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Single-agent divarasib in patients with KRAS G12C-positive non-small cell lung cancer: long-term follow-up of a phase I study
Sacher, A. G. Miller, W. H., Jr. Patel, M. R. Paz-Ares, L. Santoro, A. Ahn, M. J. Dziadziuszko, R. Freres, P. Luo, J. Bowyer, S.
Sacher, A. G.
Miller, W. H., Jr.
Patel, M. R.
Paz-Ares, L.
Santoro, A.
Ahn, M. J.
Dziadziuszko, R.
Freres, P.
Luo, J.
Bowyer, S.
Abstract
Divarasib (GDC-6036), an oral, highly potent and selective next-generation KRAS G12C inhibitor, has demonstrated a manageable safety profile and promising antitumor activity in patients with advanced KRAS G12C-positive non-small cell lung cancer (NSCLC). Here, we report long-term (≥1 year) follow-up of single-agent divarasib from the ongoing, open-label, and multicenter phase I study (ClinicalTrials.gov identifier: NCT04449874). The primary objective was safety, and the other objectives included preliminary antitumor activity. Overall, 65 patients with advanced KRAS G12C-positive NSCLC received single-agent oral divarasib 50-400 mg once daily and 31 patients (48%) were treated beyond 1 year. Divarasib continued to be well tolerated, and the safety profile beyond 1 year was consistent with the overall safety profile. In patients with measurable disease at baseline across all dose levels (n = 63), the confirmed objective response rate was 55.6% (95% CI, 42.5 to 68.1), and the median duration of response was 18.0 months (95% CI, 11.1 to 24.9). The median progression-free survival was 13.8 months (95% CI, 9.8 to 25.4) in the overall population (N = 65) and 15.3 months (95% CI, 12.3 to 26.1) among patients assigned to the 400-mg dose level (n = 44). With extended follow-up, divarasib demonstrated long-term safety and antitumor activity in patients with advanced KRAS G12C-positive NSCLC.
Authors
Sacher, A. G.
Miller, W. H., Jr.
Patel, M. R.
Paz-Ares, L.
Santoro, A.
Ahn, M. J.
Dziadziuszko, R.
Freres, P.
Luo, J.
Bowyer, S.
Desai, J.
Markman, B.
De Miguel, M.
Deva, S.
Falcon, A.
Alonso, G.
Guedes, J. D.
Kim, S. H.
Krebs, M. G.
Laurie, S. A.
Massarelli, E.
Medina, L.
Prenen, H.
Amatu, A.
Van Dongen, M.
Choi, Y.
Hou, X.
Qi, T.
Lin, M. T.
Koli, K.
Mayo, M. C.
Yau, K. K.
Royer-Joo, S.
Chang, J.
Jun, T.
Dharia, N. V.
Schutzman, J. L.
Lorusso, P.
Miller, W. H., Jr.
Patel, M. R.
Paz-Ares, L.
Santoro, A.
Ahn, M. J.
Dziadziuszko, R.
Freres, P.
Luo, J.
Bowyer, S.
Desai, J.
Markman, B.
De Miguel, M.
Deva, S.
Falcon, A.
Alonso, G.
Guedes, J. D.
Kim, S. H.
Krebs, M. G.
Laurie, S. A.
Massarelli, E.
Medina, L.
Prenen, H.
Amatu, A.
Van Dongen, M.
Choi, Y.
Hou, X.
Qi, T.
Lin, M. T.
Koli, K.
Mayo, M. C.
Yau, K. K.
Royer-Joo, S.
Chang, J.
Jun, T.
Dharia, N. V.
Schutzman, J. L.
Lorusso, P.
Affiliation
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada.
Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL.
Hospital Universitario 12 de Octubre, Madrid, Spain.
Department of Biomedical Sciences, Humanitas University, IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Rozzano, Milan, Italy.
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Medical University of Gdańsk, Gdańsk, Poland.
University Hospital of Liege, Liege, Belgium.
Dana-Farber Cancer Institute, Harvard Medical School and Brigham and Women's Hospital, Boston, MA.
Linear Clinical Research Ltd, Perth, Australia.
Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
Alfred Health and Monash University, Melbourne, Australia.
START-Madrid CIOCC HM Sanchinarro, Madrid, Spain.
Auckland City Hospital, Auckland, New Zealand.
Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Hospital Universitario Vall d'Hebrón, Barcelona, Spain.
Hospital de Base de São José do Rio Preto, São José do Rio Preto, Brazil.
Seoul National University Bundang Hospital, Seongnam, South Korea.
The Christie NHS Foundation Trust and Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom.
Ottawa Hospital Research Institute, Ottawa, ON, Canada.
City of Hope-Comprehensive Cancer Center, Duarte, CA.
Oncology Department, Hospital Virgen de la Victoria, Málaga, Spain.
University Hospital Antwerp, Edegem, Belgium.
Grande Ospedale Metropolitano Niguarda, Milan, Italy.
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Genentech, Inc, South San Francisco, CA.
Hoffmann-La Roche Limited, Mississauga, Canada.
Yale Cancer Center, Yale University, New Haven, CT.
Description
Date
2025
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Citation
Sacher AG, Miller WH, Jr., Patel MR, Paz-Ares L, Santoro A, Ahn MJ, et al. Single-Agent Divarasib in Patients With KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2025 Oct 20;43(30):3249-53. PubMed PMID: 40632992. Pubmed Central PMCID: PMC12527784 manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Epub 2025/07/09. eng.