459MO - Phase Ia study to evaluate GDC-6036 monotherapy in patients with solid tumors with a KRAS G12C mutation

Background

Advanced-stage tumors harboring a KRAS G12C mutation have limited treatment options. GDC-6036, a highly potent and selective KRAS G12C inhibitor, has shown robust tumor growth inhibition in multiple preclinical models of a variety of tumor types.

Methods

As part of an ongoing phase I dose-escalation/expansion study (NCT04449874), patients (pts) with KRAS G12C mutant other solid tumors (oST), exclusive of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) (NSCLC and CRC reported elsewhere), were administered GDC-6036 orally once a day in 21-day cycles until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1).

Results

As of 28 Jan 2022, 14 pts with pretreated oST (4 cholangiocarcinoma, 3 pancreatic adenocarcinoma, and 1 each: anus, appendix, breast, duodenum, endometrial, lung neuroendocrine, and stomach cancers) had received GDC-6036 monotherapy at 400 mg. Median (range) number of prior cancer therapies was 2 (1-8). No dose-limiting toxicities were reported across NSCLC, CRC and oST. Median (range) time on study treatment was 63.5 (8-151) days among oST pts, and median GDC-6036 dose intensity was 99%. Five (36%) pts had discontinued study treatment (4 radiographic progression and 1 death due to disease progression). The most frequent GDC-6036-related AEs reported in ≥ 2 pts were nausea, vomiting, diarrhea, alanine aminotransferase increased, and aspartate aminotransferase increased. Two (14%) pts required a dose modification (interruption, 1 pt; reduction, 1 pt; no withdrawal) for GDC-6036-related AEs. Across NSCLC, CRC and oST pts, the mean half-life for GDC-6036 ranged from 13-17 hours at doses of 50-400 mg. The unconfirmed overall response rate (ORR) in the oST pts was 21% (3/14 pts; anus, lung neuroendocrine and stomach cancers), while the confirmed ORR was 14% (2/14 pts).

Conclusions

GDC-6036 demonstrated an acceptable safety profile, a PK profile compatible with once-daily dosing, and encouraging efficacy in pts with pretreated oST with a KRAS G12C mutation. Data from additional pts will be presented.

Clinical trial identification

NCT04449874.

Editorial acknowledgement

Andrew Occiano (Genentech, Inc.) provided editing and writing assistance, which was funded by Genentech, Inc.

Legal entity responsible for the study

Genentech, Inc.

Funding

Genentech, Inc.

Disclosure

M. Patel: Financial Interests, Personal, Speaker’s Bureau: Exelis, Genentech/Roche, Taiho Pharmaceutical, Celgene; Financial Interests, Personal, Advisory Board: Mirati, Daiichi; Financial Interests, Personal, Advisory Role: Pharmacyclics/Janssen, Pfizer/EMD Serono; Financial Interests, Personal, Other, Travel Expenses: Pfizer, Pharmacyclics, Bayer, Janssen Oncology, Genentech; Non-Financial Interests, Institutional, Funding: Acerta Pharma ADC Therpeutics Agenus Aileron Therapeutics AZ Bicycle Therapeutics BioNTech AG Blueprint Boehringer Ingelheim Calithera Biosciences Celgene Checkpoint Therapeutics CicloMed Clovs Oncology Curis Cyteir Daiichi Sankyo eFFECTOR Therapeutics L. M.J. De Miguel: Financial Interests, Personal, Advisory Role: Syneos, Janssen, MSD; Financial Interests, Institutional, Funding: AbbVie, Array, Achilles, Basilea, Bayer, Biontech, Faron, MSD, Novartis, Cytomex, Genentech, Genmab, Janssen, Menarini, Nektar, Catalym, Regeneron, Zenith. T. Burns: Financial Interests, Personal, Advisory Board: Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals Inc, Blueprint Medicines Corporation (BPMC), Emd Serono Inc., Mirati Therapeutics, Inc.; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Other, DSMB: Advarra, Inc. A. Falcon Gonzalez: Financial Interests, Personal, Advisory Board: Seagen, Novartis, Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Lilly, Grunenthal pharma, Roche. T.W. Kim: Financial Interests, Institutional, Research Grant: AstraZeneca, SanofiAventis. M.G. Krebs: Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal and Institutional, Advisory Role: Roche, Seattle Genetics; Financial Interests, Personal, Invited Speaker: Roche, Janssen, AstraZeneca; Financial Interests, Personal, Other, Travel Expenses: Immuntep, BerGenBio, Janssen; Financial Interests, Personal, Other: Janssen; Financial Interests, Personal, Advisory Board: Roche, Bayer, Guardant Health. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. J. Desai: Financial Interests, Personal, Advisory Role: Beigene, Pierre Fabre, Bayer, GlaxoSmithKline, Merck KGaA, Boehringer Ingelheim, Roche/Genentech, Daiichi Sankyo EUrope Gmbh; Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Institutional, Funding: Roche, GlaxoSmithKline, Novartis, Bionomics, BeiGene, Lilly, Bristol-Myers Squibb, AstraZeneca/MedImmune. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: Sotio, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Institutional, Invited Speaker: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Other, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Other, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Other, Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; Other, NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, External Advisory Board - Member: University of Arizona; Other, External Scientific Advisory Board - Member: University of New Mexico; Other, Scientific External Advisory Board - Member: University of California at San Diego. A. Sacher: Financial Interests, Institutional, Invited Speaker: Genentech-Roche, BMS, AstraZeneca, Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly. Y. Choi, N. Dharia, M.T. Lin, S. Mandlekar, S. Royer-Joo, J.L. Schutzman: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol-Mayers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. All other authors have declared no conflicts of interest.