Divarasib Improves Survival Vs Approved KRAS G12C Inhibitors in NSCLC

Divarasib, an oral next-generation KRAS G12C inhibitor, improved progression-free survival (PFS) and overall survival (OS) vs the approved first-generation KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati) in patients with previously treated KRAS G12C-mutated advanced or metastatic non–small cell lung cancer (NSCLC), according to results from the phase 3 Krascendo 1 study (NCT06497556).¹

Divarasib is now the first KRAS G12C inhibitor to demonstrate superiority over other approved agents in the class in a randomized head-to-head comparison. Full efficacy data from the study have not yet been disclosed and will be submitted to health authorities and presented at an upcoming medical meeting, according to Genentech, the developer of divarasib.¹

The safety profile of divarasib in Krascendo 1 was consistent with prior clinical data, with no new safety signals identified and the most common treatment-related adverse events described as manageable and reversible.¹

Krascendo 1 is a phase 3, randomized, open-label, multicenter, global study evaluating divarasib monotherapy vs investigator's choice of sotorasib once daily or adagrasib twice daily in adults with previously treated KRAS G12C-mutant advanced or metastatic NSCLC.1 A total of 338 patients were enrolled and randomized. The primary endpoint was BICR-assessed PFS, with OS as a key secondary endpoint; additional secondary endpoints include confirmed objective response rate, duration of response, and safety.

"The superior survival demonstrated in this global head-to-head comparison of KRAS G12C inhibitors confirms the potential of divarasib to improve clinical outcomes for people with KRAS G12C non-small cell lung cancer," Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, stated in a news release. ¹ "These results should establish divarasib as a new standard of care for previously-treated lung cancer patients with this genetically defined tumor subtype."

Phase 1 Data for Divarasib

Prior to Krascendo 1, a phase 1 study (NCT04449874) showed divarasib at 400 mg once daily produced a confirmed objective response rate (ORR) of 53.4% (95% CI, 39.9%-66.7%) and a median PFS of 13.1 months (95% CI, 8.8-not estimable) in patients with KRAS G12C-mutated NSCLC at the primary data cutoff.² The median duration of response was 14.0 months (95% CI, 8.3-not estimable) and the median time to response was 1.3 months.

Long-term follow-up of the phase 1 study, reported in the Journal of Clinical Oncology at a minimum follow-up of 1 year, showed a confirmed ORR of 55.6% (95% CI, 42.5%-68.1%) across all dose levels in 63 patients with measurable disease, with a median PFS of 13.7 months (95% CI, 8.1-not estimable) at the recommended phase 2 dose of 400 mg once daily.³ At the extended follow-up, 48% of patients had been treated beyond 1 year, and the safety profile remained consistent with the initial report.

In the phase 1 study, adverse events of any grade were reported in 93% of patients across all solid tumor types, with grade 3 events occurring in 11% and grade 4 events in 1%; no grade 5 treatment-related events were reported.² In the NSCLC cohort specifically, the most common adverse events were nausea (78%), vomiting (63%), diarrhea (60%), and fatigue (27%), the large majority of which were low grade and manageable with supportive care.²

Dose reductions occurred in 14% of patients and treatment discontinuation due to adverse events in fewer than 5%.2 In preclinical studies, divarasib demonstrated 5 to 20 times greater potency and up to 50 times greater selectivity than sotorasib and adagrasib, providing a mechanistic rationale for the clinical differentiation observed in Krascendo 1.1.

Next Steps

Genentech is pursuing a comprehensive phase 3 development program for divarasib in NSCLC across three studies. Krascendo 2 (NCT06793215) is evaluating divarasib plus pembrolizumab (Keytruda) as a chemotherapy-free first-line combination vs chemotherapy plus pembrolizumab in previously untreated KRAS G12C-mutant advanced NSCLC. Krascendo 3 (NCT07541170) is evaluating adjuvant divarasib vs immunotherapy or observation in patients with resected stage II-IIIB KRAS G12C-mutant NSCLC following standard-of-care chemoimmunotherapy.1

The FDA granted divarasib breakthrough therapy designation in 2022 and orphan drug designation for KRAS G12C NSCLC in 2026.¹

References

1. Genentech's divarasib shows superiority in head-to-head phase III trial against approved KRAS G12C inhibitors in non-small cell lung cancer. News release. Genentech. July 1, 2026. Accessed July 3, 2026. https://www.gene.com/media/press-releases/15119/2026-07-01/genentechs-divarasib-shows-superiority-i

2. Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. Published online August 24, 2023. doi:10.1056/NEJMoa2303810

3. Sacher A, Ou SI, Spira AI, et al. Single-agent divarasib in patients with KRAS G12C-positive non-small cell lung cancer: long-term follow-up of a phase I study. J Clin Oncol. Published online 2025. doi:10.1200/JCO-25-00040