TL;DR
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 advanced or metastatic KRAS G12C-mutant non-small cell lung cancer. The trial also found longer median overall and progression-free survival, with fewer severe treatment-related side effects, though gastrointestinal symptoms were more common. The findings do not establish whether divarasib is approved or available for routine use.
A phase III trial found that divarasib, a next-generation KRAS G12C inhibitor, was associated with a 44% lower risk of death than sotorasib or adagrasib among people with previously treated advanced or metastatic non-small cell lung cancer. The results, reported at the European Society for Medical Oncology congress in Madrid and published in the New England Journal of Medicine, also showed longer median survival and fewer severe treatment-related adverse events with divarasib.
The randomized Krascendo 1 trial enrolled 338 patients and assigned them equally to divarasib or a control group treated with an existing KRAS G12C inhibitor. Most control-arm patients, 91%, received sotorasib; the remainder received adagrasib. The participants had advanced or metastatic cancer with a KRAS G12C mutation and had already received treatment.
Median overall survival was 17.7 months with divarasib, compared with 12 months in the control group. The reported hazard ratio for death was 0.56, with a 95% confidence interval of 0.41 to 0.78. Median progression-free survival was 9.8 months versus 5.7 months, respectively. Progression-free survival measures time before the cancer worsens or a patient dies; it is distinct from overall survival.
Confirmed responses occurred in 58.4% of patients receiving divarasib and 32.3% in the control group. Median response duration was 11.9 months with divarasib and 6.9 months with the older drugs. At 12 months, 43.9% of the divarasib group and 24% of controls were alive without disease progression.
How the Survival Results Compare
The findings matter because sotorasib and adagrasib are approved options for previously treated KRAS G12C-mutant lung cancer, and the trial directly compared divarasib with those drugs. Its survival results suggest the newer inhibitor could change treatment discussions if the findings are accepted by regulators and translated into clinical practice. The study report describes Krascendo 1 as the first randomized head-to-head comparison of a next-generation KRAS G12C inhibitor with the earlier agents.
The safety results also offer a mixed picture rather than a simple reduction in side effects. Grade 3 or higher treatment-related adverse events occurred in 24.6% of divarasib patients, compared with 34.5% in the control group. Serious treatment-related adverse events occurred in 7.8% versus 15.2%, and side effects led to treatment discontinuation in 4.8% versus 11.7%. However, gastrointestinal toxicities were more frequent with divarasib, making tolerability and the duration of symptoms relevant to patients and clinicians.
Where Divarasib Fits in Treatment
KRAS G12C is a mutation found in a subset of non-small cell lung cancers. Sotorasib and adagrasib, the two drugs used in the control arm, had been approved for previously treated KRAS-mutant lung cancer since 2021 and 2022, respectively, according to the report. Trial presenter Ferdinandos Skoulidis of the University of Texas MD Anderson Cancer Center characterized their efficacy as modest.
Skoulidis described divarasib as a selective inhibitor designed for greater potency against KRAS G12C than the older drugs. The trial’s comparison is particularly relevant because earlier evidence had not come from a randomized head-to-head study of this kind. The results were presented at ESMO and published at the same time in a medical journal, but the source report does not state that divarasib has received regulatory approval.
““very strong””
— Benjamin Besse, ESMO-invited discussant from Gustave Roussy
Approval and Patient Access Questions
The report does not say whether divarasib has been submitted for approval, when regulators might decide, or whether it is available outside the clinical trial. The survival figures describe outcomes among trial participants and do not predict what will happen for every patient. The report also does not provide enough detail to determine how results vary across patient subgroups or how the findings compare with treatments not included in the control arm.
The trial did not allow patients assigned to the control group to switch to divarasib. Besse questioned that decision, saying patients in the control arm could not access the newer drug during the study. That design may affect how the survival comparison is interpreted, although the supplied report does not quantify the effect. Longer-term information about symptom duration and quality of life is also not provided in the report.
Regulatory Review and Follow-Up Data
The next steps will depend on whether the trial sponsor seeks regulatory approval and how agencies evaluate the results. The supplied report gives no application or decision timetable, so any approval date remains unknown. Clinicians and patients will also need information on access, prescribing guidance and how divarasib fits alongside other available treatments.
Further reporting or trial publications may clarify longer-term survival, patient-reported quality of life and the duration of side effects. Those details will help put the survival advantage in context, especially given Besse’s concern that standard toxicity grades do not capture how long symptoms persist. For now, the reported findings support a comparison within the trial population, not a guarantee of benefit for an individual patient.
Key Questions
What did the trial find about the risk of death?
The report says divarasib was associated with a 44% lower risk of death during the trial than the control treatments, sotorasib or adagrasib. Median overall survival was 17.7 months with divarasib and 12 months in the control group.
Who took part in the Krascendo 1 trial?
The trial randomized 338 patients with previously treated advanced or metastatic non-small cell lung cancer carrying a KRAS G12C mutation. They were assigned to divarasib or an existing inhibitor; 91% of the control group received sotorasib.
Was divarasib easier to tolerate?
Some serious side-effect measures were lower with divarasib: grade 3 or higher treatment-related events occurred in 24.6% of that group versus 34.5% of controls. But gastrointestinal toxicities were more common with divarasib, at 91% versus 68.4%; Skoulidis said they were mostly mild and manageable.
Is divarasib approved for lung cancer?
The source report does not state that divarasib is approved or provide a regulatory timetable. It reports trial results and Skoulidis’s view of the drug’s potential; that is not the same as approval by a regulator.
Source: rss
