The Phase III Krascendo 1 trial (NCT06497556) positions divarasib as a potential new standard of care in previously treated KRAS G12C-mutant NSCLC, after demonstrating superior progression-free and overall survival against first-generation KRAS G12C inhibitors.
Written By: Anamika Koshti, Pharm D
Reviewed By: Pharmacally Editorial Team
On July 2, 2026, Roche announced positive topline results from Krascendo 1 (NCT06497556), its Phase III head-to-head study comparing divarasib, an investigational next-generation KRAS G12C inhibitor, directly against the approved first-generation agents sotorasib and adagrasib in patients with previously treated KRAS G12C-mutant advanced or metastatic non-small cell lung cancer (NSCLC). The study met both its primary endpoint of progression-free survival (PFS) and the key secondary endpoint of overall survival (OS), with statistical significance for OS achieved at the interim analysis.
KRAS G12C in NSCLC: A High-Burden, Poor-Prognosis Target
Lung cancer remains the leading cause of cancer-related deaths globally, claiming roughly 1.8 million lives each year, with NSCLC accounting for approximately 85% of all cases. KRAS is among the most frequently mutated oncogenes in lung cancer, occurring in approximately 25% of newly diagnosed lung cancers. The G12C variant, one of the most common KRAS mutations, is found in around 14% of NSCLC cases and is associated with poor prognosis.
The KRAS G12C mutation locks the KRAS protein in its constitutively active state, driving continuous, unregulated signalling that fuels tumour growth. While the approval of first-generation inhibitors sotorasib and adagrasib represented a significant step forward, there remained a substantial unmet need for therapies capable of delivering improved and more durable clinical outcomes in this setting.
Krascendo 1 Trial Design
Krascendo 1 is a Phase III (NCT06497556), randomised, open-label, multicentre study enrolling 338 adults with previously treated KRAS G12C-mutant advanced or metastatic NSCLC. Participants were randomised to receive either divarasib (once daily) or investigator’s choice of sotorasib (once daily) or adagrasib (twice daily). The primary endpoint was blinded independent central review (BICR)-assessed PFS, with OS, confirmed objective response rate, and duration of response among the key secondary endpoints. Krascendo 1 is notable as the only global head-to-head study comparing a KRAS G12C inhibitor directly against approved first-generation agents in this setting.
Trial Results
Divarasib achieved clinically meaningful and statistically significant improvements in both PFS and OS compared with sotorasib or adagrasib. Notably, statistical significance for OS was reached at the interim analysis, a particularly meaningful result given the poor prognosis of this patient population. As the only global Phase III study directly comparing KRAS G12C inhibitors, Krascendo 1 provides the first head-to-head evidence that a next-generation KRAS G12C inhibitor can improve survival over currently approved therapies.
No new safety signals were identified during the study, and the safety profile of divarasib remained consistent with previous clinical experience. The most common treatment-related adverse events were reported to be manageable and reversible.
Mechanism of Action: What Sets Divarasib Apart
Divarasib is a next-generation, oral KRAS G12C inhibitor designed to selectively bind the mutant KRAS G12C protein and lock it in its inactive (‘off’) state, thereby shutting down tumour-driving signalling pathways. In preclinical studies, divarasib demonstrated greater potency and selectivity compared with first-generation KRAS G12C inhibitors, sotorasib and adagrasib, a differentiation that has now translated into superior clinical outcomes in a global Phase III trial.
Clinical Implications
Levi Garraway, MD, PhD, Roche’s Chief Medical Officer and Head of Global Product Development, described the results as confirmation of divarasib’s potential to improve clinical outcomes in KRAS G12C NSCLC, adding that the superior survival data from a global head-to-head comparison should position divarasib as a new standard of care for previously treated patients with this genetically defined tumour subtype.
Divarasib’s Broader Development Programme
Roche is advancing divarasib through a comprehensive Phase III clinical programme across multiple stages of KRAS G12C-mutant NSCLC. Alongside the positive Krascendo 1 study in previously treated patients, the ongoing Krascendo 2 (NCT06793215) trial is evaluating divarasib in combination with pembrolizumab as a chemotherapy-free first-line regimen, while Krascendo 3 (NCT07541170) is investigating adjuvant divarasib following standard-of-care chemoimmunotherapy in patients with resected stage II–IIIB disease. Divarasib received FDA Breakthrough Therapy Designation in 2022 and Orphan Drug Designation for KRAS G12C NSCLC in 2026. Roche plans to present the Krascendo 1 data at an upcoming medical meeting and submit the results to health authorities to support potential regulatory approvals.
What This Means for Patients?
For people living with KRAS G12C-positive non-small cell lung cancer, treatment options often become limited after the cancer stops responding to the first treatment. Although the currently available KRAS-targeted medicines have improved care for many patients, the disease can still progress, highlighting the need for more effective treatment options.
The results from the Krascendo 1 study suggest that divarasib may help patients live longer and keep their cancer under control for a longer period compared with the currently approved KRAS-targeted medicines. While the treatment must still be reviewed by health authorities before it becomes widely available, these findings offer new hope for patients with previously treated KRAS G12C-positive lung cancer and could lead to a new standard treatment option in the future.
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About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.