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Poster session 07

362P - Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation

Date

10 Sep 2022

Session

Poster session 07

Topics

Clinical Research

Tumour Site

Colon and Rectal Cancer

Presenters

Jayesh Desai

Citation

Annals of Oncology (2022) 33 (suppl_7): S136-S196. 10.1016/annonc/annonc1048

Authors

J. Desai1, S. Han2, M.D. Forster3, T.W. Kim4, G. Alonso Casal5, E. Shacham Shmueli6, S.E. Bowyer7, M.J. De Miguel8, A. Falcon Gonzalez9, R.H. Jones10, M.G. Krebs11, W.H. Miller12, L. Paz-Ares13, P. Lorusso14, A. Sacher15, N. Dharia16, M.T. Lin16, J.L. Schutzman16, Z. Shi17, M. Patel18

Author affiliations

  • 1 Medical Oncology Department, Peter MacCallum Cancer Centre, 3000 - Melbourne/AU
  • 2 Department Of Internal Medicine, Seoul National University Hospital, 110-744 - Seoul/KR
  • 3 Oncology Dept., UCL Cancer Institute/University College London Hospitals, WC1B 5JU - London/GB
  • 4 Oncology Department, Asan Medical Center - University of Ulsan College of Medicine, 138-931 - Seoul/KR
  • 5 Medical Oncology Department, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 6 Oncology, Chaim Sheba Medical Center, 52621 - Ramat Gan/IL
  • 7 Medical Oncology, Sir Charles Gairdner Hospital & Linear Clinical Research, 6009 - Nedlands/AU
  • 8 Early Phase Clinical Trial Unit, START MADRID, Hospital Universitario HM Sanchinarro – CIOCC, 28050 - Madrid/ES
  • 9 Medical Oncology, Hospital Universitario Virgen del Rocio, 41013 - Seville/ES
  • 10 Consultant Colorectal, Velindre Cancer Centre - Velindre NHS University Trust - NHS Wales, CF14 2TL - Cardiff/GB
  • 11 Experimental Cancer Medicine Team, The Christie NHS Foundation Trust and The University of Manchester, M20 4BX - Manchester/GB
  • 12 Oncology Department, Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, H3T 1E2 - Montreal/CA
  • 13 Medical Oncology Department - Edificio Maternidad 2ª Planta, Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc and Universidad Complutense, 28041 - Madrid/ES
  • 14 Medical Oncology, Yale Smilow Cancer Center, 06520 - New Haven/US
  • 15 Medical Oncology And Hematology Department, Princess Margaret Cancer Centre, University Health Network, M5G 2M9 - Toronto/CA
  • 16 Early Clinical Development Oncology, Genentech, Inc., 94080 - South San Francisco/US
  • 17 Devsci Obd, Genentech, Inc., 94080 - South San Francisco/US
  • 18 Drug Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute, 34230 - Sarasota/US
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Abstract 362P

Background

The oncogenic KRAS G12C mutation is found in ∼4% CRC patients (pts). GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor, with robust tumor growth inhibition in multiple preclinical models.

Methods

As part of an ongoing phase I dose-escalation/expansion study (NCT04449874), pts with advanced and metastatic KRAS G12C mutant CRC were administered GDC-6036 50-400 mg 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). Serial circulating tumor DNA (ctDNA) levels were assessed using the PredicineBEACON MRD assay.

Results

As of 28 Jan 2022, 43 pts with CRC were enrolled (n, 50 mg: 2; 100 mg: 7; 200 mg: 4; 400 mg: 30). Median (range) number of prior cancer therapies was 3 (1-7). No dose-limiting toxicities were reported across all solid tumors. Median (range) time on study treatment was 2.8 (0.1-11.2) months among pts with CRC and median GDC-6036 dose intensity was 100%. Sixteen (37%) pts discontinued study treatment (13 due to RECIST progression, 2 due to symptomatic deterioration, 1 patient withdrawal). The most frequent GDC-6036-related AEs (≥ 10% pts) were nausea, diarrhea, vomiting, dyspepsia, fatigue, and decreased appetite; the only Grade ≥3 AE was diarrhea (3 pts, 7%; all Grade 3). AEs were manageable with supportive measures. Five (12%) pts required a dose modification (interruption [4 pts] or reduction [1 pt]; no withdrawal) for GDC-6036-related AEs. Across all solid tumor patients, 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 pts with CRC was 29% (12/41 pts with measurable disease; 1 complete response), while the confirmed ORR was 20% (8/41 pts) across dose levels in this ongoing study. Among responders, a decrease in ctDNA levels was observed as early as C1D15.

Conclusions

In patients with KRAS G12C mutant CRC, GDC-6036 demonstrated encouraging antitumor activity and early reduction in ctDNA along with acceptable and manageable safety, and PK profile compatible with once daily dosing. 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

J. Desai: Financial Interests, Personal, Advisory Role: BeiGene, Pierre Fabre, Bayer, GlaxoSmithKline, Merck KGaA, 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. M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer, Merck, MSD, Novartis, Roche, Takeda, ultrahuman, Transgene, Ixogen, Immunotep; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Merck; Financial Interests, Institutional, Invited Speaker: StarPharma, Roche. T.W. Kim: Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi Aventis. S.E. Bowyer: Financial Interests, Personal, Advisory Board: Ipsen, Sanofi, Lilly; Financial Interests, Personal, Other, Virtual Meeting Sponsorship: Bristol Myers Squibb, MSD, Australia. 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. A. Falcon Gonzalez: Financial Interests, Personal, Advisory Board: Seagen, Novartis, Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Lilly, Grunenthal pharma, Roche. R.H. Jones: Financial Interests, Institutional, Other, Access to trial data owned by NHS Sponsor: AZ; Financial Interests, Institutional, Invited Speaker, participation in commercial trial: Roche, Genentech, Bayer, Orion, Starpharma, Genmab, G1 therapeutics, Sanofi, H3 Biomedicine, BioNTech, Boehringer, BMS. M.G. Krebs: Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Advisory Role: Roche, Seattle Genetics; Financial Interests, Personal, Invited Speaker: Roche, Janssen, AstraZeneca; Financial Interests, Personal, Other, Travel Support for Meetings: Immutep, BerGenBio, Janssen; Financial Interests, Personal, Advisory Board: Janssen, Roche, Bayer, Guardant Health. W.H. Miller: Financial Interests, Personal, Other, Consultant fees: Merck, BMS, Roche, GSK, Novartis, Amgen, Mylan, EMD Serono, Sanofi; Financial Interests, Personal, Other, Honoraria/speaker's bureau: BMS, Merck; Financial Interests, Personal, Other, Honoraria/Speaker’s Bureau: Roche, GSK, Novartis, Amgen, Mylan, EMD Serono, Sanofi; Financial Interests, Institutional, Research Grant, Grant: Merck, CIHR, CRS, Terry Fox Research Institute, SWCRF, CCSRI; Financial Interests, Institutional, Other, Clinical Trial: Merck, MiMic, Astellas, BMS, Novartis, GSK, Incyte, Pfizer, Sanofi, Ocellaris Pharma, Alkermes, Genentech, Array, Exelixis, VelosBio, Esperas Pharma. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, Pharmamar, Beigene, Daiichi, 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, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, Pharmamar; Financial Interests, Personal, Invited Speaker: 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. 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, 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, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; 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, Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Other, Other, Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; Other, Other, NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, Other, External Advisory Board - Member: University of Arizona; Other, Other, External Scientific Advisory Board - Member: University of New Mexico; Other, 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. N. Dharia: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. M.T. Lin: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. J.L. Schutzman: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. Z. Shi: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. 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; 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. All other authors have declared no conflicts of interest.

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