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The phase III KRAScendo 1 trial found that divarasib was associated with a 44% lower risk of death and longer median overall survival than sotorasib or adagrasib in previously treated advanced or metastatic KRAS G12C-mutant lung cancer. The results were presented at the 2026 ESMO congress and published in the New England Journal of Medicine; longer-term outcomes and access to the drug remain unresolved.
A phase III trial found that divarasib reduced the risk of death by 44% compared with sotorasib or adagrasib among patients 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 in Madrid 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 receiving one of the two older drugs. Most control-group participants—91%—received sotorasib. The trial’s primary endpoint was progression-free survival, or the time patients lived without their cancer worsening.
Median progression-free survival was 9.8 months with divarasib, compared with 5.7 months in the control group. The hazard ratio was 0.58 (95% confidence interval 0.44 to 0.76; P<0.001). At 12 months, 43.9% of patients in the divarasib group were alive without disease progression, compared with 24% of controls.
Overall survival also favored divarasib: the reported hazard ratio was 0.56 (95% CI 0.41 to 0.78; P<0.001). At 12 months, the overall survival rates were 67.1% with divarasib and 49.2% with control treatment. Confirmed responses occurred in 58.4% of divarasib recipients and 32.3% of controls; median response duration was 11.9 months versus 6.9 months.
Survival Gains and Treatment Trade-Offs
The findings offer a direct comparison between a newer KRAS G12C inhibitor and the two approved drugs used in the control group, addressing a practical treatment question for patients whose advanced lung cancer has already been treated. The measured differences in overall survival, progression-free survival and response could affect future treatment decisions if regulators and clinical guidelines support divarasib’s use.
The safety results showed a mixed pattern rather than an absence of side effects. Grade 3 or higher treatment-related adverse events were reported in 24.6% of divarasib recipients, compared with 34.5% of controls; serious treatment-related events occurred in 7.8% and 15.2%, respectively. Treatment discontinuation due to treatment-related events was also less common with divarasib, at 4.8% versus 11.7%.
Gastrointestinal effects were more frequent with divarasib: 91% experienced gastrointestinal toxicities, compared with 68.4% in the control group. Skoulidis said these effects were mostly mild, manageable with standard supportive care and reversible. The rates of hepatotoxic effects were lower with divarasib, at 26.9% versus 39.2%. These results matter to patients weighing potential survival benefit against the type, severity and duration of treatment burden.
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How Divarasib Was Compared
Sotorasib and adagrasib have been approved for previously treated KRAS-mutant lung cancers since 2021 and 2022, respectively. The report describes their efficacy as modest and presents divarasib as a next-generation, selective inhibitor designed to bind the inactive form of KRAS G12C. The trial is described as the first randomized head-to-head study comparing a next-generation KRAS G12C inhibitor with the earlier drugs.
Ferdinandos Skoulidis of the University of Texas MD Anderson Cancer Center presented the results at the ESMO congress. He said divarasib “represents a new standard of care” for this patient group. That is his assessment of the findings, not a statement that a regulatory authority has approved divarasib or adopted it as a standard treatment.
ESMO discussant Benjamin Besse of Gustave Roussy raised a separate issue with the trial design: patients assigned to the control group were not allowed to switch to divarasib. He questioned whether patients should be denied access to the newer drug during a survival study. The report says regulators typically seek a clear signal of benefit, but does not provide further detail on the trial’s crossover decision.
““That’s not something we can tolerate anymore.””
— Benjamin Besse, MD, PhD, Gustave Roussy
Approval, Access and Long-Term Effects
The report gives trial results but does not say whether divarasib has been submitted for approval, when a regulatory decision might occur, or whether it is available to patients outside the study. Skoulidis’s description of the drug as a potential new standard is a clinical interpretation; the article does not report a new approval or guideline change.
The reported median survival figures are trial results, not a prediction for every patient. The source does not provide additional follow-up beyond the figures described, so the durability of the survival difference remains to be established. It also does not give detailed patient-level outcomes for subgroups, such as those with a history of central nervous system involvement.
How side effects affect patients over time remains another open issue. Although the report says gastrointestinal effects were mostly mild and reversible, it does not specify their duration for individual patients. Besse argued that toxicity grading should account for chronic treatment burden. The trial also did not allow control-group patients to cross over to divarasib, a design choice he challenged.
Regulatory Review and Follow-Up
The next steps are not specified in the source report. Regulators may review the published trial data, but no application, review timetable or decision is reported here. Clinicians and patients will also need information on how divarasib fits into treatment guidelines and access arrangements before the findings can be translated into routine care.
Further follow-up could clarify how durable the survival advantage is, how long side effects last and which patients are most likely to benefit. For now, the reported evidence is a randomized comparison in previously treated advanced or metastatic KRAS G12C-mutant lung cancer, and should not be assumed to apply to other lung cancers or earlier stages of disease.
Key Questions
What did the trial find about survival?
Median overall survival was 17.7 months with divarasib and 12 months with sotorasib or adagrasib. The reported hazard ratio was 0.56, which the report describes as a 44% lower risk of death during the trial.
Which patients were studied?
The trial included 338 patients with previously treated advanced or metastatic non-small cell lung cancer carrying a KRAS G12C mutation. The results do not establish benefit for other cancer types or earlier-stage disease.
Was divarasib safer than the older drugs?
Some serious or high-grade treatment-related events were less common with divarasib, but side effects still occurred. Gastrointestinal toxicities were more frequent—91% versus 68.4% in the control group—while hepatotoxic effects were less frequent.
Is divarasib approved for routine treatment?
The source report does not state that divarasib has received regulatory approval or that treatment guidelines have changed. Its approval status and availability are not established by the information provided.
Could patients in the control group switch to divarasib?
No. The report says crossover was not allowed. ESMO discussant Benjamin Besse criticized that decision, arguing that patients assigned to the older drugs could not access divarasib during the study.
Source: medpagetoday.com
