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In the phase III KRASCENDO 1 trial, divarasib was associated with a 44% lower risk of death than sotorasib or adagrasib among patients with previously treated KRAS G12C-mutant advanced lung cancer. Median overall survival was 17.7 months with divarasib and 12 months with the control drugs; longer follow-up and questions about treatment access remain relevant.
A phase III trial found that divarasib lowered the risk of death by 44% compared with sotorasib or adagrasib in people with previously treated, advanced or metastatic KRAS G12C-mutant non-small cell lung cancer. Median overall survival was 17.7 months with divarasib and 12 months with the older drugs, according to results presented at the European Society for Medical Oncology congress and published in the New England Journal of Medicine.
The randomized KRASCENDO 1 trial enrolled 338 patients, assigning them in equal proportions to divarasib or a control group treated with one of the first-generation KRAS G12C inhibitors. Most patients in the control group—91%—received sotorasib. The study involved people whose advanced or metastatic cancer had already been treated.
Divarasib also improved the trial’s primary endpoint, progression-free survival: the median was 9.8 months, compared with 5.7 months in the control group. The risk of disease progression or death was lower with divarasib (hazard ratio 0.58; 95% confidence interval 0.44 to 0.76). At 12 months, 43.9% of patients receiving divarasib were alive without progression, compared with 24% of those receiving the older drugs.
Confirmed responses occurred in 58.4% of the divarasib group and 32.3% of the control group. Median response duration was 11.9 months versus 6.9 months. Ferdinandos Skoulidis, the trial presenter from the University of Texas MD Anderson Cancer Center, said divarasib had fewer severe treatment-related adverse events overall, although the types and frequency of side effects differed.
Survival Gains and Side Effects
The findings offer a direct comparison between a next-generation KRAS G12C inhibitor and the two drugs already approved for this mutation in previously treated lung cancer. The reported survival difference may matter to patients and clinicians weighing treatment options after earlier therapy, particularly because overall survival is a measure of how long patients live, not only how long their cancer remains stable.
The safety results were mixed rather than uniformly better. Grade 3 or higher treatment-related adverse events occurred in 24.6% with divarasib, compared with 34.5% in the control group; serious treatment-related events occurred in 7.8% and 15.2%, respectively. Treatment-related events led to discontinuation in 4.8% versus 11.7%. Gastrointestinal effects, including diarrhea, nausea and vomiting, were more common with divarasib—91% versus 68.4%—while reported liver toxicity was less common, at 26.9% versus 39.2%. Skoulidis said most gastrointestinal events were mild, manageable with standard supportive measures and reversible.
These figures describe trial participants and do not establish that every patient will have the same benefit or side effects. The study’s results may inform treatment decisions and regulatory discussions, but individual care depends on a patient’s cancer and overall circumstances.
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A Direct Test Against Approved Drugs
Sotorasib and adagrasib have been approved for previously treated KRAS-mutant lung cancer since 2021 and 2022, respectively, according to the report. Skoulidis described their efficacy as modest. Divarasib was engineered as a selective inhibitor of the inactive state of KRAS G12C, with the aim of greater target potency and selectivity than those earlier agents.
KRASCENDO 1 is described in the report as the first randomized head-to-head trial comparing a next-generation KRAS G12C inhibitor with first-generation drugs. That design provides a direct comparison within the study, although it does not settle every question about how the medicines compare in wider clinical practice or against other treatment strategies.
The trial was presented at the ESMO congress in Madrid on October 26, 2026, and published concurrently in the New England Journal of Medicine. The report identifies Skoulidis as the presenter and Benjamin Besse of Gustave Roussy as the invited discussant.
“Very strong”
— Benjamin Besse, MD, PhD, Gustave Roussy
Access, Follow-Up and Patient Burden
The trial did not allow patients assigned to the control group to cross over to divarasib, according to the report. Besse questioned that decision, saying patients in the control arm could not access the newer drug during the study. The report says regulators and agencies often seek a clear survival signal, but it does not provide further details about the decision-making process for this trial.
The results supplied do not state the duration of follow-up, whether the survival analysis was final, or how outcomes varied across patient subgroups. The reported median survival figures are study results, not a guarantee of an individual outcome. The trial also found more gastrointestinal toxicities with divarasib, while the duration and day-to-day burden of those symptoms were not fully captured by the grading information described.
Investigators reported adverse events leading to death in 6% of divarasib recipients and 4.1% of controls; none were judged treatment-related. The source does not establish how the findings will affect approval status, clinical guidelines or access to divarasib.
Regulatory Review and Clinical Use
The results are now available in a peer-reviewed journal and have been presented to the oncology community. The supplied report does not name a regulatory filing, decision date or guideline change, so the next formal steps are not confirmed. Any changes to treatment availability or recommendations would depend on subsequent regulatory and clinical review.
Further follow-up could clarify how durable the survival difference is and how treatment effects vary across patients. Clinicians and patients will also need more information on the length and practical impact of side effects, alongside the survival and response data, when considering the findings in individual cases.
Key Questions
What did the trial find about divarasib and survival?
In KRASCENDO 1, median overall survival was 17.7 months with divarasib and 12 months with sotorasib or adagrasib. The trial reported a 44% lower risk of death during the study with divarasib; this is a comparison between trial groups, not a prediction for an individual patient.
Which patients were studied?
The trial enrolled 338 people with previously treated, advanced or metastatic KRAS G12C-mutant non-small cell lung cancer. It compared divarasib with a control group in which 91% received sotorasib.
Did divarasib delay cancer progression?
Yes. Median progression-free survival was 9.8 months with divarasib, compared with 5.7 months in the control group. At 12 months, 43.9% of the divarasib group were alive without progression, versus 24% of the control group.
What side effects were reported?
Severe and serious treatment-related adverse events were less frequent with divarasib in the trial. Gastrointestinal effects were more common, while reported liver toxicity was less common than in the control group. The study presenter said most gastrointestinal events were mild and manageable, but symptom duration and personal risk can vary.
Is divarasib now a new standard treatment?
The trial presenter called divarasib a potential new standard of care, but that is his assessment of the findings. The source material does not report a regulatory decision or a change to treatment guidelines.
Source: rss
