Multinational phase 1b trial of divarasib plus cetuximab for KRAS G12C-positive colorectal cancer

KRAS G12C mutation is seen in approximately 4% of colorectal cancers (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor had modest activity as a single agent for KRAS G12C-positive CRC. Epidermal growth factor receptor (EGFR) has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Arm C of a multinational phase 1b trial evaluated simultaneous inhibition of KRAS G12C with divarasib and EGFR with cetuximab among patients with KRAS G12C-positive CRC. The safety profile of the combination (primary end point) was manageable and consistent with what has been seen with the single agents divarasib and cetuximab. The figure shows the antitumor activity of the combination. The objective response rate was 62.5% in KRAS G12C inhibitor-naïve patients. The median duration of response was 6.9 months and the median progression-free survival was 8.1 months. The authors conclude that these results support the further investigation of this combination for KRAS G12C-positive CRC.