Multinational phase 3 trial of divarasib compared with sotorasib or adagrasib for previously treated KRAS G12C-mutated advanced or metastatic NSCLC

Divarasib, a next-generation, oral KRAS G12C inhibitor, is more potent and selective in vitro the the first-generaion KRAS G12C inhibitors sotorasib and adagrasib. In a multinational phase 3 trial, patients with previously treated KRAS G12C-mutated advanced or metastatic non-small cell lung cancer (NSCLC) were randomized to receive divarasib orally at a dose of 400 mg once daily (n=167) or control treatment (sotorasib at a dose of 960 mg once daily, n=156, or adagrasib at a dose of 600 mg twice daily, n=15). Treatment was continued until disease progression, unacceptable toxicity, loss of clinical benefit, withdrawal of consent, death, or trial termination. The primary endpoint was progression-free survival assessed by blinded independent central review. The median progression-free survival was 9.8 months with divarasib and 5.7 months with control treatment (HR 0.58; p<0.001), while the median overall survival was 17.7 months versus 12.0 months (HR 0.56; p<0.001). Among 328 response-evaluable participants, confirmed response occurred in 58.4% in the divarasib group and 32.3% in the control group, with median duration of response 11.9 months versus 6.9 months. Fewer grade 3 or 4 treatment-related adverse events were noted with divarasib (24.6%) than with control treatment (34.5%). The authors conclude that among patients with previously treated