1253O - Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours

Background

NVL-655 is a potent, brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to address key limitations of prior generation ALK TKIs (1G, 2G, 3G); it demonstrates preclinical activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations, while avoiding TRK inhibition, which is associated with neurologic toxicities.

Methods

The global ALKOVE-1 phase (ph) 1 (NCT05384626) enrolled pts with pretreated advanced ALK+ solid tumors. Key objectives were selection of a recommended ph 2 dose (RP2D), safety, and efficacy (RECIST 1.1, investigator assessment). Data cut: 23 March 2024.

Results

133 pts (131 NSCLC, 2 other) received NVL-655 (15-200 mg orally once daily [QD]) in ph 1. Pts previously received a median of 3 (range: 1-8) prior anticancer therapies, including 2G ALK TKI or lorlatinib (100%), ≥1 2G ALK TKI & lorlatinib (79%), ≥3 ALK TKIs (46%), and chemotherapy (56%); 56% had a history of treated/untreated CNS metastases. A maximum tolerated dose was not reached. 150 mg QD was selected as the RP2D, providing favorable safety, activity and exposure exceeding targeted efficacy thresholds for ALK resistance mutations. Most common TRAEs were ALT increase (33%), AST increase (29%), constipation (15%), nausea (12%) and dysgeusia (11%); 2% discontinued due to TRAEs. Table: 1253O

NE, not estimable; NR, not reached∗13/15 responses ongoing (DOR range 1.1-9.0 m)CNS activity, including complete resolution of CNS metastases in lorlatinib-experienced pts, was observed.

Conclusions

NVL-655 demonstrated encouraging efficacy & durability in heavily pretreated ALK+ NSCLC pts, including pts who exhausted available therapies (including lorlatinib), with ALK single and compound resistance mutations, and with CNS metastases. Safety was favorable, consistent with the ALK-selective, TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent for previously treated pts.

Clinical trial identification

NCT05384626.

Editorial acknowledgement

Legal entity responsible for the study

Nuvalent, Inc.

Funding

Nuvalent, Inc.

Disclosure

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. J.J. Lin: Financial Interests, Personal, Speaker, Consultant, Advisor: Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Inc., Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Ellipses, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Yuhan, Merus, Regeneron, Pfizer, Turning Point Therapeutics; Financial Interests, Institutional, Local PI: Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, Inc., Novartis; Financial Interests, Personal, Other, Travel Support: Pfizer, Menrus. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Immunocore, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Pyramid Biosciences, Alentis Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, D3 Bio Limitied, Fate Therapeutics, Gilead Sciences, Hookipa Biotech, Lilly, Normunity, Novocure, Pfizer, Revolution Medicines, Sanofi-Aventis, Seagen, Synthekine, Takeda Pharmaceuticals, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics, ArriVent BioPharma, Bayer, LockBody Therapeutics, Taiho Oncology. 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Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, Astrazeneca, Merck Sharp & Dohme Corp., BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President. ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BeiGene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. 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J. Mazieres: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Pfizer, Jiangsu Hengruii, Blueprint, Daiichi Sankyo, Novartis, Amgen; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Pierre Fabre, BMS, Illumina. A. Swalduz: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer - Ingelheim, Ipsen, Janssen, Lilly, MSD, Pfizer, Roche, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, Daiichi Sankyo, Janssen, Roche, Pfizer, Sanofi. A.R. 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Liu: Financial Interests, Personal, Advisory Board: AnHeart, Amgen, AstraZeneca, Bayer, EMD Serono, Jazz, Johnson and Johnson, Merck, Novartis, Pfizer, Roche, Sterimax, Takeda; Financial Interests, Personal, Coordinating PI: Takeda, AstraZeneca; Financial Interests, Personal, Research Grant: Boehringer Ingelheim, Pfizer, AstraZeneca, Takeda; Financial Interests, Personal, Local PI: Nuvalent, Inc. B.J. Solomon: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Merck, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Amgen, Roche-Genentech, Eli Lilly, Takeda, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Employed as a consultant Medical Oncologist at Peter MacCallum Cancer Centre: Peter MacCallum Cancer Centre; Financial Interests, Personal, Member of Board of Directors: Cancer Council of Victoria, Thoracic Oncology Group of Australasia; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Steering Committee Member, Principal Investigator and Steering committee Chair: Roche/Genentech, Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis. D.R. Camidge: Financial Interests, Personal, Advisory Role: AbbVie, AnHeart, Apollomic, AstraZeneca/Daiichi Sankyo-BeiGene, BMS, Eli Lilly, Genesis, Sutro, Takeda, Aveo, Coherus, Gilead, Hengrui (DSMB), Imagene (SAB), Immunocare, Janssen, Liambio, Merck KGa, Mirati, Nalo, Newsoara, Nextcure, Prelude, Roche, sanofi, Seattle Genetics, Sutro, Valence, Xencor, EMD Serono, Elevation, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Regeneron, Takeda, Theseus, Xcovery; Financial Interests, Institutional, Local PI: Nuvalent, Inc., AbbVie, AstraZeneca, Blueprint, Dizal, Inhibrx, Karyopharm, Pfizer, Phosplatin, Rain, Roche/Genentech, Seattle Genetics, Takeda, Turning Point, Verastem. W. Swe, Y. Sun, J. Shen, V.W. Zhu: Financial Interests, Personal, Full or part-time Employment: Nuvalent; Financial Interests, Personal, Stocks/Shares: Nuvalent. E. Felip: Financial Interests, Personal, Local PI: Nuvalent, Inc.