Augtyro (repotrectinib) / ZAI Lab, BMS - LARVOL DELTA

Taletrectinib, a next generation selective ROS1 inhibitor, inhibits growth of ROS1 wild-type and ROS1-G2032R xenografts (AACR 2025) - P2 | "While several inhibitors for ROS1 have been FDA approved, including crizotinib, entrectinib and, more recently, repotrectinib, each present unique challenges. Taletrectinib is being evaluated in patients with locally advanced or metastatic ROS1-positive NSCLC in two Phase 2 single-arm pivotal studies: TRUST-I (NCT04395677) in China, and TRUST-II (NCT04919811), a global study. Based on the integrated analysis of the TRUST-I and TRUST-II clinical studies, an NDA has been submitted for taletrectinib to the U.S. FDA for the treatment of patients with locally advanced or metastatic ROS1-positive NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • NTRK2 • SLC34A2

Crystal structure of drug-resistant ROS1 G2032R in complex with zidesamtinib, a clinical-stage ROS1 inhibitor with best-in-class potential (AACR 2025) - "Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, and repotrectinib are FDA-approved for treatment of ROS1-positive NSCLC. Analysis of our ROS1 G2032R crystal structure and FEP modeling provide a structural explanation for how ROS1 G2032R impairs the binding of many ROS1 TKIs while maintaining high sensitivity to zidesamtinib. The data presented here, together with previously disclosed preclinical and clinical data, support our design of zidesamtinib as a differentiated ROS1 TKI with best-in-class potential for the treatment of ROS1-positive NSCLC."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NTRK2 • ROS1

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), the NCCN Drugs & Biologics Compendium (NCCN Compendium), the NCCN Radiation Therapy Compendium, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC) for Gastric Cancers, Version 1.2025. (NCCN)

NCCN guideline • Gastric Cancer • Microsatellite Instability

REPOSE: REPotrectinib in ROS1-positive Non-small Cell Lung Cancer Patients With Active Brain mEtastasis (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: MedSIR | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Zai Lab Announces Acceptance of Supplemental New Drug Application for Repotrectinib for Patients with NTRK-Positive Solid Tumors (Businesswire) - "Zai Lab Limited...announced that China’s National Medical Products Administration (NMPA) has accepted the supplemental New Drug Application (sNDA) for repotrectinib for the treatment of adult patients with solid tumors that harbor a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The application is intended for patients whose disease is locally advanced or metastatic, or where surgical resection is likely to result in severe morbidity, and who have either progressed following prior therapies or have no satisfactory alternative treatment options."

China filing • Solid Tumor • NTRK

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer, Version 2.2025. (NCCN)

NCCN guideline • Gastric Cancer

Molecular Testing and Targeted Therapies in Hepatobiliary Cancers: A Review. (PubMed, JAMA Surg) - "Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue-agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease."

IO biomarker • Journal • Tumor mutational burden • Biliary Cancer • Biliary Tract Cancer • Hepatocellular Cancer • Hepatology • Microsatellite Instability • Oncology • Solid Tumor • BRAF • HER-2 • MSI • NTRK • RET • TMB

REPLOT Trial: Phase II study of repotrectinib with or without fulvestrant in patients with HR+ HER2- metastatic invasive lobular carcinoma previously treated with endocrine therapy and CDK4/6 inhibition (AACR 2025) - "Abstract is embargoed at this time."

Clinical • Metastases • P2 data • Oncology • HER-2

ANS03, a novel, orally bioavailable small-molecule type II ROS1/NTRK inhibitor, effectively overcomes clinically relevant ROS1/NTRK resistance mutations and exhibits potent antitumor activity in preclinical tumor models (AACR 2025) - "ANS03 also had better activity against the ROS1 L2086F mutation when compared to both Repotrectinib and NVL-520. Non-clinical studies of ANS03 showed it is a potent, orally bioavailable Type II ROS1/NTRK inhibitor with remarkable activity against various pathogenetic ROS1/NTRK alterations and with favorable absorption, distribution, pharmacokinetics, efficacy, and tolerability profiles in vivo. The compound will enter Phase 1 clinical development in the US and China soon."

Preclinical • Oncology • NTRK • NTRK1

Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions. (PubMed, Cancer) - "First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%...Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges...Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability...In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) the NCCN Drugs & Biologics Compendium (NCCN Compendium), the NCCN Radiation Therapy Compendium, the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC), and NCCN Chemotherapy Order Templates (NCCN Templates) for Hepatocellular Carcinoma, Version 1.2025. (NCCN)

NCCN guideline • Hepatocellular Cancer

Efficacy of subsequent therapy following the progression of crizotinib in advanced ROS1+ NSCLC in real word setting (ELCC 2025) - "Next-generation ROS1-TKI (repotrectinib, taletrectinib, TL-139) demonstrated superior efficacy over non-next-generation TKI (PFS: 13.9 m vs 4.4 m, HR = 0.46, 95%CI: 0.24–0.86, p = 0.04; ORR: 70% vs 20%, p = 0.002). ORR was 66.7% for patients carrying G2032R mutation treated with next-generation TKI while non-next-generation TKI presented dismal response in another 7 patients with secondary ROS1 mutation (G2032R, D2033N, L2026M, S1986F), only 1 patient with L2026M mutation showed response to lorlatinib, the rest of them demonstrated progressive disease... Next-generation ROS1-TKI should be the preferred subsequent choice after the resistance of crizotinib especially for patients with ROS1 secondary mutation. Lolatinib should also be considered particularly in patients with CNS metastases while entrectinib should no be routinely recommended. IO-based combination treatment was no better than traditional platinum-doublet chemo plus anti-VEGF therapy."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

A Phase 1 Study to Evaluate the Potential Drug Interactions Between Repotrectinib and Metformin, Digoxin, and Rosuvastatin in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Turning Point Therapeutics, Inc. | N=12 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Oncology • Solid Tumor • NTRK1 • NTRK2 • NTRK3 • ROS1

Progression-Free Survival and Objective Response Rates As Surrogate Endpoints for Overall Survival Among Patients With ROS1+ Locally Advanced or Metastatic Non-Small Cell Lung Cancer Receiving ROS1 Tyrosine Kinase Inhibitors (ISPOR 2025) - "R2 was calculated along with 95% confidence intervals (CIs) using a bootstrapping method. Twelve cohorts from non-randomized clinical trials involving treatment with crizotinib, entrectinib, lorlatinib, brigatinib or ceritinib were identified; repotrectinib cohorts were excluded. The current analysis demonstrated strong associations between OS and both PFS and ORR among TKI-treated patients with ROS1+ aNSCLC, lending support to previous real world evidence evaluating surrogacy of PFS. However, uncertainty was substantial and the lack of head-to-head evidence precluded assessment of the correlation between treatment effects."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Cost Per PFS-Based Responder for TKI-Naive Patients Receiving Repotrectinib or Entrectinib in ROS1 Fusion Positive Non-Small Cell Lung Cancer (NSCLC) in the United States (US) (ISPOR 2025) - "This study demonstrates the economic and clinical benefits of repotrectinib versus entrectinib in TKI-naive patients with ROS1+ NSCLC. Cost per PFS-based responder provides a pragmatic evaluation of the investment required to extend progression-free outcomes in ROS1+ NSCLC patients."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Cost-Effectiveness Analyses of Repotrectinib in TKI-Naïve Patients with ROS1+ Advanced Non-Small Cell Lung Cancer (ISPOR 2025) - "This study aims to evaluate the cost-effectiveness of repotrectinib versus SoC in TKI-naïve patients with ROS1+ advanced NSCLC. The model takes a hypothetical UK NHS perspective and estimates outcomes/costs of repotrectinib versus entrectinib over a 30-year time horizon at a 3.5% annual discount rate. Repotrectinib is a cost-effective option for TKI-naïve patients with ROS1+ advanced NSCLC. These findings were robust across a variety of scenarios and sensitivity analyses."

Clinical • Cost effectiveness • HEOR • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Zai Lab Announces Fourth Quarter and Full Year 2024 Financial Results and Recent Corporate Updates (Businesswire) - "Tisotumab Vedotin (Tissue Factor ADC): BLA submission in recurrent or metastatic cervical cancer following progression on or after chemotherapy in the first quarter of 2025. Bemarituzumab (FGFR2b): BLA submission in first-line gastric cancer in the first half of 2025. Repotrectinib (ROS1/TRK): supplementary NDA submission in NTRK+ solid tumors in the first half of 2025. Tumor Treating Fields (TTFields): Marketing Authorization Application submissions in second-line+ NSCLC following progression on or after platinum-based chemotherapy and in first-line pancreatic cancer...Second-Line+ Extensive-Stage SCLC (ES-SCLC): Zai Lab to present updated data at a major medical conference in the first half of 2025. Zai Lab plans to initiate a pivotal study in 2025...Other neuroendocrine tumors: Zai Lab to initiate a global Phase 1 study in the first half of 2025...ZL-6201 (LRRC15 ADC): Zai Lab to provide preclinical data update and initiate a global Phase 1 study in sarcoma."

China filing • Clinical data • New P1 trial • Preclinical • Cervical Cancer • Gastric Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Sarcoma • Small Cell Lung Cancer • Solid Tumor

The Potential Long-Term Comparative Effectiveness of Larotrectinib vs Repotrectinib for Treatment of NTRK Gene Fusion-Positive Cancers (ISPOR 2025) - P1, P1/2, P2 | "We extrapolated results from clinical studies of larotrectinib and repotrectinib in locally advanced or metastatic NTRK gene fusion-positive cancers in adults. Larotrectinib may produce substantial life expectancy and quality-adjusted life-year gains relative to repotrectinib. Additional data with more mature data will further inform this comparison."

HEOR • Oncology • NTRK

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting. (PubMed, Lung Cancer) - "For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI...For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib...In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib...Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in..."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • ROS1

The information-seeking behaviour of health care providers for drug-drug interaction signals with lung cancer agents (ELCC 2025) - "The five most queried lung cancer drugs were repotrectinib (25%), osimertinib (17%), paclitaxel (14%), lorlatinib (11%) and afatinib (6%). The results show that HCPs find a clinically relevant interaction in almost half of all queries. The data give insights of the global population's commonly used lung cancer drugs and comedications. The information could serve both educational activities on DDIs and prioritize DDI studies with lung cancer agents."

Lung Cancer • Oncology • Solid Tumor

Population-Adjusted Indirect Treatment Comparisons of Repotrectinib Among Patients with ROS1+ NSCLC. (PubMed, Cancers (Basel)) - "The analysis demonstrated the strong benefits of repotrectinib in PFS, which was robust across different SAs and supported by numerically favorable results for DoR (where available) and ORR. These results, alongside the published TRIDENT-1 clinical data, further support repotrectinib as a potential new standard of care for TKI-naïve patients with ROS1+ aNSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

CA127-1072: A Study to Assess the Effect of Voriconazole and Quinidine on the Pharmacokinetics of a Single Dose of Repotrectinib in Healthy Participants (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial primary completion date: Dec 2024 ➔ Jul 2025 | Trial completion date: Dec 2024 ➔ Jul 2025

Trial completion date • Trial primary completion date

Tumor-Agnostic Approvals of T-DXd and Repotrectinib Carry the Field Forward (OncLive) - "Barata also noted that care teams are in the process of adapting and figuring out optimal workflows with the arrival of more pan-tumor approvals. 'For germline [testing], do you have a genetic counselor, or do you have to do the pretest counseling, and then what do you do with the positive results? Do you have a genetic counselor there, or do you have to provide a remote genetic counseling service? All those are relevant, important questions that the care teams are struggling to figure out the right answer to, and my guess is the right answer is not the same for all the care teams out there.'"

Media quote

Augtyro: Expiry of patents related to composition-of-matter in US in 2035 (Bristol-Myers Squibb) - Annual Report 2024: Regulatory data protection in US until 2035

Commercial • Patent • Lung Cancer • Non Small Cell Lung Cancer • Oncology

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), the NCCN Radiation Therapy Compendium, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC) for Breast Cancer, Version 1.2025. (NCCN)

NCCN guideline • Breast Cancer