Roche (SIX: RO; OTCQX: RHHBY) has reported that divarasib, its investigational next-generation KRAS G12C inhibitor, demonstrated statistically significant and clinically meaningful improvements in both progression-free survival and overall survival against the two currently approved KRAS G12C inhibitors in a randomized Phase III head-to-head trial. The result, from the Krascendo 1 study, is the first time a KRAS-targeted agent has prospectively beaten an approved standard of care in a direct comparison — with divarasib potentially on course to reshape the second-line treatment landscape for the roughly 14% of NSCLC patients whose tumors carry the G12C mutation.
The significance extends beyond a single trial win. Both Amgen's Lumakras (sotorasib) and Bristol Myers Squibb's Krazati (adagrasib) — the drugs divarasib was tested against — hold only accelerated approvals in the US, granted on the basis of response rate data from single-arm studies. Neither has successfully converted to full approval at present. Divarasib now enters regulatory discussions backed by superiority data in overall survival from a randomized, active-controlled Phase III trial, a considerably stronger evidentiary foundation than either predecessor carried at the time of their approvals.
The Krascendo 1 trial enrolled 338 adults with previously treated KRAS G12C-mutant advanced or metastatic NSCLC, randomizing them to receive divarasib once daily or investigator's choice of sotorasib once daily or adagrasib twice daily. The study met its primary endpoint of PFS and key secondary endpoint of OS. Divarasib achieved statistically significant improvements in PFS over the comparator arm, and — notably — statistical significance for OS was reached at a pre-specified interim analysis, underscoring the strength of the treatment effect despite immature survival follow-up.
Specific hazard ratios, median survival figures, and response rates were not disclosed in the July 2 announcement; full data are expected at an upcoming medical congress and will accompany regulatory submissions. The safety profile was described as consistent with earlier divarasib data, with no new signals identified and the most common treatment-related events characterized as manageable and reversible.
A competitive field
The KRAS G12C inhibitor class arrived in 2021 with sotorasib's accelerated approval, ending more than three decades of failed attempts to drug the RAS family. Adagrasib followed in December 2022. While sotorasib and adagrasib established KRAS G12C inhibition as a therapeutic strategy, they delivered median PFS of only six to seven months, with acquired resistance emerging as the principal limitation. Divarasib was designed to address potency and selectivity limitations of the first generation.
The competitive landscape is also evolving beyond the approved first-generation agents. Revolution Medicines and other developers are advancing KRAS G12C inhibitors with distinct mechanisms, including active-state (G12C-ON) inhibitors and tri-complex approaches designed to overcome resistance to GDP-state inhibitors.