[en] 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.
Disciplines :
Oncology
Author, co-author :
Sacher, Adrian G ; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Miller, Wilson H; Lady Davis Institute and Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada
Patel, Manish R ; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL
Paz-Ares, Luis; Hospital Universitario 12 de Octubre, Madrid, Spain
Santoro, Armando ; Department of Biomedical Sciences, Humanitas University, IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Rozzano, Milan, Italy
Ahn, Myung-Ju ; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Dziadziuszko, Rafal ; Medical University of Gdańsk, Gdańsk, Poland
Freres, Pierre ; Université de Liège - ULiège > Département des sciences cliniques
Luo, Jia ; Dana-Farber Cancer Institute, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
Bowyer, Samantha; Linear Clinical Research Ltd, Perth, Australia
Desai, Jayesh ; Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
Markman, Ben ; Alfred Health and Monash University, Melbourne, Australia
De Miguel, Maria ; START-Madrid CIOCC HM Sanchinarro, Madrid, Spain
Deva, Sanjeev; Auckland City Hospital, Auckland, New Zealand
Falcon, Alejandro ; Hospital Universitario Virgen del Rocio, Sevilla, Spain
Lee JK, Sivakumar S, Schrock AB, et al: Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol 6:91, 2022
Nassar AH, Adib E, Kwiatkowski DJ: Distribution of KRAS (G12C) somatic mutations across race, sex, and cancer type. N Engl J Med 384:185-187, 2021
de Langen AJ, Johnson ML, Mazieres J, et al: Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: A randomised, open-label, phase 3 trial. Lancet 401:733-746, 2023
Hong DS, Fakih MG, Strickler JH, et al: KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020
Jänne PA, Riely GJ, Gadgeel SM, et al: Adagrasib in non-small-cell lung cancer harboring a G12C mutation. N Engl J Med 387:120-131, 2022
Ou SHI, Janne PA, Leal TA, et al: First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRASG12C solid tumors (KRYSTAL-1). J Clin Oncol 40:2530-2538, 2022
Skoulidis F, Li BT, Dy GK, et al: Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 384:2371-2381, 2021
Purkey H: Discovery of GDC-6036, a clinical stage treatment for KRAS G12C-positive cancers. Presented at the AACR Annual Meeting, New Orleans, April 8-13, 2022, 2022
Sacher A, LoRusso P, Patel MR, et al: Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med 389:710-721, 2023
Dy GK, Govindan R, Velcheti V, et al: Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. J Clin Oncol 41:3311-3317, 2023
Gadgeel SM, Janne PA, Spira A, et al: MA06.04 KRYSTAL-1: Two-year follow-up of adagrasib (MRTX849) monotherapy in patients with advanced/metastatic KRASG12C-mutated NSCLC. J Thorac Oncol 18:S118, 2023
Postow MA, Callahan MK, Wolchok JD: Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974-1982, 2015
Li BT, Falchook GS, Durm GA, et al: OA03.06 CodeBreaK 100/101: First report of safety/efficacy of sotorasib in combination with pembrolizumab or atezolizumab in advanced KRAS p.G12C NSCLC. J Thorac Oncol 17:S10-S11, 2022
Janne PA, Smit EF, de Marinis F, et al: LBA4 preliminary safety and efficacy of adagrasib with pembrolizumab in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Immunooncol Technol 16:100360, 2022
Sacher A, Miller W Jr, Paz-Ares L, et al: OA14.06 divarasib single-agent long-term follow-up and atezolizumab combination treatment in patients with KRAS G12C-positive NSCLC. J Thorac Oncol 19:S42-S43, 2024
