Roche divarasib cuts death risk by 44% vs first-gen KRAS inhibitors
Roche has reported pivotal Phase III data showing its next-generation KRAS G12C inhibitor divarasib significantly outperformed approved first-generation agents in patients with previously treated KRAS G12C-mutated non-small cell lung cancer. The Krascendo 1 study, the first global head-to-head trial of a next-generation KRAS G12C inhibitor against established standards of care, met both its primary and key secondary endpoints, and the results were presented as a late-breaking abstract at the 2026 ESMO Congress in Madrid and simultaneously published in the New England Journal of Medicine.
Patients receiving divarasib monotherapy had a 44% lower risk of death compared with those treated with sotorasib or adagrasib (OS hazard ratio 0.56, 95% CI: 0.41–0.78; p=0.0005). Median overall survival reached 17.7 months in the divarasib arm, against 12.0 months in the control arm. Progression-free survival was equally favourable, with divarasib reducing the risk of disease progression or death by 42% (PFS HR 0.58, 95% CI: 0.44–0.76; p<0.0001), translating to a median PFS of 9.8 months versus 5.7 months. The confirmed objective response rate with divarasib was 58%, nearly double the 32% recorded for sotorasib or adagrasib, and median duration of response extended to 11.9 months compared with 6.9 months.
Clinical and safety profile
The safety data are notable given that patients remained on divarasib for a median of 11.3 months, more than twice as long as those in the control arm at 5.0 months. Despite this extended exposure, fewer patients discontinued divarasib due to treatment-related adverse events (4.8% versus 11.7%), and the rate of serious treatment-related adverse events was roughly half that seen with sotorasib or adagrasib (7.8% versus 15.2%). The most common adverse events were gastrointestinal in nature, principally diarrhoea, nausea and vomiting, alongside hepatotoxicity, consistent with the known class profile of KRAS G12C inhibitors. No new safety signals were identified.
Levi Garraway, Roche's Chief Medical Officer and Head of Global Product Development, said the Krascendo 1 results "reinforce divarasib's best-in-class profile" and that the company is working with health authorities to bring the drug to patients. Study lead author Ferdinandos Skoulidis, Professor of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, described divarasib as "the first KRAS inhibitor to meaningfully improve overall survival" in this setting.
Market context and regulatory path
The KRAS G12C mutation affects approximately 12–14% of NSCLC cases, a patient population historically associated with poor prognosis. First-generation inhibitors sotorasib (Amgen) and adagrasib (Mirati/Bristol Myers Squibb) established proof of concept but delivered modest survival gains and were plagued by acquired resistance. Divarasib's head-to-head superiority in OS is a meaningful clinical advance and, if approved, would place significant competitive pressure on both products. The US FDA granted divarasib Breakthrough Therapy Designation in 2022 and Orphan Drug Designation for this indication in 2026, both of which should facilitate an expedited regulatory review in the United States.
Roche is also running Krascendo 2, evaluating divarasib in combination with pembrolizumab as a chemotherapy-free first-line regimen against chemo-immunotherapy, and Krascendo 3 in the adjuvant setting after resection. A positive outcome across those studies could position divarasib across multiple lines of therapy, substantially broadening its addressable market. Several competing next-generation KRAS inhibitors and combination strategies, including covalent and non-covalent approaches from companies including Revolution Medicines, are also in late-stage development, making the regulatory timeline and label scope critical variables for Roche's commercial prospects in this space.