1081O - ctDNA reduction and clinical efficacy of the darovasertib + crizotinib (daro + crizo) combination in metastatic uveal melanoma (MUM)

Background

MUM has limited effective therapies. Driver mutations in GNAQ/11 occur in >95% of MUM, activating protein kinase C (PKC) signaling. Darovasertib (IDE196), an oral PKC inhibitor, has clinical activity in MUM (Br J Cancer. 2023;128(6):1040-1051). Crizotinib, an oral c-MET inhibitor, showed synergy with Daro pre-clinically. This phase 1/2 study evaluated the combination in first line (1L) and pretreated MUM.

Methods

Eligibility included RECIST 1.1 measurable disease, ECOG 0-1 and adequate organ function. Dose escalation used a 3 + 3 design with 3 escalation cohorts, followed by expansion at 300 mg BID Daro + 200 mg BID Crizo. Safety, efficacy, and circulating tumor (ct) DNA were assessed.

Results

At 08Mar2023 data cut-off, of 68 MUM pts treated at the expansion dose (safety population (SP)) as of September 2022, 63 were evaluable for response (per-protocol efficacy population (PPEP)). The PPEP had a large tumor burden: 66% with largest metastatic lesion > 3cm, 64% with hepatic + extrahepatic disease, & 60% with elevated LDH. HLA-A2*02:01 status (n=51 tested): 63% neg., 37% pos. In the SP, the most common drug-related adverse events (AEs) (>30%) were diarrhea, nausea, edema, fatigue, hypotension & rash. AEs were largely Grade 1-2. Related Serious AEs were seen in 6 (9%) pts and AEs leading to discontinuation in 4 (6%) pts. In the PPEP, 30% had a confirmed partial response (cPR) with 92% of patients having tumor shrinkage. First-line (1L) pts (n=20) had a cPR of 45% with 95% of patients having tumor shrinkage. Median PFS (mPFS) in both PPEP and 1L pts was ∼7 months. In pts with hepatic only disease (n=20 pts, 1L and pretreated), an ORR of 35% and mPFS was 11 months. Clinical efficacy was seen in both HLA-A2 pos. and neg. pts. There were deep & sustained ctDNA molecular responses in the majority of pts.

Conclusions

Initial evaluation of Daro + Crizo in both 1L & pretreated pts with MUM showed a manageable safety profile and clinical efficacy that appears superior to current standards of care. ctDNA was reduced in almost all pts. These data support the registrational phase II/III study for potential accelerated approval in 1L HLA-A2 neg. MUM, where there are no FDA approved therapies.

Clinical trial identification

NCT03947385.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

IDEAYA Biosciences.

Disclosure

M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, Eisai, IQVIA, Merck, Moderna; Financial Interests, Personal, Other, Consulting: iTeos; Financial Interests, Institutional, Research Grant: Ascentage 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 Therapeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Bayer, Arvinas, ASCO, Astellas, 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. 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. M.O. Butler: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck, Novartis, Sanofi, Pfizer; Financial Interests, Personal, Advisory Board: Merck, Bristol Myers Squibb, Novartis, Adaptimmune, Instil Bio, Iovance, Sun Pharma, GSK, Sanofi, LaRoche Possey, Pfizer, Medison, IDEAYA, Regeneron; Financial Interests, Personal, Research Grant: Merck, Takara Bio, Novartis. R. Carvajal: Financial Interests, Personal, Advisory Board: Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath, Eisai, Hengrui, IDEAYA, Immunocore, InxMed, Iovance, Merck, Novartis, OncoSec, Pierre Fabre, Puretech Health, Regeneron, Sanofi, TriSalus. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, iOnctura SA; Financial Interests, Personal, Other, Consultancy: Aadi Bioscience, Clarion Healthcare, Debiopharm, Monte Rosa Therapeutics, Cullgen, Pfizer, Merus N.V., Macrogenics, Oncology One, Envision Pharma, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero de Empleo y Seguridad, Chinese University of Hong Kong, Boxer Capital LLC, Tang Advisors LLC, Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millennium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, Aadi Bioscience, Nuvation, Fore Biotherapeutics, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, IDEAYA, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer; Other, Travel: European Society for Medical Oncology; Other: VHIO/Ministero de Empleo y Seguridad Social. M. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, OncoSec, Merck, Sanofi, IDEAYA, Pierre Fabre, Eisai, Nektar, Regeneron. K.B. Kim: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Aveo, Regeneron, Sanofi; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Institutional, Funding, Moderna has provided funding to the institution for conducting a clinical trial of Moderna's drug: Moderna. T. Wise-draper: Financial Interests, Personal, Other, Consultant: Shattuck Labs, Need Inc.; Financial Interests, Personal, Advisory Board: Exicure, Rakuten Medical, Merck & Co.; Financial Interests, Personal, Invited Speaker: Physician Education Resource; Financial Interests, Personal, Other, Consultant for Molecular Tumor Board: Caris Life Sciences; Financial Interests, Personal, Ownership Interest: High Enroll; Financial Interests, Personal, Research Grant: BMS, Merck & Co., Tesaro/GSK, AstraZeneca, Janssen; Financial Interests, Personal and Institutional, Local PI: BMS, EMD Serono, Replimune, AstraZeneca, Alkermes, Exicure, Shattuck Labs, Boston Medical, Debio Pharm, Eli Lilly, Epizyme, Iovance, Agenus, SQZ Biotech, Triumvera, Adlai Nortye, Yingli, Vyriad, IDEAYA, MINK, Sinogen. S. Khan: Financial Interests, Personal, Advisory Board: Castle Biosciences, Replimune Inc. A.K.S. Salama: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Iovance, Regeneron, Replimune, Novartis, Pfizer; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Ascentage, IDEAYA, Immunocore, Merck, Regeneron, Replimune, Seagen; Financial Interests, Institutional, Trial Chair: Olatec. 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 Therapeutics, FujiFilm, ImmunSensor, Simcha Therapeutics, Repertoire Immune Sciences, Nektar Therapeutics, Synthorx Inc., Istari Oncology, IDEAYA Biosciences, Rubius Therapeutics, University of Arizona, Senwha Biosciences, Storm Therapeutics, Werewolf Therapeutics, Fate Therapeutics, Y-mab Therapeutics, Agenus; Financial Interests, Personal, Local PI: Bioeclipse Therapeutics. M. Maurer: Financial Interests, Personal, Other, Independent Medical Consultant for ongoing Healthy Volunteer study: The Global Health Drug Discovery Institute (GHDDI); Financial Interests, Personal, Full or part-time Employment, Full time employee of IDEAYA Biosciences; Financial Interests, Personal, Stocks/Shares, Own stock in BMS (BMY): BMS; Financial Interests, Personal, Stocks/Shares, Own stock and stock options in IDEAYA Biosciences (IDYA); Non-Financial Interests, Member, Regular member: ASCO. M. Abed: Financial Interests, Personal, Full or part-time Employment: IDEAYA Biosciences, Zentalis. B. Mitchell: Financial Interests, Personal, Full or part-time Employment, Employee of IDEAYA. Biosciences; Financial Interests, Personal, Stocks/Shares, Employee Stock Options: IDEAYA Biosciences. 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. M. Orloff: Financial Interests, Personal, Advisory Board: Tirsalus, Delcath, Replimune, IDEAYA Biosciences; Financial Interests, Personal, Speaker’s Bureau: Immunocore. All other authors have declared no conflicts of interest.