Adagrasib/Pembrolizumab Yields Improved Survival in KRAS G12C-Mutated NSCLC

Results from the KRYSTAL-7 trial showed that efficacy was improved with adagrasib/pembrolizumab for KRAS G12C-mutated NSCLC.

Adagrasib (Krazati) plus pembrolizumab (Keytruda) improved efficacy for patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC), according to results from the phase 2 KRYSTAL-7 trial (NCT04613596) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Per the investigator assessment, the overall response rate (ORR) was 44% (95% CI, 36%-53%) in all patients; 1% had a complete response, 43% had a partial response, 37% had stable disease, 8% had progressive disease, and 11% were not evaluable (NE). The disease control rate was 81% (95% CI, 74%-87%).

In the biomarker-evaluable population, the ORR was 36% (90% CI, 23%-50%) for patients with a PD-L1 tumor proportion score (TPS) of less than 1%, it was 41% (90% CI, 25%-58%) for patients with a PD-L1 TPS from 1% to 49%, and for 50% or more it was 61% (90% CI, 46%-74%).

The median progression-free survival (PFS) was 11.0 months (95% CI, 5.8-14.0). At 12 months, the PFS rate was 48%, and at 18 months it was 38%. The median overall survival (OS) was 18.3 months (95% CI, 14.3-not evaluable [NE]). The OS rate at 12 months was 62%, and at 18 months it was 52%.

The median follow-up was 22.8 months. Of note, 30% of patients received subsequent anticancer therapy, which included either chemotherapy (n = 21) or chemotherapy with a checkpoint inhibitor therapy (n = 9).

The median PFS for patients with PD-L1 TPS of less than 1% was 8.2 months (95% CI, 2.7-13.6), for TPS of 1% to 49% it was 13.5 months (95% CI, 2.3-NE), and for 50% or more it was 27.7 months (95% CI, 9.6-NE). At 12 months, the PFS rates were 38%, 53%, and 65%, while at 18 months, they were 29%, 37%, and 51%, respectively.

The median OS for patients with PD-L1 TPS of less than 1% was 15.5 months (95% CI, 9.6-NE), for 1% to 49% it was 14.3 months (95% CI, 8.3-NE), and for 50% or more it was not reached (95% CI, 19.4-NE). The OS rate at 12 months was 58%, 57%, and 78%, while at 18 months it was 42%, 48%, and 69%, respectively.

“In the phase 2 KRYSTAL-7 study, first-line adagrasib plus pembrolizumab demonstrated promising efficacy with a chemotherapy-free regimen in patients with KRAS G12C-mutated NSCLC,” wrote Pasi A. Jänne, MD, PhD, senior vice president for Translational Medicine, director of the Belfer Center for Applied Cancer Sciences, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, senior physician, David M. Livingstone, MD, Chair at Dana-Farber Cancer Institute, and professor of medicine at Harvard Medical School.

“Efficacy was enriched among patients with PD-L1 TPS of 50% or more. Treatment escalation, such as concurrent chemotherapy, may be useful for patients with PD-L1 TPS less than 50% and certain other patients who are high-risk.”

The trial assessed 150 patients who received adagrasib at 400 mg by mouth twice a day plus 200 mg of intravenous pembrolizumab every 3 weeks. Patients were eligible for treatment if they had advanced or unresectable or metastatic NSCLC with a KRAS G12C mutation; no prior systemic therapy for advanced or metastatic disease; a known PD-L1 TPS; and were treated with neurologically stable brain metastases were allowed.

The primary end point was ORR per investigator assessment. Secondary end points included duration of response and PFS per investigator assessment, plus OS and safety.

Overall, 99% of patients received treatment, 77% discontinued adagrasib, 28% had disease progression, 22% had adverse effects, 9% had global deterioration of health, 8% died, 7% withdrew, and less than 1% were lost to follow-up. Of note, patient disposition was similar between the overall population and the biomarker-evaluable population.

Baseline characteristics included a median patient age of 67 years, 48% were female, 76% were White, and 93% were non-Hispanic or Latino. Additionally, 96% had adenocarcinoma histology, 98% were current or former smokers, and 62% had an ECOG performance status of 1. At baseline, 19% had adrenal metastases, 31% had bone metastases, 16% had central nervous system metastases, and 17% had liver metastases. PD-L1 status included 26% having a TPS of less than 1%, 18% having a TPS of 1% to 49%, and 26% having a TPS of 50% or more.

Regarding safety based on PD-L1 status, 96% with a TPS of less than 50% had any grade treatment-related adverse effects (TRAEs), 57% had grade 3, 14% had grade 4, and 3% had grade 5. TRAEs that led to adagrasib dose interruption occurred in 68%, adagrasib dose reduction in 53%, adagrasib discontinuation in 5%, pembrolizumab discontinuation in 20%, and combination discontinuation in 7%, with 24% having any-grade immune-related AEs.

For patients with a PD-L1 TPS of 50% or more, 93% had any grade TRAEs, 59% had grade 3, 6% had grade 4, and 0% had grade 5. TRAEs leading to dose interruption with adagrasib occurred in 65% of patients, adagrasib dose reduction in 41%, adagrasib discontinuation in 9%, pembrolizumab discontinuation in 11%, combination discontinuation in 6%, and any grade immune-related AEs occurred in 19%.

For all patients, 95% had any grade TRAEs, 58% had grade 3, 11% had grade 4, and 2% had grade 5. TRAEs leading to adagrasib dose interruption occurred in 67% of patients, 48% had adagrasib dose reduction, 7% had adagrasib discontinuation, 17% had pembrolizumab discontinuation, and 7% had combination discontinuation. Any grade immune-related AEs occurred in 22% of patients.

The most common any-grade TRAEs included nausea (56%), diarrhea (47%), alanine aminotransferase increase (ALT; 40%), and aspartate transaminase increase (AST; 36%). Grade 3 or higher TRAEs that were most common included AST increase (14%), lipase increase (13%), and ALT increase (11%)

Additionally, immune-related AEs included pneumonitis (12%), hypothyroidism (7%), hepatitis (4%), adrenal insufficiency (2%), and hyperthyroidism (1%).

Reference

Janne P, Theelen W, Garassino M, et al. First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study. Presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. Chicago, IL, May 30-June 2, 2025. doi:10.1200/JCO.2025.43.16_suppl.8500