Roche divarasib beats first-gen KRAS G12C drugs in Phase III NSCLC trial
Roche has announced positive topline results from its Phase III Krascendo 1 study, in which divarasib, a next-generation KRAS G12C inhibitor, outperformed the currently approved first-generation KRAS G12C inhibitors sotorasib and adagrasib in patients with previously treated advanced or metastatic non-small cell lung cancer. The 338-patient randomised, open-label study met both its primary endpoint of progression-free survival (PFS) and key secondary endpoint of overall survival (OS), with statistical significance achieved for OS at the interim analysis.
The KRAS G12C mutation affects approximately 14% of NSCLC cases and is associated with a poor prognosis. Divarasib is designed to selectively lock the mutant KRAS G12C protein in its inactive state, blocking the continuous cell-growth signalling that drives tumour proliferation. In preclinical studies, it has demonstrated greater potency and selectivity compared with sotorasib and adagrasib. Roche reported no new safety signals, with the most common treatment-related events described as manageable and reversible.
Trial significance
Krascendo 1 is described by Roche as the only global head-to-head study comparing a KRAS G12C inhibitor directly against first-generation approved agents in this indication. That trial design lends clinical credibility to the superiority claim, though full results, including hazard ratios, objective response rates and the safety breakdown, have yet to be disclosed publicly. Roche said data will be submitted to health authorities and presented at an upcoming medical meeting.
Levi Garraway, Roche's Chief Medical Officer and Head of Global Product Development, said the results "confirm the potential of divarasib to improve clinical outcomes for people with KRAS G12C non-small cell lung cancer" and argued they "should establish divarasib as a new standard of care" in this genetically defined patient subgroup.
The US FDA granted divarasib Breakthrough Therapy Designation in 2022, and earlier this year added Orphan Drug Designation for the KRAS G12C NSCLC indication, both of which are likely to support an expedited regulatory review process once a submission is filed.
Competitive landscape and regulatory path
The KRAS G12C inhibitor space has evolved rapidly since sotorasib (Lumakras, Amgen) received the first approval for the indication in 2021, followed by adagrasib (Krazati, Mirati/Bristol Myers Squibb). However, both agents face documented limitations including acquired resistance and modest overall survival data, which have constrained their commercial uptake relative to early expectations. Divarasib's ability to demonstrate OS superiority at an interim analysis in an already-treated, poor-prognosis population represents a meaningful clinical advance, if borne out in the final dataset.
Roche is also running two further Phase III studies under the Krascendo umbrella: Krascendo 2 evaluates divarasib in combination with pembrolizumab as a chemotherapy-free first-line regimen, and Krascendo 3 examines adjuvant divarasib in resected stage II to IIIB KRAS G12C NSCLC. The breadth of this programme suggests Roche is positioning divarasib for multiple lines of therapy across the disease spectrum, a strategy that would substantially expand the addressable patient population if the later studies succeed.
Lung cancer remains the leading cause of cancer-related death globally, accounting for approximately 1.8 million deaths annually, with NSCLC making up around 85% of cases. The KRAS G12C subgroup represents a large and historically difficult-to-treat segment, and a clearly superior second-line agent would address a genuine unmet need. Investors and clinicians will now look closely at the full data presentation, particularly the mature OS curve and the durability of response data, before drawing firm conclusions about the label and commercial trajectory.