Divarasib as Compared with Sotorasib or Adagrasib in KRAS G12C-Mutated NSCLC.
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. 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
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. 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. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included overall survival, confirmed overall response, duration of response, patient-reported outcomes, and safety. 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%). 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.).
