Divarasib as Compared with Sotorasib or Adagrasib in KRAS G12C–Mutated NSCLC

Background Divarasib, a next-generation, oral KRAS G12C inhibitor, is more potent and selective in vitro than the first-generation KRAS G12C inhibitors sotorasib and adagrasib. Methods In this phase 3, international, open-label trial, patients with previously treated *KRAS* G12C–mutated advanced or metastatic non–small-cell lung cancer (NSCLC) were randomly assigned to receive divarasib orally at a dose of 400 mg once daily or control treatment (sotorasib orally at a dose of 960 mg once daily or adagrasib orally at a dose of 600 mg twice daily) until the occurrence of disease progression, unacceptable adverse events, loss of clinical benefit, withdrawal of consent, death, or trial termination. Results A total of 338 patients received divarasib (167 patients) or control treatment (171 patients; 156 received sotorasib and 15 received adagrasib). The median follow-up was 14.3 months. The median progression-free survival was 9.8 months with divarasib and 5.7 months with control treatment (hazard ratio for disease progression or death, 0.58; 95% confidence interval [CI], 0.44 to 0.76; P<0.001). The median overall survival was 17.7 months with divarasib and 12.0 months with control treatment (hazard ratio for death, 0.56; 95% CI, 0.41 to 0.78; P<0.001). Of the 328 patients who could be evaluated for response, a confirmed response occurred in 58.4% in the divarasib group and in 32.3% in the control group. The median duration of response was 11.9 months with divarasib and 6.9 months with control treatment. Fewer grade 3 or 4 treatment-related adverse events were noted with divarasib (24.6%) than with control treatment (34.5%). Conclusions Among patients with previously treated *KRAS* G12C–mutated advanced or metastatic NSCLC, divarasib led to significantly longer progression-free and overall survival than control treatment. (Supported by F. Hoffmann–La Roche; Krascendo 1 ClinicalTrials.gov number, NCT06497556 .)