KRAS G12D remains the most common KRAS mutation in oncology, accounting for 26% of all KRAS mutations and occurring in approximately 5% of patients with non-small cell lung cancer (NSCLC).1 Despite its prevalence, no targeted therapies have been approved for clinical use in this patient population.
However, a recent phase 1 trial published in The New England Journal of Medicine evaluated the safety and preliminary antitumor activity of setidegrasib, a first-in-class KRAS G12D-targeted protein degrader, in patients with previously treated advanced NSCLC or pancreatic ductal carcinoma harboring this mutation.2
“KRAS G12D has historically been one of the most challenging KRAS alterations to target,” said study coauthor Anup Kasi, MD, MPH, Associate Professor of Medicine at the University of Kansas Medical Center. “The most important takeaway from these data is that direct targeting of KRAS G12D is becoming clinically actionable. Early signs of clinical activity in this setting represent meaningful progress, as this mutation has long been considered ‘undruggable.’”
The study’s primary objective was to evaluate safety, including adverse events and dose-limiting toxicites.1 Seventy-six participants received a weekly 600 mg dose of setidegrasib, with treatment-related adverse events occurring in 93% of patients. The most common were nausea and infusion-related reactions.2
In the group of 45 patients with NSCLC treated with 600 mg of setidegrasib, the objective response rate (ORR), consisting entirely of partial responses, was 36% (95% CI, 22% to 51%). Among responders, 76% maintained their response at six months. Median progression-free survival (PFS) was 8.3 months (95% CI, 4.1 months to not estimable), and the estimated 12-month overall survival (OS) was 59% (95% CI, 40% to 74%).2
Among the 32 patients who received the 600 mg dose in a second- or third-line setting, the ORR was 38%, with a median PFS of 11.2 months (95% CI, 5.6 months to not estimable).2
“What stands out is the signal of activity in a heavily pretreated population,” Dr. Kasi said. “For lung cancer, an encouraging durability was observed, particularly in the 2/3L setting. Additionally, observing activity across tumor types highlights the broader potential of targeting KRAS G12D beyond a single disease setting.”
Overall, the investigators concluded that setidegrasib demonstrated antitumor activity with a management safety profile, with only two participants discontinuing because of treatment-related adverse events.1
Dr. Kasi noted that the findings represent an important step forward and support continued development of KRAS G12D-targeted therapies.
“They may eventually move into earlier lines of therapy, potentially in combination regimens,” he said. “Over time, we may see a paradigm shift where KRAS-directed therapies are integrated similarly to how other oncogenic drivers are treated in lung cancer.”
References
1. Park W, Kasi A, Spira AI, et al. Setidegrasib in advanced non-small-cell lung cancer and pancreatic cancer. N Engl J Med. 2026;394(14):1409-1420. doi:10.1056/NEJMoa2600752
2. Stenger M. Setidegrasib in advanced NSCLC and pancreatic cancer harboring the KRAS p.G12D variant. ASCO Post. Published April 7, 2026.
