2026-04-29T16:56:12Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/230992024-11-29T22:58:19Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud author Desai, Jayesh author Alonso, Guzman author Kim, Se Hyun author Cervantes, Andres author Karasic, Thomas author Medina, Laura author Shacham-Shmueli, Einat author Cosman, Rasha author Falcon, Alejandro author Gort, Eelke author Guren, Tormod author Massarelli, Erminia author Miller, Wilson H author Paz Ares, Luis Gonzaga::1025::600 author Prenen, Hans author Amatu, Alessio author Cremolini, Chiara author Kim, Tae Won author Moreno, Victor author Ou, Sai-Hong I author Passardi, Alessandro author Sacher, Adrian author Santoro, Armando author Stec, Rafal author Ulahannan, Susanna author Arbour, Kathryn author Lorusso, Patricia author Luo, Jia author Patel, Manish R author Choi, Yoonha author Shi, Zhen author Mandlekar, Sandhya author Lin, Mark T author Royer-Joo, Stephanie author Chang, Julie author Jun, Tomi author Dharia, Neekesh V author Schutzman, Jennifer L author Han, Sae-Won funder Roche Holding Genentech 2024-09-16T08:17:02Z 2024-09-16T08:17:02Z 2024-01 Nat Med . 2024;30(1):271-278. 10.1038/s41591-023-02696-8 1546-170X Nature medicine 38052910 https://hdl.handle.net/20.500.12105/23099 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. eng Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. research article