Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC.

Abstract

Kristen Rat Sarcoma viral oncogene (KRAS) mutations are one of the most common oncogenic drivers found in 12-14% of non-small cell lung cancer (NSCLC) and 4% of colorectal cancer tumors. Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations. In preclinical studies, divarasib was 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib. While sotorasib met its primary endpointin the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed. Adagrasib has demonstrated clinical benefitin the phase I/II KRYSTAL-1 study setting, however, 44.8% of patients reported grade 3 or higher toxicities. Divarasib has been studied in a phase I dose expansion cohort with promising efficacy [objective response (ORR) 53.4% and PFS 13.1 months]. Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.