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

Previously, single-arm phase I and II studies of sotorasib demonstrated antitumor activity in KRAS G12C-mutant NSCLC ^[2][3], and it was subsequently compared with docetaxel in a randomized phase III trial ^[4]. However, these patients are not homogeneous: downstream of lung cancer driver genes there is marked biological and clinical heterogeneity, and co-mutations, particularly alterations in tumor suppressor genes, can influence tumor phenotype and outcomes ^[1]; KEAP1, SMARCA4, and CDKN2A co-mutations have in particular been identified as independent determinants of poor efficacy of KRAS G12C inhibitor monotherapy ^[6]. Thus, the key question is not merely whether targeted agents can work, but whether a new-generation drug can demonstrate survival benefit in a direct randomized comparison while also maintaining a favorable safety profile.

This international, open-label phase III Krascendo 1 study (NCT06497556) enrolled patients with previously treated KRAS G12C-mutant advanced or metastatic NSCLC, randomized to receive divarasib 400 mg once daily, or sotorasib 960 mg once daily or adagrasib 600 mg twice daily. A total of 338 patients were treated: 167 in the divarasib group and 171 in the control group (sotorasib 156; adagrasib 15), with a median follow-up of 14.3 months. Median PFS with divarasib was 9.8 months versus 5.7 months in the control group (HR for disease progression or death 0.58; 95% CI 0.44–0.76; P<0.001); median OS was 17.7 months versus 12.0 months (HR for death 0.56; 95% CI 0.41–0.78; P<0.001). Among the 328 patients evaluable for response, the confirmed response rate was 58.4% versus 32.3%, and the median duration of response was 11.9 months versus 6.9 months; grade 3–4 treatment-related adverse events occurred in 24.6% versus 34.5%.

A previous phase I study of divarasib had already shown a confirmed response rate of 53.4% and median PFS of 13.1 months in 60 patients with NSCLC ^[5], but single-arm results cannot replace randomized head-to-head evidence. In this study, within the same randomized framework, divarasib extended both PFS and OS compared with the predominantly sotorasib-based control, improved confirmed responses and prolonged the duration of response, with fewer reported grade 3–4 treatment-related adverse events, thereby translating its more potent and more selective in vitro advantages into quantifiable differences in clinical survival and safety.

Interpretation still requires caution: the trial was open-label with a median follow-up of 14.3 months, and long-term benefit remains to be verified; only 15 patients in the control group received adagrasib, and the abstract reported the two control arms pooled, so this abstract is insufficient to judge the effect of divarasib relative to adagrasib alone. The study also covered only previously treated advanced or metastatic NSCLC and did not provide subgroup results for biomarkers such as KEAP1, SMARCA4, and CDKN2A ^[6]; how these co-mutations affect drug selection and differential benefit remains to be answered.