Phase 2 KRYSTAL-7 Study: First Look at Efficacy, Survival Data of Adagrasib Plus Pembrolizumab

The phase 2 KRYSTAL-7 study demonstrated “promising clinical efficacy and a manageable safety profile regardless of PD-L1 status” in patients with advanced or metastatic KRAS^G12C-mutated non-small cell lung cancer (NSCLC) who were treated with first-line adagrasib plus pembrolizumab, according to a presentation at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting.

Pasi Jänne, MD, PhD, FASCO, of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, presented results from phase 2, including efficacy and safety data and the first disclosure of survival data during the Metastatic NSCLC session at the ASCO 2025 Annual Meeting.

Phase 2 investigated the clinical activity and safety profile of first-line adagrasib plus pembrolizumab for the treatment of advanced or metastatic KRAS^G12C-mutated NSCLC in patients with PD-L1 tumor expression of 50% or higher.

Patients received 400 mg of oral adagrasib twice daily plus 200 mg of intravenous pembrolizumab every three weeks. The investigators explained that the primary endpoint of the study was the investigator-assessed objective response rate (ORR), and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) as assessed by the investigator, overall survival (OS), and safety.

The researchers reported that as of August 23, 2024, a total of 149 patients had received adagrasib in combination with pembrolizumab. The median age of the patients was 67 years, and 48% of the total cohort were female. Sixty-two percent had an ECOG performance score of 1, and the median OS follow-up point was 22.8 months. The ORR was 44.3% (95% CI, 36.2-52.7).

According to the results, the median DOR was 26.3 months and the median PFS was 11.0 months, with an 18-month PFS rate of 37.6%. The median OS was 18.3 months, with an 18-month OS rate of 51.8%.

Among patients with PD-L1 expression of 50% or less, the median ORR was 34 (35.8%), the median DOR was 18.2, and the median PFS was 6.9, with an 18-month PFS rate of 29.8%. Among patients with PD-L1 expression of at least 50%, the median OR was 32 (59.3%), the median DOR was 26.3, and the median PFS was 27.7, with an 18-month PFS rate of 50.7%.

In addition, treatment-related adverse events of any grade were observed in 94.6% of patients, and three grade 5 treatment-related adverse events were reported (pneumonia [n=2]; pneumonitis [n=1]). The investigators also observed hepatic treatment-related adverse events, including increases in alanine aminotransferase (39.6%), aspartate aminotransferase (35.6%), and alkaline phosphatase (19.5%). Two percent of patients discontinued adagrasib and 6.7% discontinued pembrolizumab due to hepatic treatment-related adverse events, while 0.7% discontinued both therapies.

In reflecting on the results, the investigators noted that “these data represent the largest dataset evaluating a first-line KRAS^G12C inhibitor plus PD-(L)1 inhibitor in this population presented to date.”

“The phase 3 portion of KRYSTAL-7, comparing first-line [adagrasib] plus [pembrolizumab] vs [pembrolizumab] monotherapy in pts with KRAS^G12C-mutated NSCLC and PD-L1≥50%, is ongoing and recruiting,” the researchers concluded.