Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial

Desai, J; Alonso, G; Kim, SH; Cervantes, A; Karasic, T; Medina, L; Shacham-Shmueli, E; Cosman, R; Falcon, A; Gort, E; Guren, T; Massarelli, E; Miller, WH, Jr; Paz-Ares, L; Prenen, H; Amatu, A; Cremolini, C; Kim, TW; Moreno, V; Ou, SI; Passardi, A; Sacher, A; Santoro, A; Stec, R; Ulahannan, S; Arbour, K; LoRusso, P; Luo, J; Patel, MR; Choi, Y; Shi, Z; Mandlekar, S; Lin, MT; Royer-Joo, S; Chang, J; Jun, T; Dharia, NV; Schutzman, JL; Han, SW

Author(s): Desai, J; Alonso, G; Kim, SH; Cervantes, A; Karasic, T; Medina, L; Shacham-Shmueli, E; Cosman, R; Falcon, A; Gort, E; Guren, T; Massarelli, E; Miller, WH, Jr; Paz-Ares, L; Prenen, H; Amatu, A; Cremolini, C; Kim, TW; Moreno, V; Ou, SI; Passardi, A; Sacher, A; Santoro, A; Stec, R; Ulahannan, S; Arbour, K; LoRusso, P; Luo, J; Patel, MR; Choi, Y; Shi, Z; Mandlekar, S; Lin, MT; Royer-Joo, S; Chang, J; Jun, T; Dharia, NV; Schutzman, JL; Han, SW;
Details: Publication Year 2024-01,Volume 30,Issue #1,Page 271-278
Journal Title: Nature Medicine
Publication Type: Research 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.
Publisher: Springer Nature
Keywords: Humans; Cetuximab/adverse effects/genetics; *Proto-Oncogene Proteins p21(ras)/genetics; *Colorectal Neoplasms/drug therapy/genetics/pathology; ErbB Receptors/genetics; Progression-Free Survival; Mutation/genetics
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1038/s41591-023-02696-8
Open Access at Publisher's Site: https://doi.org/10.1038/s41591-023-02696-8
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-02-01 06:31:40

Last Modified: 2024-02-01 06:31:54