1139TiP - IDE196 (darovasertib) in combination with crizotinib versus investigator’s choice of treatment as first-line therapy in HLA-A2 negative metastatic uveal melanoma

Background

Activating mutations in GNAQ & GNA11 (GNAQ/11), the Gα subunits of certain G protein-coupled receptors, have been observed in >90% of patients (pts) with uveal melanoma (UM) and are considered genetic disease drivers. These mutations are present in other solid tumors, including cutaneous and mucosal melanoma, and are recorded in The Cancer Genome Atlas (TCGA) and FoundationOne databases. IDE196 (Darovasertib, previously known as LXS196) is a selective protein kinase C inhibitor which has demonstrated preliminary anti-tumor activity in patients with metastatic UM (MUM). In a phase I/II study the combination of IDE196+ crizotinib (a MET inhibitor) demonstrated an objective response rate (ORR) of 45% in treatment-naïve patients with MUM. The purpose of this study is to determine clinical and safety outcomes of IDE196 in combination with crizotinib in adult participants with HLA-A2 negative MUM.

Trial design

Study IDE196-002 (NCT05987332) is a phase II/3, multi-arm, multi-stage, multicenter, global, open-label study for first-line therapy for HLA-A*02:01 negative patients with MUM who will be randomized to receive either IDE196 + crizotinib or investigator's choice of treatment (ipilimumab + nivolumab, pembrolizumab or dacarbazine). Approximately 260 and 120 MUM pts will be enrolled in phase II (phase IIa and 2b) and phase III portions of the study, respectively. The primary endpoints of the phase IIa portion are to determine the recommended phase II dose of IDE196 + crizotinib for expansion in the phase IIb portion of the trial and to compare the Progression Free Survival (PFS) of IDE196 + crizotinib vs the investigator’s choice per RECIST 1.1, as assessed by the Blinded Independent Central Review (BICR) committee. Secondary endpoints include ORR, disease control rate (DCR), safety and pharmacokinetics parameters. The primary endpoint of the phase III portion is to compare IDE196 + crizotinib to investigator’s choice of treatment with respect to overall survival (OS).

Clinical trial identification

NCT05987332.

Editorial acknowledgement

Legal entity responsible for the study

IDEAYA Biosciences.

Funding

IDEAYA Biosciences.

Disclosure

M.O. Butler: Financial Interests, Personal, Advisory Board: BMS, Merck, Novartis, Adaptimmune, Iovance, GSK, Sanofi, laRoche Possey, Pfizer, Medison, IDEAYA, Regeneron; Financial Interests, Personal, Invited Speaker: BMS, Merck, Novartis, Sanofi, Pfizer; Financial Interests, Personal, Advisory Board, Safety Review Committee: Adaptimmune; Financial Interests, Institutional, Other, Conduct Clinical Trial: TCR2, Novartis, Sanofi, Immunocore, GSK, Pfizer, Merck, Bristol Myers Squibb, Regeneron, AstraZeneca, Adaptimmune, IDEAYA Biosciences, Amgen, Instil Bio, Turnstone Biologics, Iovance, Ankara; Financial Interests, Institutional, Research Grant, support clinical trial: Merck; Financial Interests, Institutional, Funding, support clinical trial: Takara Bio; Financial Interests, Institutional, Funding, support quality improvement project: Novartis. B. Chmielowski: Financial Interests, Personal, Other, DMC: Nektar; Financial Interests, Personal, Advisory Board: Novartis, Delcath Systems, Instil Bio, Replimune; Financial Interests, Institutional, Local PI, Clinical trial support: Bristol Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Biotherapeutics, Xencor, Compugen, Iovance, PACT Pharma, RAPT Therapeutics, Immunocore, Ascentage, Atreca, Replimune, IDEAYA Biosciences, Instil Bio; Financial Interests, Institutional, Local PI, clinical trial support: Adagene, TriSalus Life Sciences, Kinnate Biopharma, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences. R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, MaviVAX SA, T3 Pharma, Pfizer, Simcere. M.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre Fabre, Eisai, Nektar, Regeneron. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscienc, Boehringer Ingelheim Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InconVir, Jazz Pharmaceutical, Krystal Biotech, NucMito Pharmaceuticals, OnKure, Remix Therapeutics. J. Moser: Financial Interests, Personal, Advisory Board: BMS, Amunix, Thirona Bio, Adagene, IQVIA, Incyte, Boxer Capital, Oberland Capital; Financial Interests, Personal, Other, Consultant: Imaging Endpoints; Financial Interests, Personal, Invited Speaker: Immunocore, Caris Life Sciences; Financial Interests, Personal, Other, Molecular Tumor Board Member: Caris Life Sciences; Financial Interests, Institutional, Coordinating PI: Novocure; Financial Interests, Institutional, Local PI: Genentech, Alpine Immune Sciences, Amgen, Trishula Therapuetics, FujiFilm, ImmunSensor, Simcha Therapeutics, Repertoire Immune Sciences, Nektar Therapeutics, Synthorx Inc, Istari Oncology, Ideaya Biosciences, Rubius Therapuetics, University of Arizona, Senwha Biosciences, Storm Therapuetics, Werewolf Therapeutics, Fate Therapuetics, Y-mab Therapuetics, Agenus; Financial Interests, Personal, Local PI: Bioeclipse Therapeutics. S. Khan: Financial Interests, Personal, Advisory Board: Castle Biosciences, Replimmune Inc. K.B. Kim: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Arvinas, Cryoport; Financial Interests, Institutional, Funding, Moderna has provided funding to the institution for conducting a clinical trial of Moderna's drug: Moderna; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Merck, Regeneron, Iovance Biotherapeutics, ImmunoCore, Astex Pharmaceuticals, Ideaya Biosciences, Summit Pharmaceuticals. J. Lutzky: Financial Interests, Personal, Other, reviewed grant applications for department of defense: general dynamics; Financial Interests, Personal, Advisory Board: Regeneron, Immunocore; Financial Interests, Personal, Other, safety monitoring committee: agenus, Celldex; Financial Interests, Institutional, Research Grant, Funding for institutional trial: BMS; Financial Interests, Institutional, Local PI: Trisalus, Takeda, Vyriad, Tango, Immunocore, Replimune, Oncohost, Dragonfly, Iovance, Ideaya. M. Shackleton: Financial Interests, Personal, Invited Speaker, Have given paid lectures about melanoma management: Novartis, Pierre Fabre; Financial Interests, Personal, Advisory Board, Have given paid lectures about melanoma management: MSD, BMS; Financial Interests, Personal, Advisory Board: Roche; Non-Financial Interests, Advisory Role, Advised regarding TGA and PBAC approval of avelumab for Merkel Cell Cancer: Merck; Non-Financial Interests, Advisory Role: Ideaya. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Pierre Fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre Fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS; Financial Interests, Personal, Other, Travel support: Pierre Fabre; Financial Interests, Personal, Other, Advisory Board: Immunocore. D. Beaupre: Financial Interests, Personal, Full or part-time Employment, Employee: Ideaya; Financial Interests, Personal, Stocks/Shares, Stock: Ideaya; Non-Financial Interests, Leadership Role, CMO of organization: Ideaya; Non-Financial Interests, Institutional, Proprietary Information, Access to company confidential information: Ideaya. G.W. Cole Jr: Financial Interests, Personal, Full or part-time Employment: Ideaya Biosciences; Financial Interests, Personal, Stocks/Shares: Ideaya Biosciences; Non-Financial Interests, Member: ASCO. H. Patel: Financial Interests, Personal, Full or part-time Employment, Medical Director or Clinical Research and Pharmacovigilance: Heron Therapeutics; Financial Interests, Personal, Full or part-time Employment, Sr Medical Director: Ideaya Biosciences; Financial Interests, Personal, Stocks/Shares: Ideaya Biosciences. M. Orloff: Financial Interests, Personal, Invited Speaker: Immunocore; Financial Interests, Personal, Advisory Board: replimune, Ideaya, Delcath, Immunocore; Financial Interests, Institutional, Local PI: Immunocore, Ideaya, Ascentage, Foghorn, Iovance, Linneaus, trisalus. All other authors have declared no conflicts of interest.