Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC

BackgroundEntrectinib is a potent CNS-active ROS1 tyrosine kinase inhibitor (TKI). Previous integrated analyses of three phase 1/2 trials (STARTRK-2 [NCT02568267]; STARTRK-1 [NCT02097810]; ALKA-372-001 [EudraCT 2012-000148-8]), showed that entrectinib had overall and intracranial (IC) efficacy in pts with ROS1-fp NSCLC. We report updated data with longer follow-up and more pts than previous analyses from these studies.MethodsEfficacy-evaluable pts were ROS1 TKI-naïve and ≥18 years old, and had locally advanced/metastatic ROS1-fp NSCLC, ≥1 entrectinib dose and ≥12 months (mos) follow-up from first post-treatment initiation tumour assessment. All pts who had received ≥1 entrectinib dose were safety evaluable. Tumour response was assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and then every 8 weeks. Primary endpoints were ORR and duration of response (DoR). Key secondary endpoints: progression-free survival (PFS); overall survival (OS); IC-ORR; IC-DoR; safety.ResultsAs of 16 July 2023, 198 pts were efficacy evaluable; median age was 54 years (range 20–86). Median follow-up was 49.4 mos. Entrectinib showed efficacy in pts with ROS1-fp NSCLC, including those with or without baseline CNS metastases (mets) (Table). In pts with baseline CNS mets by BICR (n=67), IC-ORR was 40.3% (95% CI 28.5–53.0) and median IC-DoR was 12.9 mos (95% CI 8.0–22.2). In the subset of pts who received entrectinib as first-line (1L) treatment (1L cohort, n=85; exploratory analyses; Table), ORR was 68.2% (95% CI 57.2–77.9); median DoR was 35.6 mos (95% CI 14.8–40.4); median PFS was 17.5 mos (95% CI 12.0–30.4). Overall, 247 pts were safety evaluable; safety data were in line with the known safety profile of entrectinib. Table: 1290P Efficacy evaluable (N=198) Baseline CNS mets ∗ (n=68) No baseline CNS mets ∗ (n=130) 1L cohort (n=85) ORR†, n (%) [95% CI] 133 (67.2) [60.2–73.7] 42 (61.8) [49.2–73.3] 91 (70.0) [61.3–77.7] 58 (68.2) [57.2–77.9] CR 29 (14.6) 5 (7.4) 24 (18.5) 14 (16.5) PR 104 (52.5) 37 (54.4) 67 (51.5) 44 (51.8) Median DoR†, mos (95% CI) 20.4 (14.9–33.3) 14.9 (11.0–20.2) 33.1 (15.3–38.7) 35.6 (14.8–40.4) Median PFS†, mos (95% CI) 15.8 (12.0–21.1) 10.0 (7.7–15.5) 26.3 (15.7–36.6) 17.5 (12.0–30.4) Median OS, mos (95% CI) 46.9 (41.0–67.4) 25.7 (16.1–40.2) 57.7 (45.0–NE) 52.3 (44.6–NE) ∗ By investigator; †By blinded independent central review. NE, not evaluable ConclusionsConsistent with previous reports, entrectinib continues to show overall and IC efficacy and a manageable safety profile in pts with ROS1-fp NSCLC, including those who received it in 1L.Clinical trial identificationSTARTRK-2 (NCT02568267); STARTRK-1 (NCT02097810); ALKA-372-001 (EudraCT 2012-000148-8).Editorial acknowledgementThird party medical writing assistance, under the direction of the authors, was provided by Tahmina S. Alam, MA, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.Legal entity responsible for the studyF. Hoffmann-La Roche Ltd.FundingF. Hoffmann-La Roche Ltd.DisclosureM.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health, Zai Lab; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences, Ellipses; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche, Zai Lab. S. Lu: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Hutchinson MediPharma, ZaiLab, GenomiCare, Novartis, Yuhan Corporation, Menarini, Mirati Therapeutics, Inc., Daiichi Sankyo, Inc., D3 Bio Limited, Simcere, Takeda, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Hansoh; Non-Financial Interests, Personal, Member of Board of Directors: Innovent biologics, Inc.; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchinson, BMS, Heng Rui BeiGene, Roche, Hansoh; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Hansoh. A.E. Drilon: Financial Interests, Personal, Advisory Board: Bayer, MonteRosa, AbbVie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Loxo/Lilly, AnHeart Therapeutics; Financial Interests, Personal, Advisory Role: MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude, Zymeworks; Financial Interests, Personal, Invited Speaker: 14ner/Elevation Oncology, Amgen, AbbVie, ArcherDX, AstraZeneca, BeiGene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Mercus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Springer Healthcare, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem; Financial Interests, Personal, Other, Copyright (filed/pending): Selpercatinib-Osimertinib; Financial Interests, Personal, Other, Food/beverage: Merck, Puma, Mercus, Boehringer Ingelheim; Financial Interests, Personal, Other, CMS honoria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Clinical Care Options, EPG Health, JNCC/Harborside, Liberum, Remedica Ltd., Lungevity; Financial Interests, Institutional, Research Funding, Associated research: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Financial Interests, Institutional, Research Funding, Copyright (filed/pending): selpercatinib-osimertinib; Financial Interests, Institutional, Research Funding: Foundation Medicine; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Stocks or ownership: Equity: mBrace. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics, Merck, MSD. C. Xue: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd. D. Bradley: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Royalties: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks or ownership: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. X. Hu: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis; Financial Interests, Institutional, Other: Merck Sharpe & Dohme. All other authors have declared no conflicts of interest.