Patients with previously treated advanced KRAS G12C–mutant non–small cell lung cancer (NSCLC) had improved progression-free and overall survival and saw improved disease control when treated with the next-generation KRAS-targeted therapy divarasib, according to researchers from The University of Texas MD Anderson Cancer Center. Results from the global phase III Krascendo 1 study were published by Skoulidis et al in The New England Journal of Medicine and presented at the European Society for Medical Oncology (ESMO) Congress 2026 (Abstract LBA5).
In the trial, researchers compared divarasib with two currently approved KRAS G12C inhibitors, sotorasib or adagrasib, in patients with NSCLC whose disease had progressed after prior treatment. Treatment with divarasib reduced the risk of disease progression by 42% and the risk of death by 44%. Median overall survival improved with divarasib to 17.7 months vs 12 months with sotorasib/adagrasib.
“For patients with KRAS G12C–mutant lung cancer, extending survival while delaying cancer progression are the outcomes that matter most,” said principal investigator Ferdinandos Skoulidis, MD, PhD, Professor of Thoracic/Head and Neck Medical Oncology at MD Anderson. “Divarasib significantly improved both measures compared with currently available KRAS inhibitors. These results establish divarasib as a new standard of care and offer hope for patients whose treatment options have been limited after their cancer progresses.
KRAS is one of the most commonly altered genes in NSCLC, and these mutations allow cancer cells to grow uncontrollably. Approximately 14% of patients with NSCLC have a specific type of mutation, known as KRAS G12C. While KRAS was once thought to be ‘undruggable,’ in recent years, KRAS G12C inhibitors, including sotorasib and adagrasib, became the first approved therapies designed to specifically target the mutation.
Divarasib is a next-generation oral targeted therapy designed to block KRAS G12C more effectively than the therapies that are currently approved. The treatment works by locking the abnormal KRAS protein in an inactive state, essentially switching off a key signal that cancer cells depend on to grow and survive.
Krascendo 1 is the first phase III trial to directly compare a next-generation KRAS inhibitor with approved KRAS-targeted treatments, providing important evidence about whether a newer generation of these medicines can help patients live longer.
Other Key Findings
The trial enrolled 338 patients with previously treated advanced or metastatic KRAS G12C–mutant NSCLC at 151 centers across 26 countries. Participants were randomly assigned to receive either divarasib, sotorasib, or adagrasib.
After a median follow-up of 14.3 months, patients treated with divarasib experienced a median progression-free survival of 9.8 months compared with 5.7 months for those receiving standard KRAS inhibitors. At 1 year, 44% of patients receiving divarasib remained free from disease progression or death vs 24% of those in the control group.
In addition to improved overall survival, patients were nearly twice as likely to respond to treatment with divarasib vs the control treatment. The overall response rate was 58.4% compared with 32.3% for standard therapy, and responses lasted longer, with a median duration of response of 11.9 months vs 6.9 months.
Importantly, improved efficacy did not come at the cost of increased toxicity. Divarasib was better tolerated, with severe treatment-related side effects occurring in 25% of patients compared with 35% of those receiving current KRAS-targeted therapies, despite receiving divarasib treatment twice as long.
Limitations of the study include its open-label design and the relatively small number of patients in the control group who received adagrasib. In addition, patients with untreated brain metastases were not eligible for enrollment.
DISCLOSURE: For full disclosures of the study authors, visit nejm.org.
