Next-generation KRAS inhibitor divarasib extends survival in advanced lung cancer

Patients with previously treated advanced KRAS G12C-mutant non-small cell lung cancer lived significantly longer when treated with the next-generation targeted therapy divarasib, according to Phase 3 results from the global Krascendo 1 study, published in The New England Journal of Medicine and presented at the European Society for Medical Oncology Congress 2026 by researchers from The University of Texas MD Anderson Cancer Center.

In the trial, divarasib was compared head-to-head with the two currently approved KRAS G12C inhibitors, sotorasib and adagrasib, in patients whose cancer 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 reached 17.7 months with divarasib compared with 12 months for patients receiving sotorasib or adagrasib.

The study 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 divarasib, sotorasib or adagrasib. After a median follow-up of 14.3 months, patients treated with divarasib had a median progression-free survival of 9.8 months versus 5.7 months for those on the standard KRAS inhibitors. At one year, 44% of patients receiving divarasib remained free from disease progression or death, compared with 24% of the control group.

Responses were also more frequent and more durable. Patients were nearly twice as likely to respond to divarasib, with an overall response rate of 58.4% versus 32.3% for standard therapy. The median duration of response was 11.9 months with divarasib compared with 6.9 months for the approved inhibitors.

Tolerability did not come at the cost of efficacy. Severe treatment-related side effects occurred in 25% of patients receiving divarasib compared with 35% of those receiving current KRAS-targeted therapies, even though patients stayed on divarasib twice as long.

Divarasib is an oral targeted therapy designed to block KRAS G12C more effectively than currently approved drugs. It works by locking the abnormal KRAS protein in an inactive state, switching off a key growth signal that cancer cells depend on. KRAS is one of the most commonly altered genes in NSCLC, and approximately 14% of NSCLC patients carry the specific G12C mutation. KRAS G12C inhibitors such as sotorasib and adagrasib were the first approved therapies designed to target the mutation directly.

Krascendo 1 is the first Phase 3 trial to directly compare a next-generation KRAS inhibitor with approved KRAS-targeted treatments. “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, professor of Thoracic/Head and Neck Medical Oncology at MD Anderson. “Divarasib significantly improved both measures compared with currently available KRAS inhibitors.”

The study has limitations. Its open-label design, the relatively small number of patients in the control group who received adagrasib, and the exclusion of patients with untreated brain metastases may affect how broadly the findings apply. The trial was sponsored by F. Hoffmann-La Roche Ltd. and Genentech, Inc., with author disclosures and funding information listed in the journal publication.

Subject of Research: Phase 3 trial of the next-generation KRAS G12C inhibitor divarasib in previously treated advanced non-small cell lung cancer

Article Title: ESMO 2026: New targeted therapy improved survival for patients with KRAS-mutated lung cancer

Article References: ESMO 2026: New targeted therapy improved survival for patients with KRAS-mutated lung cancer. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: divarasib, KRAS G12C, non-small cell lung cancer, targeted therapy, Phase 3 trial, Krascendo 1, sotorasib, adagrasib, overall survival, ESMO 2026, MD Anderson, New England Journal of Medicine