1256MO - Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours

Background

Zidesamtinib is a brain-penetrant, TRK-sparing, highly selective ROS1 tyrosine kinase inhibitor (TKI) with activity against diverse ROS1 fusions and resistance mutations including G2032R.

Methods

The global ARROS-1 phase (ph) 1 (NCT05118789) enrolled pts with heavily pretreated advanced/metastatic ROS1+ solid tumors. Key objectives were selection of a recommended ph 2 dose (RP2D) and evaluation of safety and efficacy (RECIST 1.1, investigator assessment). Data cut: 12 March 2024.

Results

104 pts (99 NSCLC, 5 other) received zidesamtinib (25-150 mg orally once daily [QD]) in ph 1. Pts had a median of 3 (range: 1-11) prior anticancer therapies, including any ROS1 TKI (99%); lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); ≥2 ROS1 TKIs (69%); and chemo (66%). 53% had history of CNS metastases (mets). 100 mg QD was selected as the RP2D with no observed dose relationships for safety or efficacy. No dose-limiting toxicity or discontinuation due to treatment-related adverse event (TRAE) occurred. TRAE led to dose reduction in 5.8%. Most common TRAEs were peripheral edema (18%) and transaminase increase (12%); TRAEs were grade ≥3 in 7.7%. 73 pts with ROS1+ NSCLC were response-evaluable (Table). Table: 1256MO

NE, not estimable; NR, not reached.∗ 2 complete responses (CRs), ongoing with DOR 16.6+ and 23.5+mMedian follow-up for response evaluable pts 9.4m (range, 0.8 - 25.8m)

In pts with known ROS1 G2032R, ORR was 65% (11/17) with mDOR 15.8m (6, NE) among repo-naïve pts and ORR was 38% (3/8) among repo-pretreated pts. In pts with measurable intracranial (IC) mets and ≥2 prior ROS1 TKIs (all with prior lorlatinib and/or repo), IC ORR was 57% (4/7), and IC DOR range was 1.9+ - 17.3+m with no IC progression.

Conclusions

Zidesamtinib demonstrated encouraging efficacy and durability in pts with pretreated ROS1+ NSCLC, including those who had exhausted available therapies, with ROS1 resistance mutations including G2032R, and/or with CNS mets. Safety was favorable and consistent with the highly ROS1-selective and TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent in pts with TKI-naïve and pretreated ROS1+ NSCLC.

Clinical trial identification

NCT05118789.

Editorial acknowledgement

Legal entity responsible for the study

Nuvalent Inc.

Funding

Nuvalent Inc.

Disclosure

B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BeiGene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd., 4D Pharma, AbbVie, Da Voltera, Eli Lilly, Ellipse pharma Ltd., F-Star, GSK, Janssen, Onxeo, OSE Immunotherapeutics, Socar research, Taiho Oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Blueprint Medicines, Daiichi Sankyo, Pfizer, Roche-Genentech, Turning Point Therapeutics, Nuvalent, Enliven, Prelude therapeutics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, OSE Immunotherapeutics, Sanofi, Taiho; Financial Interests, Institutional, Steering Committee Member: BeiGene, GSK, Janssen, Takeda, Genmab; Financial Interests, Institutional, Funding: Cristal Therapeutics. A.E. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc., EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd.; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, PUMA, Merus; Other: Boehringer Ingelheim. B.C. Cho: Financial Interests, Personal, Other, Consulting role: Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Medpacto, Blueprint medicines, RandBio, Hanmi, GC Cell, Gilead, Ridgeline Discovery GmbH; Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc., J INTS Bio, Therapex Co., Ltd., Gilead, Amgen, AstraZeneca, Regeneron, Seagen, Samsung Bioepis; Financial Interests, Personal, Member of Board of Directors: Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc., Gencurix Inc., Bridgebio therapeutics, KANAPH Therapeutic Inc., Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Personal, Royalties: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: CHA Bundang Medical Center, MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, Gradiant Bioconvergence, Therapex, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, JINTSbio, Hanmi, Daewoong Pharmaceutical Co., Ltd., Vertical Bio AG, Korea Institute of Oriental Medicine, National Research Foundation of Korea, KHIDI; Other, Founder: DAAN Biotherapeutics; Other, Invited speaker: ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer, Liangyihui Network Technology Co., Ltd. D.R. Camidge: Financial Interests, Personal, Advisory Role: AbbVie, AnHeart, Apollomics, Astra Zeneva/Daiichi, BeiGene, BMS, Eli Lilly, Genesis, Sutro, Takeda, Apollomics, Aveo, Coherus, Gilead, Hengrui (DSMB), Imagene (SAB), Immunocore, Janssen, Lianbio, Merck KGa, Mirati, Nalo, Newsoara, Nextcure, Prelude, Roche, Sanofi, Seattle Genetics, Valence, Xencor, EMD Serono, Elevation, Hummingbird, Janssen, Medtronic, Mersana (ILD Adjucation Committee), Onkure, Regeneron, Thesus, Xcovery; Financial Interests, Personal, Local PI: Blueprint, AbbVie, AstraZeneca, Dizal, Inhibrix, Karyopharm, Nuvalent, Pfizer, Phosplatin, Rain, Roche/Genetech, Seattle Genetics, Takeda, Turning Point, Verastem. J. Neal: Financial Interests, Personal, Advisory Board: AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, AnHeart Therapeutics; Financial Interests, Institutional, Funding: Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen, AbbVie, Novocure; Other, Honoraria: CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, HMP Education. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim, Anbogen, IMPACT Therapeutics; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics; Financial Interests, Institutional, Other, Local principal investigator: Nuvalent. S.V. Liu: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Daiichi Sankyo, Elevation Oncology, Genentech / Roche, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Regeneron, Sanofi; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Catalyst, RAPT Therapeutics, Gilead, Guardant Health, Merus, Takeda, Revolution Medicines, Amgen, AbbVie, Boehringer Ingelheim, Mirati, Pfizer; Financial Interests, Institutional, Local PI: Alkermes, Elevation Oncology, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics, AbbVie, AstraZeneca, Puma; Financial Interests, Institutional, Steering Committee Member: Genentech; Financial Interests, Institutional, Coordinating PI: OSE Immunotherapeutics; Non-Financial Interests, Member: ASCO, IASLC. M. Nagasaka: Financial Interests, Institutional, Local PI: Nuvalent; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyao, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly, Bayer, Regeneron, BMS, Genentech; Financial Interests, Personal, Speaker, Consultant, Advisor: Caris Life Sciences; Financial Interests, Institutional, Speaker, Consultant, Advisor: Blueprint Medicines, Janssen, Mirati, Takeda; Financial Interests, Institutional, Stocks/Shares: MBrace Therapeutics. S.C. Kao: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, MSD, BMS, Roche, Amgen, BeiGene, Boehringer Ingelheim, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: MSD, BMS, Roche, AstraZeneca, Pfizer, Takeda, BeiGene, Daiichi Sankyo; Financial Interests, Institutional, Other, Research grant: AstraZeneca; Non-Financial Interests, Principal Investigator: Nuvalent, AstraZeneca. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc., Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. A.J. Van Der Wekken: Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Takeda; Financial Interests, Institutional, Advisory Board: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Local PI: Nuvalent, Inc. C.C. Lin: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, BMS, Boehringer, Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Invited Speaker: AstraZeneca, Amgen, BMS, Boehringer, Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Local PI: Nuvalent, Inc. J.R. Bauman: Financial Interests, Personal, Advisory Board: EMD Serono, Pfizer; Financial Interests, Institutional, Local PI: Nuvalent. S. Gadgeel: Financial Interests, Personal, Advisory Board: Pfizer, Genentech-Roche, Takeda, Regeneron, Amgen, Gilead, Arcus, Eisai, Lilly, Novartis, BMS, AnnHeart, I-MAB; Financial Interests, Personal, Advisory Board, IDMC: AstraZeneca; Financial Interests, Personal, Advisory Board, Additional Travel Support to attend meetings: Merck, Mirati; Financial Interests, Institutional, Local PI: Nuvalent. M. Samant, J. Shen, Y. Sun, V.W. Zhu, V.A. Upadhyay: Financial Interests, Personal, Full or part-time Employment: Nuvalent; Financial Interests, Personal, Stocks/Shares: Nuvalent. J.J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics, Nuvalent, Elevation Oncology, C4 Therapeutics, Bayer, Novartis, Mirati Therapeutics, Regeneron, CLaiM Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines, Genentech; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Institutional, Local PI: Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Novartis, Hengrui Therapeutics, Pfizer, Nuvalent.