616MO - Long-term follow-up of single-agent divarasib in patients with KRAS G12C-positive solid tumors

Background

Divarasib (GDC-6036) is an oral, highly potent, and selective KRAS G12C inhibitor. We report the long-term safety and clinical activity of single-agent divarasib in patients with advanced KRAS G12C-positive solid tumors.

Methods

As part of an ongoing phase I study (NCT04449874), patients received single-agent oral divarasib 50-400 mg daily until intolerable toxicity or disease progression. Assessments included safety (NCI-CTCAE v5) and preliminary antitumor activity (RECIST v1.1). Confirmed response was defined as complete or partial response on 2 consecutive tumor assessments at ≥4 weeks apart.

Results

As of 1 January 2024, 153 patients had received single-agent divarasib (non-small cell lung cancer [NSCLC]: n=65; colorectal cancer [CRC]: n=61; other solid tumors [OST]: n=27). Median treatment duration was 9.57 months (range: 0-37.3) and median lines of prior systemic therapy was 2 (range: 0-8). No patients had prior KRAS G12C inhibitor treatment. Among 43 patients (31 NSCLC, 8 CRC, and 4 OST) who continued divarasib beyond 1 year, 20 (47%) experienced a new-onset treatment-related adverse event (TRAE) after a year. One patient (2%) experienced a new-onset Grade 3 TRAE (weight decreased); no patients experienced new-onset Grade 4-5 TRAEs. One patient (2%) experienced a new-onset Grade 2 TRAE (nausea) that led to dose reduction. No new-onset TRAEs led to divarasib withdrawal. Preliminary activity, including objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR), are presented in the table for patients receiving divarasib 400 mg. Table: 616MO

ORR, PFS and DOR for patients receiving divarasib 400 mg

Conclusions

Single-agent divarasib was well tolerated with few new-onset TRAEs after 1 year and continued to demonstrate durable clinical activity in patients with advanced KRAS G12C-positive solid tumors.

Clinical trial identification

NCT04449874.

Editorial acknowledgement

Editorial assistance was provided by Andrew Occiano (Genentech, Inc.).

Legal entity responsible for the study

Genentech, Inc.

Funding

Genentech, Inc.

Disclosure

E. Garralda: Financial Interests, Personal, Invited Speaker: MSD, Roche, Thermo Fisher, Novartis, SeaGen; Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte, Medscape; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: 1TRIALSP; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. M.R. Patel: Financial Interests, Personal, Advisory Board: Daiichi, Janssen, Accutar; Financial Interests, Institutional, Local PI, institution received research funding: Daiichi. T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech, Genome Insight. A.G. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly, BridgeBio, Hotspot Therapeutics. 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Santoro: Financial Interests, Personal, Advisory Board: BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD; Financial Interests, Personal, Financially compensated role: Sanofi, Incyte; Financial Interests, Personal, Invited Speaker: Takeda, BMS, Roche, AbbVie, Amgen, Celgene, AstraZeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD. J. Desai: Financial Interests, Personal, Invited Speaker: Pierre Fabre, Merck KGaA, Novartis; Financial Interests, Personal, Advisory Board: Bayer, Boehringer Ingelheim, Roche/Genentech, Pfizer, Amgen, Pierre Fabre, beigene, Axelia, Ellipses; Financial Interests, Coordinating PI: Roche/Genentech, BeiGene; Financial Interests, Local PI: Amgen, AstraZeneca, GSK, Novartis; Financial Interests, Steering Committee Member: Pfizer; Non-Financial Interests, Principal Investigator: beigene, Roche/Genentech, Amgen, Pfizer, Novartis, Boehringer, MapCure, Springworks, AstraZeneca, Vivace, Incyte; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Leadership Role: Australia New Zealand Sarcoma Association; Other, Not-for-profit, Director-uncompensated: Cancer Trials Australia. L.G. 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A. Falcon Gonzalez: Financial Interests, Personal, Advisory Board: Seagen, Novartis, Pfizer, AstraZeneca, Roche, Esteve; Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Lilly, Grunenthal pharma, Roche, AstraZeneca, Daiichi Sankyo. M. De Miguel: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. S.E. 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R. Dziadziuszko: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Pfizer, Novartis, Takeda, MSD, Bristol Myers Squibb, Bayer; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Coordinating PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional, Local PI: MSD, Amgen, Celon Pharma, Pfizer, Novartis, Bristol Myers Squibb, Eli Lilly, Loxo; Financial Interests, Personal and Institutional, Other, Subinvestigator and ad hoc Consultant: PDC* line Pharma; Financial Interests, Local PI: OSE Immunotherapeutics; Non-Financial Interests, Institutional, Product Samples: Novartis, Pfizer, AstraZeneca, Roche. S. Han: Financial Interests, Institutional, Local PI: Hanmi, Genentech, Roche, Loxo, Mirati, MSD, Janssen, Lilly, Seagen, Arcus. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health, Zai Lab; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences, Ellipses; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche, Zai Lab. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, GenMab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Inc., Zentalis Pharmaceuticals, Molecular Templates, STCube Pharmaceuticals, Bayer, I-MAb, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials, Acutate Therapeutics; Financial Interests, Personal, Other, Safety Monitoring Board: Agios, Five Prime, Halozyme, Tyme; Financial Interests, Personal, Speaker, Consultant, Advisor: Roche/Genentech, SOTIO, SK Life Sciences, Roivant Sciences. J. Chang, T. Jun: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks or ownership: Roche. W.H. Miller: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Merck, Roche, Novartis, GSK, Amgen, Mylan, EMD, Serono, Sanofi; Financial Interests, Institutional, Research Grant: CIHR, CRS, SWCRF; Financial Interests, Institutional, Research Funding: Merck, BMS, Novartis, GSK, Roche, AstraZeneca, Methlgene, MedImmune, Sanofi, Array, MiMic, Ocellaris, Astellas, Pfizer, Genentech, Seagen. All other authors have declared no conflicts of interest.