Year: 2023
Type: article
Abstract: KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.
Source: Nature Medicine
Authors: Jayesh Desai, Guzman Alonso, Se Hyun Kim, Andres Cervantes, Thomas Karasic, Laura Medina, Einat Shacham-Shmueli, Rasha Cosman, Alejandro Falcon, Eelke Gort, Tormod Guren, Erminia Massarelli, Wilson H. Miller, Luis Paz-Ares, Hans Prenen, Alessio Amatu, Chiara Cremolini, Tae Won Kim, Victor Moreno, Sai-Hong I. Ou, Alessandro Passardi, Adrian Sacher, Armando Santoro, Rafal Stec, Susanna Ulahannan, Kathryn Arbour, Patricia Lorusso, Jia Luo, Manish R. Patel, Yoonha Choi, Zhen Shi, Sandhya Mandlekar, Mark T. Lin, Stephanie Royer-Joo, Julie Chang, Tomi Jun, Neekesh V. Dharia, Jennifer L. Schutzman, GO42144 Investigator and Study Group, Sae-Won Han
Institutions: The University of Melbourne, Peter MacCallum Cancer Centre, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology, Seoul National University Bundang Hospital, Hospital Clínico Universitario de Valencia, Abramson Cancer Center, University of Pennsylvania, Instituto de Investigación Biomédica de Málaga, Tel Aviv University, Sheba Medical Center, UNSW Sydney, The Kinghorn Cancer Centre, Hospital Universitario Virgen del Rocío, University Medical Center Utrecht, Oslo University Hospital, City Of Hope National Medical Center, City of Hope, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Universidad Complutense de Madrid, Hospital Universitario 12 De Octubre, Antwerp University Hospital, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, University of Pisa, Asan Medical Center, University of Ulsan, Hospital Universitario Fundación Jiménez Díaz, University of California, Irvine, UC Irvine Chao Family Comprehensive Cancer Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, University Health Network, University of Toronto, Princess Margaret Cancer Centre, Humanitas University, IRCCS Humanitas Research Hospital, Medical University of Warsaw, Sarah Cannon, OU Health Stephenson Cancer Center, Memorial Sloan Kettering Cancer Center, Yale Cancer Center, Yale University, Harvard University, Dana-Farber Cancer Institute, Genentech, Seoul National University Hospital, Seoul National University Cancer Hospital
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
OpenAlex ID: W4389338940