-small cell lung cancer with ROS1 Fusions; G2032R: 4

Comments changed: Preclinical study. DS-6051b, a selective ROS1/NTRK inhibitor, showed growth inhibition in ROS1-rearranged cancers with crizotinib-resistant G2032R mutation, overcoming resistance to crizotinib, lorlatinib, and entrectinib.. (First curated: 2020-04-25)

Changed Cabozantinib in Non-small cell lung cancer with ROS1 G2032R: 4

Comments changed: Preclinical study and case report highlighting ROS1-rearranged NSCLC with secondary resistance mutation, where cabozantinib overcomes crizotinib resistance by effectively inhibiting ROS1 wild-type and resistant mutants, including G2032R mutation.Cell-line evidence only. (First curated: 2020-04-25)

Changed Taletrectinib, Repotrectinib, NVL-520 in Solid tumour with ROS1 G2032R: 4

Comments changed: Preclinical study. NVL-520 is a selective and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations, showing potent targeting of ROS1 and diverse ROS1 resistance mutations with high selectivity for ROS1 G2032R over TRK.. (First curated: 2023-04-14)

Changed Crizotinib in Non-small cell lung cancer with ROS1 SLC12A2-ROS1 fusion: 4

Comments changed: Case report. Novel SLC12A2-ROS1 fusion identified in NSCLC patient, who showed significant response to crizotinib, highlighting the importance of choosing the appropriate next-generation sequencing assay.. (First curated: 2021-07-09)

Changed Crizotinib, Entrectinib, Loratinib, Taletrectinib, Repotrectinib, NVL-520 in Solid tumour with ROS1 SLC34A2-ROS1 fusion, EZR-ROS1 fusion, CD74-ROS1 fusion, GOPC-ROS1 fusion, CEP85L-ROS1 fusion: 4

Comments changed: Preclinical study. NVL-520 showed potent targeting of ROS1 and diverse ROS1 resistance mutations with high selectivity for ROS1 G2032R over TRK and brain penetration.Cell-line study. (First curated: 2023-04-14)

Changed H3B-8800 in Solid tumours, Liquid cancers with SF3B1 Oncogenic mutations: 4

Comments changed: Preclinical study. H3B-8800, an orally available splicing modulator, preferentially kills spliceosome-mutant cancer cells bearing mutations in SF3B1, U2AF1, and SRSF2 by retaining short, GC-rich introns, with loss of activity observed in drug-resistant cells with mutations in SF3b components.. (First curated: 2022-02-02)

Changed Tazemetostat in Ovarian small cell carcinoma with SMARCA4 Loss of protein expression: 4

Comments changed: Preclinical study. Tazemetostat, an EZH2 inhibitor, showed antiproliferative and antitumor effects in SMARCA2- and SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell lines and xenografts, indicating EZH2 dependence in this subset of tumors with SWI/SNF mutations.. (First curated: 2021-12-15)

Changed Palbociclib in Ovarian small cell carcinoma with SMARCA4 Loss-of-function mutations: 4

Comments changed: Preclinical study. SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cells with downregulated cyclin D1 are sensitive to CDK4/6 inhibitors, suggesting a potential therapeutic application for CDK4/6 inhibitors in SCCOHT with SMARCA4 inactivating mutations.. (First curated: 2021-04-14)

Changed Imatinib, Sunitinib in Gastrointestinal stromal tumour with PDGFRA D842V: R2

Tier changed: R2R1. Comments changed: Preclinical study. Sorafenib inhibits various KIT and PDGFRA mutant kinases associated with imatinib-resistant or sunitinib-resistant gastrointestinal stromal tumors (GIST), except for substitutions at KIT codon D816 and PDGFRA codon 842.OncoKB R1 but not blacklisted by TGA. (First curated: 2020-05-15)

Changed Therapy in Solid tumours with BRAF Class III mutations, D287, D287H, V459, V459L, G466, G466V, G466E, G466A, S467, S467L, N581, N581S, N581I, D594, D594N, D594G, D594A, D594H, F595, F595L, G596, G596D, G596R: R2

Therapy changed: FORE8394PLX8394. (First curated: 2020-09-15)

Changed Vemurafenib, Dabrafenib in Solid tumours with BRAF Class III mutations, D287H, V459L, G466V, G466E, G466A, S467L, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, G596R: R2

Comments changed: Class III mutations. Preclinical study. Tumours with class 3 BRAF mutants, characterized by impaired kinase activity or kinase-dead mutants, are sensitive to inhibition of RAS activation, particularly in the presence of coexistent mechanisms for maintaining RAS activation, such as RAS mutations or receptor tyrosine kinase signalling.. (First curated: 2020-04-26)

Changed Therapy in Melanoma with BRAF Fusions, FKBP15-BRAF fusion, TARDBP-BRAF fusion, AGK-BRAF fusion, SKAP2-BRAF fusion, CUL1-BRAF fusion, KIAA1549-BRAF fusion: R2

Therapy changed: Vemurafenib, Dabrafenib, FORE8394Vemurafenib, Dabrafenib, PLX8394. Comments changed: Preclinical study. BRAF fusion-positive melanoma cell lines showed heterogeneous responses to RAF and MEK inhibitors, with higher expression levels and dimerization domains associated with resistance and paradoxical MAPK pathway activation, while next-generation RAF inhibitors and combination with MEK inhibitors showed increased therapeutic activity.. (First curated: 2022-09-07)

Changed Vemurafenib in Solid tumours with BRAF N486_P490del: R2

Comments changed: Preclinical study. Activating in-frame deletions in protein kinases BRAF, EGFR, and HER2 drive cancer, with crystal structures revealing a mechanism of activation and resistance to certain inhibitors, such as vemurafenib.. (First curated: 2022-02-09)

Changed Therapy in Glioma with BRAF V600E and L514V: R2

Therapy changed: Vemurafenib, Dabrafenib, FORE8394Vemurafenib, Dabrafenib, PLX8394. (First curated: 2021-02-10)

Changed Afatinib, Poziotinib, Tarloxotinib in Non-small cell lung cancer with EGFR Exon 20 insertion and T790M and C797S: R2

Comments changed: Preclinical study. Cell line study. Tarloxotinib-E showed efficacy against Ba/F3 cells with EGFR exon 20 mutations, but acquired resistance was observed through T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation.. (First curated: 2021-12-29)

Changed Tarloxotinib in Non-small cell lung cancer with EGFR H773insH: R2

Comments changed: Preclinical study. Cell line study. Tarloxotinib-E showed efficacy against Ba/F3 cells with various EGFR exon 20 mutations, and acquired resistance to tarloxotinib-E was associated with secondary T790M or C797S mutations, influenced by the original EGFR exon 20 mutation.. (First curated: 2021-12-29)

Changed Afatinib in Non-small cell lung cancer with EGFR H773L and V774M: R2

Comments changed: Case report. A rare EGFR H773L/V774M compound mutation in NSCLC showed primary resistance to afatinib, suggesting it may be one of the EGFR-TKI-resistant uncommon EGFR mutations.. (First curated: 2023-03-28)

Changed Osimertinib in Non-small cell lung cancer with EGFR : R2

Alterations changed: L718V, L718Q, G719. Comments changed: Case report. Acquired EGFR L718V mutation identified as a resistance mechanism to osimertinib in a T790M-negative NSCLC patient, providing insight into osimertinib resistance.OncoKB R2 (concordant). References changed: 29506987, 31301016. (First curated: 2020-04-16)

Changed Osimertinib in Non-small cell lung cancer with EGFR L747P: R2

Comments changed: Case report. A Chinese woman with stage IV lung adenocarcinoma harboring a rare EGFR L747P mutation showed intrinsic resistance to both gefitinib and osimertinib, highlighting the challenges in treating NSCLC with rare EGFR mutations.. (First curated: 2020-06-08)

Changed Gefitinib, Erlotinib in Non-small cell lung cancer with EGFR L747P, L747S: R2

Comments changed: Preclinical and clinical study. Afatinib showed efficacy in treating lung adenocarcinoma with uncommon EGFR p.L747P and p.L747S mutations with 80% ORR and 11.97 months median PFS, and no patients acquired p.T790M resistance after afatinib failure.. (First curated: 2020-06-08)

Changed AZD4547 in Solid tumours with FGFR2 Oncogenic mutations and NOT Amplification: R2

Tier changed: R24. Comments changed: Phase 2 NCI-MATCH trial (arm W). Patients with tumors harboring FGFR aberrations treated with AZD4547 showed confirmed partial responses in 8% of patients, limited to those with FGFR1-3 point mutations or fusions, with a higher response rate of 22% in patients with FGFR fusions.No response in this cohort. (First curated: 2020-06-11)

Changed Infigratinib in Cholangiocarcinoma with FGFR2 V564F, N549H, N549K, E565A, L617V, K641R, K659M: R2

Comments changed: Preclinical study and case series. Polyclonal secondary FGFR2 mutations in the kinase domain were identified in cfDNA and biopsies of FGFR2 fusion-positive cholangiocarcinoma patients, driving acquired resistance to FGFR inhibitor BGJ398, and were surmountable by distinct FGFR inhibitors.. (First curated: 2023-02-22)

Changed Osimertinib, Gefitinib in Non-small cell lung cancer with FGFR3 FGFR3-TACC3 fusion: R2

Comments changed: Retrospective observational study. FGFR2/3 fusions, particularly FGFR3-TACC3, were identified as a rare acquired resistance mechanism in advanced NSCLC patients treated with EGFR TKIs, and combining EGFR TKIs with FGFR TKIs showed clinical benefit in patients with FGFR3-TACC3 fusions.. (First curated: 2023-06-23)

Changed Osimertinib in Non-small cell lung cancer with FGFR3 Fusion: R2

Comments changed: Retrospective observational study. Analysis of 155 EGFR-mutant lung cancer patients with acquired resistance to EGFR-TKI therapy revealed various mechanisms of resistance, with EGFR T790M mutation being the most common (63%), followed by MET amplification (5%), HER2 amplification (13%), and small cell transformation (3%), also including small number of off-target mechanism such as FGFR3 fusion.. (First curated: 2020-06-10)

Changed Infigratinib, AZD4547, Zoligratinib in Cholangiocarcinoma with FGFR3 N540K, V555M, L608V: R2

Comments changed: Preclinical study and case series. Polyclonal secondary FGFR2 mutations in the kinase domain were identified in cfDNA and biopsies of FGFR2 fusion-positive cholangiocarcinoma patients, driving acquired resistance to FGFR inhibitor BGJ398, and were surmountable by distinct FGFR inhibitors.. (First curated: 2023-02-22)

Changed Pemigatinib in Non-small cell lung cancer with FGFR3 V555M, V555L: R2

Comments changed: Phase2 FIGHT-207 basket trial. NCT03822117. Pemigatinib showed ORR of 26.5% and 9.4% in patients with FGFR fusions/rearrangements and activating non-kinase domain mutations respectively, with TP53 co-mutations associated with lack of response and BAP1 alterations with higher response rates, while FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance.Phase 2. FIGHT-207 basket. NCT03822117. Acquired resistance mutations following Pemigatinib.. (First curated: 2024-07-19)

Changed Fisogatinib in Solid tumours, Hepatocellular carcinoma with FGFR4 V550E, V550L: R2

Comments changed: Preclinical and clinical study. On-target FGFR4 kinase domain mutations were identified as a mechanism of acquired resistance to fisogatinib in HCC patients with aberrant FGF19 expression, validating FGFR4 as an oncogenic driver.Gatekeeper mutation. (First curated: 2020-05-22)

Changed Sunitinib in Colorectal adenocarcinoma with FLT3 Amplification: R2

Comments changed: Phase 2 TAPUR basket study. NCT02693535. Sunitinib showed no clinical activity in patients with metastatic colorectal cancer with FLT-3 amplification, as no objective responses were observed (ORR 0%) and only two patients had stable disease at 16 weeks, suggesting FLT-3 amplification may not be a sufficient target for sunitinib.NCT02693535. TAPUR. ORR 0%.. (First curated: 2022-10-16)

Changed Sorafenib in Acute myeloid leukaemia with FLT3 D835: R2

Comments changed: Clinical study. Relapsed or refractory FLT3-ITD(+) AML patients treated with sorafenib showed initial response but subsequent resistance was associated with the emergence of D835 mutation in leukemia initiating cells, suggesting selection of more aggressive subclones carrying both FLT3-ITD and D835 mutations.. (First curated: 2020-04-16)

Changed Vismodegib in Basal cell carcinoma with GLI1 Overexpression: R2

Comments changed: Preclinical study. Genomic analysis of basal cell carcinoma revealed that Smoothened (SMO) inhibitor resistance is associated with Hedgehog pathway reactivation through SMO mutations that impair drug binding, and copy number changes in SUFU and GLI2.. (First curated: 2020-04-16)

Changed Vismodegib in Basal cell carcinoma with GLI2 Overexpression: R2

Comments changed: Preclinical studies. Genomic analysis of basal cell carcinoma tumors and a medulloblastoma patient treated with vismodegib revealed that acquired resistance to Smoothened antagonists occurs through Hedgehog pathway reactivation via SMO mutations that either impair drug binding or constitutively activate SMO.. (First curated: 2020-04-16)

Changed Osimertinib in Non-small cell lung cancer with GNAS R201C, R201H: R2

Comments changed: Case report. A NSCLC patient with osimertinib resistance harboring GNAS R201C and R201H mutations showed stable disease after treatment with trametinib, suggesting GNAS R201 mutations confer osimertinib resistance and trametinib as a potential treatment option.. (First curated: 2023-12-14)

Changed MEK inhibitor in Gastric cancer with HGF Overexpression: R2

Comments changed: Preclinical study. Overexpression of HGF induces resistance to c-MET tyrosine kinase inhibitors in gastric cancer cells through an autocrine manner, despite c-MET TKIs inhibiting downstream signaling and cell proliferation.. (First curated: 2020-05-15)

Changed Sonidegib, Vismodegib in Solid tumours with HRAS G12V: R2

Comments changed: Preclinical study. RAS/MAPK pathway activation drives off-target mechanism of resistance to Smo inhibition, with Sufu mutations maintaining Shh pathway activity and emerging RAS/MAPK activation in Smo inhibitor-treated BCC patients.. (First curated: 2020-07-02)

Changed Ivosidenib in Acute myeloid leukaemia with IDH1 S280F: R2

Comments changed: Phase 1 trial. NCT02074839. N=174. Multiple mechanisms of resistance to ivosidenib were identified in IDH1-mutant relapsed/refractory AML, including RTK pathway mutations associated with primary resistance, and second-site IDH1 mutations and IDH2 mutations restoring 2-HG production associated with acquired resistance.. (First curated: 2021-10-06)

Changed Ruxolitinib in Liquid cancers with JAK1 F958V, F958C, P960: R2

Comments changed: Preclinical study. Cell line study identified JAK1 and JAK2-activating mutations, specifically those targeting F958 and P960 in JAK1 and Y931 in JAK2, confer resistance to ATP-competitive JAK inhibitors.Cell line study.. (First curated: 2022-05-17)

Changed Ruxolitinib in Liquid cancers with JAK2 Y931C, Y931C and V617F: R2

Comments changed: Preclinical study. Cell line study identified JAK1 and JAK2-activating mutations, specifically those targeting F958 and P960 in JAK1 and Y931 in JAK2, confer resistance to ATP-competitive JAK inhibitors.Cell line study.. (First curated: 2022-05-17)

Changed Imatinib in Melanoma with KIT Amplification: R2

Comments changed: Phase 2 trial. Imatinib demonstrates efficacy in melanomas with KIT mutations (54% response rate) but shows no response in tumors with KIT amplification only (0% ORR). KIT mutation status serves as a predictor of response, while NRAS mutations and KIT copy number gain are associated with imatinib resistance.ORR 0% in KIT amplification only. (First curated: 2020-04-23)

Changed Sorafenib in Gastrointestinal stromal tumour with KIT D816F, D816G, D816H, D816V, D816: R2

Comments changed: Preclinical study. Sorafenib inhibits various KIT and PDGFRA mutant kinases associated with imatinib-resistant or sunitinib-resistant gastrointestinal stromal tumors (GIST), except for substitutions at KIT codon D816 and PDGFRA codon 842. (Merged 2025-05-28)Secondary resistance. (First curated: 2020-05-15)

Changed Therapy in Gastrointestinal stromal tumour with KIT NOT Oncogenic mutations, V654A, T670I: R2

Therapy changed: BezuclastinibPLX9486. Comments changed: Phase 1b/2a trial. NCT02401815. In refractory GIST, the combination of Bezuclastinib (type I KIT inhibitor) and sunitinib (type II KIT inhibitor) demonstrated a median PFS of 12.1 months and clinical benefit rate of 80%. KIT wildtype tumors and those harboring V654A or T670I mutations showed lack of sensitivity to this combination therapy.. (First curated: 2023-06-27)

Changed Cabozantinib in Gastrointestinal stromal tumour with KIT V559A, V559D, D816H, D816V: R2

Comments changed: Preclinical study. Cabozantinib, a MET and VEGFR2 inhibitor, suppresses metastasis, angiogenesis, and tumor growth by inhibiting MET and VEGFR2 phosphorylation, with potential therapeutic application in cancers with dysregulated MET and VEGFR signaling. Drug sensitivity screen revealed relative insensitivity of KIT V559A, V559D, D816H, D816V to Cabozantinib.Drug sensitivity screen.. (First curated: 2021-08-13)

Changed Imatinib + Binimetinib in Gastrointestinal stromal tumour with KIT V654A, N822K, N822Y, D820G: R2

Comments changed: Phase 2 trial. NCT01991379. Imatinib plus Binimetinib showed a high ORR of 69% in treatment-naive advanced GIST patients, with 29 of 42 evaluable patients achieving confirmed PR, and median PFS of 29.9 months. Emergent secondary KIT mutations and CDKN2A alterations associated with resistance were identified.. (First curated: 2022-03-20)

Changed Midostaurin in Gastrointestinal stromal tumour with KIT V654A, T670I: R2

Comments changed: Preclinical study. ATP-competitive inhibitors midostaurin and avapritinib displayed distinct resistance profiles in exon 17-mutant KIT, with avapritinib being selectively problematic for T670I gatekeeper mutation, conferring resistance indirectly through conformational changes.. (First curated: 2020-05-15)

Changed Pemigatinib in Cancer of unknown primary with KRAS A59T, G13D: R2

Comments changed: Phase 2 FIGHT-207 basket trial. NCT03822117. Pemigatinib showed ORR of 27% and 9% in cohorts with FGFR fusions/rearrangements and activating non-kinase domain mutations, respectively, with TP53 co-mutations associated with lack of response and BAP1 alterations with higher response rates, and identified FGFR1-FGFR3 gatekeeper and molecular brake mutations as acquired resistance mechanisms. Acquired resistance mutations following Pemigatinib were identified.Phase 2. FIGHT-207 basket. NCT03822117. Acquired resistance mutations following Pemigatinib.. (First curated: 2024-07-19)

Changed Binimetinib + Encorafenib in Colorectal adenocarcinoma with KRAS Amplification: R2

Comments changed: Preclinical study and paired pre-post treatment sequencing. Identified alterations in MAPK pathway genes, including KRAS amplification, in resistant BRAF-mutant colorectal cancer tumors post-RAF inhibitor combination treatment.. (First curated: 2020-11-25)

Changed Cetuximab, Panitumumab in Colorectal adenocarcinoma with KRAS Amplification: R2

Comments changed: Preclinical study and patient sample analysis. KRAS amplification, detected in 0.67% of 1039 CRC specimens, is associated with primary resistance to EGFR-targeted therapy, with tumors or cell lines harboring this lesion being non-responsive to anti-EGFR inhibitors.Cell line study. Tumors or cell lines harboring KRAS amplification are not responsive to anti-EGFR inhibitors.. (First curated: 2022-04-19)

Changed Dabrafenib + Panitumumab in Colorectal adenocarcinoma with KRAS Amplification: R2

Comments changed: Preclinical study. Identified alterations in MAPK pathway genes, including KRAS amplification, in paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations, driving clinical acquired resistance.Paired pre-post treatment sequencing. (First curated: 2020-11-25)

Changed Crizotinib in Non-small cell lung cancer with KRAS Amplification: R2

Comments changed: Biomarker analysis. Co-occurring RAS-MAPK pathway alterations, notably in KRAS and NF1, were associated with decreased response to MET inhibitor treatment in MET exon 14 skipping mutation-positive lung cancer.Case series.. (First curated: 2021-01-03)

Changed Trametinib in Gastric cancer, Gastroesophageal junction adenocarcinoma, Oesophageal adenocarcinoma with KRAS Amplification and NOT missense variant: R2

Comments changed: Preclinical study. KRAS amplification in gastroesophageal cancer models results in insensitivity to MEK inhibition due to adaptive increase in KRAS-GTP levels, but combined MEK and SHP2 inhibition shows enhanced sensitivity, revealing a potential therapeutic strategy for KRAS-amplified tumors.Intrinsic resistance to MEK inhibitor. (First curated: 2020-09-15)

Changed Divarasib in Non-small cell lung cancer, Colorectal adenocarcinoma, Solid tumours with KRAS Amplification, G12A, G12D, G12R, G12V, G13D, R68S, H95R, Y96D, Y96H, Y96N, Q99L, A146T, Oncogenic mutation AND NOT G12C: R2

Comments changed: Phase 1/2 single arm trial. GO42144. NCT04449874. Divarasib showed confirmed response rates of 53% in NSCLC and 29% in colorectal cancer patients. Serial ctDNA assessment identifying genomic alterations associated with response and potential acquired and treatment-emergent mutations.Phase 1/2 single arm trial. GO42144. Divarasib. NCT04449874. Acquired and treatment-emergent mutations. (First curated: 2023-08-24)

Changed Crizotinib in Non-small cell lung cancer with KRAS Amplification, G12D: R2

Comments changed: Biomarker analysis. Study on MET exon 14-mutant NSCLC. Acquired resistance to MET TKIs driven by on-target secondary MET mutations (35%) and off-target mechanisms including KRAS mutations (45%).Off-target resistance. (First curated: 2020-05-31)

Changed Trastuzumab in Gastric cancer with KRAS Amplification, G13D, A146V: R2

Comments changed: Case-control study. AMNESIA. Biomarkers of primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, showing significant association between presence of genomic alterations (including KRAS mutations/amplifications) and primary resistance, with median PFS 2.6 months versus 5.2 months.. (First curated: 2020-05-27)

Changed Osimertinib in Non-small cell lung cancer with KRAS G12S: R2

Comments changed: Preclinical study and patient biopsy analysis. Heterogeneous mechanisms of resistance to third-generation EGFR inhibitors, including MET or ERBB2 amplification and KRAS(G12S) mutation, suggesting potential combination strategies such as EGFR/MEK dual inhibition to overcome resistance.Secondary resistance post Osimertinib. (First curated: 2020-03-12)

Changed Sotorasib in Non-small cell lung cancer with KRAS G12V: R2

Comments changed: Phase 1/2 study findings. Multiple treatment-emergent alterations observed in 27 patients treated with sotorasib, including alterations in KRAS, NRAS, BRAF, and other genes, associated with resistance to KRAS(G12C) inhibition.Treatment-emergent RAS and RAF hotspot mutations were also observed in both clinical samples and patient-derived xenograft models.. (First curated: 2021-11-15)

Changed Cetuximab, Cetuximab + Irinotecan in Colorectal adenocarcinoma with KRAS G13D: R2

Comments changed: Phase 2 ICECREAM trial. N=51. Response rate was 0% with cetuximab monotherapy versus 9% with cetuximab plus irinotecan in patients with KRAS G13D mutation-positive metastatic colorectal cancer.ORR 0% in G13D mutant mCRC. (First curated: 2021-04-26)

Changed Osimertinib in Non-small cell lung cancer with KRAS G13D: R2

Comments changed: Preclinical study. KRAS G13D mutation was found in PC9-AZDR clones, conferring acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells.Cell line data. Off-target resistance. (First curated: 2020-03-12)

Changed Osimertinib in Non-small cell lung cancer with KRAS Oncogenic mutations: R2

Comments changed: Biomarker analysis. In 155 tumor specimens with acquired EGFR-TKI resistance, mechanisms included EGFR T790M mutation (63%), HER2 amplification (13%), MET amplification (5%), and small cell transformation (3%), among others.Off-target mechanism. (First curated: 2020-06-10)

Changed SHP099 in Pancreatic acinar cell carcinoma with KRAS Q61H: R2

Comments changed: Preclinical study. The Q61H mutation in KRAS confers resistance to SHP2 inhibitors by decoupling KRAS from upstream regulation, impairing GTP hydrolysis, and retaining high-affinity RAF interaction.. (First curated: 2022-08-03)

Changed Crizotinib in Non-small cell lung cancer with KRAS+MET MET:exon 14 skipping mutation and KRAS:Oncogenic mutations: R2

Comments changed: KRAS mutation is identified as a mechanism of primary and secondary resistance to MET tyrosine kinase inhibitors in MET exon 14-mutant non-small cell lung cancer, with dual inhibition of MET or EGFR/ERBB2 and MEK showing potential as a therapeutic approach.. (First curated: 2020-05-15)

Changed Cetuximab, Panitumumab in Colorectal adenocarcinoma with MAP2K1 K757E, K57N: R2

Comments changed: RTK alterations and MAP2K1 mutations occur in approximately 8% of colorectal carcinoma cases, often associated with wild-type RAS/RAF, and confer resistance to anti-EGFR and/or anti-ERBB2 therapy.. (First curated: 2023-04-20)

Changed Trametinib in Histiocytosis with MAP2K1 L98_K104delinsQ: R2

Comments changed: Preclinical study. MAP2K1 L98_K104delinsQ identified in Langerhans cell histiocytosis confers resistance to MEK inhibitor trametinib and causes auto-activation of ERK pathway in vitro.. (First curated: 2021-11-10)

Changed Selumetinib in Melanoma with MAP2K1 P124L, Q56P: R2

Comments changed: Preclinical study. MEK1 mutations, particularly those affecting the allosteric drug binding pocket, alpha-helix C, and N-terminal negative regulatory helix (helix A), confer resistance to MEK and B-RAF inhibition in BRAF-mutant melanoma.. (First curated: 2020-04-16)

Changed Vemurafenib, Dabrafenib in Melanoma with MAP2K1+BRAF MAP2K1:P124 and BRAF:V600: R2

Comments changed: Retrospective analysis. 123 patients with BRAF V600-mutant metastatic melanoma showed preexisting MEK1 P124 mutations (N=12, 10%) were associated with poorer RECIST response (33% vs 72%) and shorter PFS (3.1 vs 4.8 months), indicating a subset of patients likely to benefit from combination therapies involving MEK or ERK inhibitors due to intrinsic resistance mechanism.. (First curated: 2020-05-20)

Changed Cetuximab, Panitumumab in Colorectal adenocarcinoma with MET Amplification: R2

Comments changed: Preclinical study. Amplification of the MET gene is associated with acquired resistance to EGFR targeted therapy in patients with metastatic colorectal cancer; MET inhibitors could be effective in overcoming this resistance.. (First curated: 2023-07-04)

Changed Gefitinib, Erlotinib, Afatinib, Dacomitinib, Osimertinib in Non-small cell lung cancer with MET Amplification: R2

Comments changed: Preclinical and clinical study. Clonal MET amplification, observed in 3% of treatment-naive EGFR-mutant NSCLC, was associated with suboptimal response to EGFR TKI, highlighting its role as a determinant of TKI resistance.. (First curated: 2020-05-04)

Changed Trastuzumab in Gastric cancer with MET Amplification, N375S: R2

Comments changed: Case-control study (AMNESIA). Identified biomarkers (EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications) associated with primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, with significantly shorter PFS (2.6 vs 5.2 months) and OS (7.6 vs 16.1 months).. (First curated: 2020-05-27)

Changed Crizotinib in Non-small cell lung cancer with MET D1228N (D1246N): R2

Comments changed: Case report. Acquired D1228N mutation in MET kinase domain identified as a potential resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping using targeted next-generation sequencing.. (First curated: 2021-01-03)

Changed Crizotinib in Triple-negative breast cancer with MET D1228N (D1246N): R2

Comments changed: Case report. MET D1228N mutation emerged during progression on crizotinib in MET-amplified triple-negative breast cancer, conferring resistance to crizotinib but retaining sensitivity to cabozantinib.. (First curated: 2020-05-15)

Changed Capmatinib, Tepotinib, Savolitinib in Non-small cell lung cancer with MET D1228N (D1246N), D1228 (D1246): R2

Comments changed: On-target secondary MET kinase domain mutations and off-target mechanisms including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRAF drive resistance to MET TKIs in MET exon 14-mutant NSCLC.. (First curated: 2020-05-31)

Changed Glesatinib in Non-small cell lung cancer with MET H1094Y (H1112Y), L1195V (L1213V): R2

Comments changed: Preclinical study. Study analysed tissue or plasma NGS data from 20 MET exon 14-mutant NSCLC patients at the time of MET TKI resistance, identifying on-target (MET kinase domain mutations, MET exon 14-mutant allele amplification) and off-target (KRAS mutations, EGFR, HER3, BRAF amplifications) resistance mechanisms in 75% of patients.. (First curated: 2020-05-31)

Changed Infigratinib, AZD4547, Rogaratinib in Gastric cancer with MET Overexpression: R2

Comments changed: Preclinical studies on FGFR1-amplified lung cancer cell lines identified diverse mechanisms of primary and acquired drug resistance to FGFR inhibitors, including NRAS amplification, DUSP6 deletion, and MET upregulation/amplification, which reactivate MAPK pathway and confer resistance, suggesting rational combination therapies to improve FGFR inhibitor treatments.PDX models; Off-target mechanism. References changed: 28630215, 2742907328630215; 27429073. (First curated: 2020-05-22)

Changed Crizotinib in Non-small cell lung cancer with MET Y1230H (Y1248H): R2

Comments changed: Case report. Preexisting MET Y1230C mutation confers acquired resistance to crizotinib in NSCLC with MET exon 14 skipping, detected at low frequency pretreatment and in ctDNA at progression.Case report. Acquired resistance. (First curated: 2021-01-03)

Changed Crizotinib in Non-small cell lung cancer with MET Y1230S (Y1248S), D1228N (D1246N), D1228H (D1246H), F1200I (F1218I), L1195V (L1213V), S244fs: R2

Comments changed: Retrospective analysis. Targeted sequencing analysis of 289 patients with METex14-mutated NSCLC revealed co-occurring RAS-MAPK pathway alterations associated with decreased MET TKI treatment response, and preclinical models showed that combining crizotinib with MEK inhibitor trametinib overcame this resistance.Case series.. (First curated: 2021-01-03)

Changed Crizotinib in Non-small cell lung cancer with MET+TP53 MET:Exon 14 skipping mutation and TP53:Oncogenic mutations: R2

Comments changed: Case series. Co-occurring RAS-MAPK pathway alterations (e.g., KRAS, NF1) are associated with decreased response to MET inhibitors in METex14-mutated NSCLC. Combined inhibition of MET and MEK signaling overcomes this resistance in preclinical models. TP53 mutation was observed in 7 of 12 cases following crizotinib exposure.Case series. TP53 mutation shown in post-exposure to crizotinib 7 of 12 cases.. (First curated: 2021-01-03)

Changed Atezolizumab, Atezolizumab + Cobimetinib in Colorectal adenocarcinoma with Microsatellite Instability Stable: R2

Comments changed: Phase 3 IMblaze370 trial. NCT02788279. Atezolizumab with or without cobimetinib did not improve OS versus regorafenib in microsatellite-stable metastatic colorectal cancer, with an ORR of 4/273 (1%) in the atezolizumab groups, highlighting the challenge of expanding immunotherapy benefits to tumours with lower baseline immune inflammation.Phase 3. IMBlaze370. ORR 4/273 (1%) in the Atezolizumab groups.. (First curated: 2021-08-15)

Changed Durvalumab in Endometrial cancer with Microsatellite Instability Stable: R2

Comments changed: Phase 2 trial. PHAEDRA. NCT03015129. Durvalumab demonstrated an objective tumor response rate of 47% in mismatch repair-deficient (dMMR) endometrial cancer versus 3% (1 of 35) in mismatch repair-proficient (pMMR) tumors, with median progression-free survival of 1.8 months in the pMMR group.PHAEDRA. Phase 2. ORR in the pMMR cohort was 3% (1 of 35) with median PFS of 1.8 months.. (First curated: 2023-07-14)

Changed FOLFOX + Bevacizumab + Durvalumab + Oleclumab in Colorectal adenocarcinoma with Microsatellite instability+Mismatch repair NOT Microsatellite instability:high AND NOT Mismatch repair:deficient: R2

Comments changed: Phase 1B/2. COLUMBIA-1. NCT04068610. N=59. Durvalumab + oleclumab added to FOLFOX and bevacizumab did not significantly improve ORR (62% vs 46%) in metastatic microsatellite-stable colorectal cancer.Phase 1B/2. COLUMBIA-1. NCT04068610. N=59. Durvalumab + oleclumab added to FOLFOX and bevacizumab did not significantly improve ORR (61.5% vs 46.2%) in metastatic microsatellite-stable colorectal cancer.. (First curated: 2025-04-23)

Changed Nivolumab + FLOX in Colorectal adenocarcinoma with Microsatellite instability+Mismatch repair NOT Microsatellite instability:high AND NOT Mismatch repair:deficient: R2

Comments changed: Randomized Phase 2. METIMMOX trial. NCT03388190. N=80. In microsatellite stable disease, alternating FLOX + nivolumab showed no PFS advantage over FLOX alone (9.2 months each).Randomized Phase 2. METIMMOX trial. NCT03388190. N=80. In microsatellite stable disease, no PFS advantage was observed with alternating FLOX + nivolumab over FLOX alone (both 9.2 months).. (First curated: 2023-03-02)

Changed Androgen receptor antagonist, GnRH agonist, CYP17A1 inhibitor, Enzalutamide, Apalutamide in Prostate cancer with MYCN Amplification: R2

Comments changed: Preclinical study. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer, highlighting restored AR signalling, AR bypass signalling, and complete AR independence as potential resistance mechanisms.Off-target mechanism. (First curated: 2020-04-26)

Changed Crizotinib in Non-small cell lung cancer with NF1 Oncogenic mutations: R2

Comments changed: Preclinical study and cfDNA analysis of 289 patients showed co-occurring RAS-MAPK pathway alterations limit response to MET inhibitors in MET exon 14 skipping mutation-positive lung cancer, and resistance was overcome by combining crizotinib with MEK inhibitor trametinib.Case series.. (First curated: 2021-01-03)

Changed Imatinib in Melanoma with NRAS Amplification: R2

Comments changed: Phase 2 trial of imatinib in metastatic melanoma with KIT amplifications and/or mutations, showing effectiveness in tumors with KIT mutations (54% response rate) but not in those with KIT amplifications only, with potential resistance mechanisms including NRAS mutations and KIT copy number gain.. (First curated: 2020-04-23)

Changed Talazoparib in Lung squamous cell carcinoma with PALB2 Oncogenic mutations: R2

Comments changed: Phase 2 S1400G study. NCT02154490. Talazoparib demonstrated limited activity in homologous recombination repair-deficient squamous cell lung cancer with ORR of 4% in primary analysis population and 11% in full eligible population.Lung-MAP Substudy S1400G. ORR primary population 4%. (First curated: 2021-03-16)

Changed Imatinib in Gastrointestinal stromal tumour with PDGFRA : R2

Alterations changed: D842VV561D, N659K, D842Y, D842_I843delinsIM, D842_H845del, I843_H846del, Exon 18 deletion. Tier changed: R24. Comments changed: Preclinical study. Various PDGFRA mutations showed different in vitro sensitivity to imatinib, with exon 12 and 14 mutations being imatinib-sensitive, while most exon 18 mutations, particularly D842V, were imatinib-resistant, except for D842Y, D846Y, N848K, Y849K, and HDSN845-848P. (Entry updated/corrected 2025-05-28.)Cell line study.. (First curated: 2022-01-25)

Changed Imatinib, Sorafenib, Sunitinib in Gastrointestinal stromal tumour with PDGFRA D842V: R2

Comments changed: Preclinical study. Sorafenib inhibits various KIT and PDGFRA kinase mutations associated with imatinib and sunitinib resistance in gastrointestinal stromal tumors, except for substitutions at KIT codon D816 and PDGFRA codon 842.. (First curated: 2022-01-25)

Changed Imatinib, Nilotinib, Sorafenib in Chronic eosinophilic leukaemia with PDGFRA FIP1L1-PDGFRA fusion and T674I: R2

Comments changed: Case report. A patient with FIP1L1-PDGFRA-positive chronic eosinophilic leukemia developed imatinib resistance due to T674I mutation, and showed limited clinical activity to subsequent nilotinib and sorafenib treatments.. (First curated: 2022-01-25)

Changed Imatinib in Mastocytosis with PDGFRA : R2

Alterations changed: FIP1L1-PDGFRA fusion and T674I. Comments changed: FIP1L1-PDGFRA fusion tyrosine kinase is identified as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome, with relapse correlating with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.Primary resistance. (First curated: 2020-05-15)

Changed Olaratumab in Soft tissue sarcomas with PDGFRA Protein expression: R2

Comments changed: Preclinical study. Olaratumab, a PDGFRA antibody, showed no significant antitumor effects as a single agent or in combination with doxorubicin in a panel of patient-derived soft tissue sarcoma xenografts.Negative Xenograft data. (First curated: 2020-04-16)

Changed Osimertinib in Non-small cell lung cancer with PIK3CA G118D: R2

Comments changed: Preclinical study. Amplification of EGFR wild-type alleles was found to confer acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors, with the Src-AKT pathway also contributing to resistance.Cell line data. Off-target resistance. (First curated: 2020-03-12)

Changed Trametinib in Pancreatic acinar cell carcinoma with RAF1 Fusion; GATM-RAF1 fusion: R2

Comments changed: Case report. Pancreatic acinar cell carcinoma with RAF1 fusion demonstrated inferior response to MEK inhibitor therapy with no objective response. Concomitant CDKN2A loss was reported.No objective response seen. Concomitant mutations reported including CDKN2A loss. (First curated: 2021-01-12)

Changed Therapy in Low-grade gliomas with RAF1 Fusion; QKI-RAF1 fusion; SRGAP3-RAF1 fusion: R2

Therapy changed: Vemurafenib, FORE8394Vemurafenib, PLX8394. (First curated: 2021-01-12)

Changed Adagrasib in Solid tumours with RAF1 RAF1-CCDC176 fusion, RAF1-TRAK1 fusion, Fusions: R2

Comments changed: Phase 1/2. KRYSTAL-1. Off-target acquired resistance mechanism identified by treatment-emergent mutations after 12 weeks of Adagrasib exposure, detected via tissue or ctDNA from blood samples. Acquired resistance to KRAS(G12C) inhibitors occurs through diverse genomic and histologic mechanisms, including acquired KRAS alterations, bypass mechanisms such as MET amplification and oncogenic fusions, and histologic transformation.Phase 1/2 KRYSTAL-1: off-target acquired resistance mechanism identified by treatment-emergent mutations after 12 weeks of exposure to Agagrasib, identified on tissue or ctDNA from blood sample.. (First curated: 2021-06-25)

Changed Vandetanib in Solid tumours with RET G810A: R2

Comments changed: Preclinical study. KIF5B-RET fusion lung adenocarcinoma modeled in transgenic mice and cell lines, showing ponatinib as the most effective inhibitor against KIF5B-RET and its drug-resistant mutants, and identifying novel vandetanib-resistant RET(G810A) mutation.. (First curated: 2020-11-17)

Changed Selpercatinib in Non-small cell lung cancer with RET G810A, G810S, G810C, G810R: R2

Comments changed: Preclinical study and Case report. RET G810 solvent front mutations mediate acquired resistance to selpercatinib in RET-driven malignancies through steric hindrance of drug binding.Case report and xenograft studies. Acquired resistance after treatment with Selpercatinib as a result by steric hinderance of drug binding.. (First curated: 2022-01-07)