Divarasib Improves Survival vs Sotorasib or Adagrasib in KRAS G12C+ NSCLC

The next-generation KRAS G12C inhibitor divarasib significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with the first-generation inhibitors sotorasib (Lumakras) or 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 trial (NCT06497556) presented at the 2026 European Society for Medical Oncology (ESMO) Congress and simultaneously published in The New England Journal of Medicine.^1,2

What were the survival outcomes?

At a median follow-up of 14.3 months, the median PFS by blinded independent central review (BICR) was 9.8 months (95% CI, 8.1-12.9) with divarasib vs 5.7 months (95% CI, 4.2-6.8) with control treatment (HR for disease progression or death, 0.58; 95% CI, 0.44-0.76; P <.001). Divarasib reduced the risk of disease progression or death by 42% vs control treatment, with a 12-month PFS rate of 43.9% vs 24.0%; investigator-assessed PFS was consistent, at a median of 11.1 months (95% CI, 8.8-14.1) vs 5.6 months (95% CI, 4.4-7.0; HR, 0.57; 95% CI, 0.43-0.75).

The trial also met its key secondary end point of OS at the first interim analysis; the median OS was 17.7 months (95% CI, 16.3-not estimable) with divarasib vs 12.0 months (95% CI, 10.0-15.2) with control treatment (HR for death, 0.56; 95% CI, 0.41-0.78; P <.001), representing a 44% reduction in the risk of death, with 12-month OS rates of 67.1% vs 49.2%.

“Krascendo 1 is the first and only global randomized phase 3 clinical trial comparing, head-to-head, a next-generation KRAS G12C inhibitor with the first-generation inhibitors,” said presenter Ferdinandos Skoulidis, MD, PhD, MRCP, a professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

The PFS and OS benefits were generally consistent across subgroups, including patients with a history of central nervous system (CNS) metastases, those with liver metastases, and those with KEAP1-mutated tumors.

What were the response outcomes?

Among the 328 patients evaluable for response by BICR, a confirmed objective response occurred in 58.4% (95% CI, 50.4%-66.1%) of the divarasib group vs 32.3% (95% CI, 25.3%-40.0%) of the control group, a statistically significant difference of 25.8 percentage points (95% CI, 15.6%-36.0%). Complete responses occurred in 4.3% vs 3.6% of patients, and partial responses in 54.0% vs 28.7%.

Responses were durable, with a median duration of response of 11.9 months (95% CI, 9.7-not estimable) with divarasib vs 6.9 months (95% CI, 5.3-8.3) with control treatment. A biomarker analysis showed that PFS and OS favored divarasib regardless of PD-L1 status.

What was the safety profile?

Grade 3 or 4 treatment-related adverse events (AEs) occurred in 24.6% of patients receiving divarasib vs 34.5% of those receiving control treatment, serious treatment-related AEs occurred in 7.8% vs 15.2%, and treatment-related AEs led to discontinuation in 4.8% vs 11.7%. The most common treatment-related AEs (TRAEs) in both groups were gastrointestinal and hepatotoxic effects; gastrointestinal events—diarrhea, nausea, and vomiting—were more frequent with divarasib but predominantly grade 1, whereas the incidence of hepatotoxic effects was lower with divarasib (26.9% vs 39.2%). No treatment-related QT prolongation or pneumonitis occurred with divarasib vs 2 and 3 patients in the control group, respectively. “Divarasib exhibited a manageable and, I would argue, a favorable safety profile compared to sotorasib or adagrasib, with a lower rate of high-grade…[TRAEs],” Skoulidis said. “This occurred despite median treatment duration being more than twice as long in patients that received divarasib [at 11.3 months vs 5.0 months].”

What is the trial design, and what are the implications?

Krascendo 1 is a phase 3, international, open-label, randomized trial that enrolled 338 patients with previously treated KRAS G12C–mutated advanced or metastatic NSCLC across 151 centers in 26 countries. Patients had received 1 to 3 prior lines of systemic therapy including platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor, were KRAS G12C inhibitor naive, had an ECOG performance status of 0 or 1, and had no active or untreated brain metastases. They were randomly assigned 1:1 to divarasib at 400 mg orally once daily (n = 167) or control treatment with sotorasib at 960 mg once daily or adagrasib at 600 mg twice daily (n = 171; 156 received sotorasib, and 15 received adagrasib). Randomization was stratified by KEAP1 mutation status, history of CNS metastases, and intended control inhibitor; crossover was not permitted.

The primary end point was PFS by BICR, and key secondary end points included OS, confirmed objective response, and patient-reported outcomes, tested in a prespecified hierarchy. Divarasib is a next-generation, oral KRAS G12C inhibitor engineered for greater potency and selectivity than the first-generation agents.

“Based on the results of the Krascendo 1 clinical trial, divarasib represents a new standard of care for patients with previously treated KRAS G12C–mutant advanced or metastatic [NSCLC],” Skoulidis concluded.

Divarasib is also being evaluated in the first-line setting in the phase 3 Krascendo 2 trial (NCT06793215) in combination with pembrolizumab (Keytruda) and in the adjuvant setting in the Krascendo 3 trial (NCT07541170).

References

1. Skoulidis F, Ahn MJ, Gadgeel S, et al. Efficacy and safety of divarasib vs sotorasib or adagrasib in previously treated, locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer: primary analysis of the phase 3 Krascendo 1 trial. Presented at: European Society for Medical Oncology (ESMO) Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA5.
2. Skoulidis F, Ahn MJ, Gadgeel S, et al. Divarasib as compared with sotorasib or adagrasib in KRAS G12C-mutated NSCLC. N Engl J Med. Published online October 25, 2026. doi:10.1056/NEJMoa2605703