KRYSTAL Data on Adagrasib Plus Pembrolizumab in KRAS-Mutated NSCLC Presented at ELCC 2025

First-line adagrasib plus pembrolizumab “continued to demonstrate promising efficacy” and showed a “manageable safety profile” in patients with non–small cell lung cancer (NSCLC) who have a KRAS G12C mutation and PD-L1 expression of at 50%, according to results from the KRYSTAL-7 trial.

Marina Garassino, MD, of the University of Chicago, presented results from the phase 2 portion of the trial during a mini oral abstract session at the European Lung Cancer Congress (ELCC) 2025 in Paris, France.

The trial previously showed that combining pembrolizumab with first-line adagrasib, an inhibitor of KRAS G12C, had “encouraging preliminary activity” with a median follow-up of 10.1 months in patients with NSCLC who have a KRAS G12C mutation and PD-L1 expression of at least 50%, according to the study investigators. Dr. Garassino reported updated data with longer follow-up during ELCC 2025.

“With 2 years of follow up, first-line adagrasib and pembrolizumab continue to demonstrate promising efficacy in patients with KRAS G12C mutated non–small cell lung cancer and PD-L1 more than 50%,” Dr. Garassino said during the oral abstract presentation.

The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1 criteria, with secondary end points including duration of response (DOR) and progression-free survival (PFS) as assessed by investigator, overall survival (OS), and safety. The study included patients with advanced or metastatic NSCLC with a KRAS G12C mutation and a known PD-L1 tumor proportion.

At the time of data cutoff, 149 patients had received adagrasib 400 mg orally twice daily plus pembrolizumab 200 mg IV once every 3 weeks. In the 54 patients with PD-L1 expression of at least 50%, the ORR was 59.3% (95% CI, 45.0-72.4). The median DOR was 26.3 months (95% CI, 26.3-not estimable [NE]), with a median PFS of 27.7 months (95% CI, 8.1-NE).

“The response rate and progression-free survival compared favorably with treatment expectations from a single-agent PD-L1 in patients with PD-L1 more than 50%,” Dr. Garassino said during the oral abstract presentation.

The 18-month PFS rate was 50.7% (95% CI, 35.5%-64.0%) with a median follow-up of 22.6 months. The median overall survival was not estimable (95% CI, 15.4%-NE) and the 18-month OS rate was 62.4% (95% CI, 47.5%-74.1%).

Treatment-related adverse events (TRAEs) of any grade occurred in nearly all 149 patients (94.6%), with TRAEs of grade 3 or 4 occurring in 68.4%. The investigators reported 3 TRAEs of grade 5, with 2 being pneumonia and 1 being pneumonitis.

The most common TRAEs of any grade were nausea (55.7%), diarrhea (47%), and alanine aminotransferase increase (39.6%) and were “mainly” grades 1 and 2. TRAEs leading to pembrolizumab discontinuation occurred in 23.5% of patients. TRAEs led to discontinuation of both agents in 6.7% of patients. TRAEs that led to adagrasib discontinuation occurred in 13.4% of patients.

“The majority of adagrasib reductions were due to grade 1, grade 2 adverse events, and the most common treatment-related adverse events leading to an adagrasib dose reduction were liver transaminase increase, nausea, and lipase,” Dr. Garassino said. “All these side effects were resolved with proper management.”

Dr. Garassino concluded by explaining the additional research that is currently being conducted on the combination treatment.

“There is an ongoing phase 3 portion that is recruiting patients with advanced metastatic non–small cell lung cancer, KRAS G12C, and PD-L1 more than 50%, and will compare the combination of adagrasib and pembrolizumab over pembrolizumab single-agent,” she said.

Reference

Garassino MC, Theelen W, Jänne PA, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) and PD-L1 =50% from the phase II portion of KRYSTAL-7. Abstract #5MO presented at: European Lung Cancer Congress 2025, March 26-29; Paris, France.

In the photo at top, Marina Garassino, MD, of the University of Chicago, presents results from the phase 2 portion of the trial during a mini oral abstract session at the European Lung Cancer Congress 2025 in Paris, France. (Photo courtesy of the European Society for Medical Oncology)