Basel, Switzerland, October 25, 2026
Roche has announced positive Phase 3 results for divarasib, an investigational next-generation KRAS G12C inhibitor, demonstrating significant survival improvements in patients with previously treated KRAS G12C-mutated non-small cell lung cancer (NSCLC). Results from the global Krascendo 1 clinical trial showed that divarasib reduced the risk of death by 44% and the risk of disease progression or death by 42% compared with currently approved first-generation KRAS G12C inhibitors, sotorasib and adagrasib. The findings were presented at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain, and simultaneously published in The New England Journal of Medicine. The trial met its primary and key secondary endpoints, providing important evidence for a targeted treatment approach in advanced lung cancer. Median overall survival reached 17.7 months with divarasib, compared with 12 months in the control group, highlighting its potential to improve outcomes for patients whose disease has progressed after previous treatment.
Phase 3 Krascendo 1 Trial Demonstrates Survival Benefits
The randomized, open-label Phase 3 Krascendo 1 study enrolled 338 adults with previously treated, locally advanced or metastatic NSCLC carrying the KRAS G12C mutation. Participants received either once-daily divarasib or an approved first-generation KRAS G12C inhibitor, sotorasib or adagrasib. The primary endpoint was progression-free survival assessed by blinded independent central review, while overall survival was a key secondary endpoint. Median progression-free survival was 9.8 months with divarasib, compared with 5.7 months for the control treatments, corresponding to a 42% reduction in the risk of disease progression or death. The 12-month progression-free survival rate was 44% in the divarasib group, compared with 24% in the control group. The confirmed objective response rate was 58% with divarasib versus 32% with sotorasib or adagrasib. Among patients who responded, the median duration of response was 11.9 months with divarasib, compared with 6.9 months in the control group. These findings indicate that the investigational therapy improved several important measures of clinical activity. The overall survival benefit was also statistically significant, with a hazard ratio of 0.56 and a reported P-value of 0.0005. The results represent a major clinical development in the treatment of previously treated KRAS G12C-mutated lung cancer.
Divarasib Targets the KRAS G12C Cancer Mutation
Divarasib is an oral, next-generation targeted therapy designed to selectively inhibit the KRAS G12C protein. The KRAS gene plays an important role in regulating cell growth and signaling. When a G12C mutation occurs, the altered protein can drive abnormal signaling that contributes to uncontrolled cancer-cell proliferation. Divarasib is designed to bind selectively to the mutated protein and lock it in an inactive state, thereby blocking tumor-driving signals. KRAS G12C mutations occur in approximately 12% to 14% of NSCLC cases, making the mutation an important target for precision oncology. Although first-generation KRAS G12C inhibitors have provided treatment options for eligible patients, resistance and disease progression remain significant challenges. The Krascendo 1 trial is particularly important because it directly compared a next-generation inhibitor with approved medicines rather than relying solely on comparisons across separate studies. The survival and response findings were consistent across clinically relevant subgroups, including patients with different PD-L1 expression levels and KEAP1 mutation status. The direct head-to-head evidence strengthens the case for further development of divarasib, although its ultimate role in clinical practice will depend on regulatory review and additional evidence.
Advertisement
Safety Profile and Future Clinical Development
Roche reported that divarasib’s safety profile was consistent with the known effects of KRAS G12C inhibitors, with no new safety signals identified. The most common treatment-related adverse events included gastrointestinal effects, such as diarrhea, nausea and vomiting, as well as liver-related toxicity. Treatment discontinuation due to treatment-related adverse events occurred in 4.8% of patients receiving divarasib, compared with 11.7% in the control group. Serious treatment-related adverse events were reported in 7.8% of the divarasib group and 15.2% of the control group. These findings suggest a potentially favorable tolerability profile, although continued monitoring remains necessary. Roche is advancing a broader Phase 3 development program investigating divarasib in different stages of NSCLC. The Krascendo 2 study is evaluating divarasib with pembrolizumab in previously untreated advanced disease, while Krascendo 3 is investigating adjuvant divarasib following standard treatment for resected disease. Divarasib remains investigational and is not yet an approved treatment. The FDA previously granted it Breakthrough Therapy Designation in 2022 and Orphan Drug Designation for KRAS G12C-mutated NSCLC in 2026. The latest results support continued regulatory engagement and further clinical evaluation of this targeted approach.
Source: Roche press release
