Adagrasib Plus Pembro Shows Promising First-Line Activity in KRAS G12C-Mutant NSCLC
Pasi A. Jänne, MD, PhD
The combination of adagrasib (Krazati) and pembrolizumab (Keytruda) demonstrated encouraging efficacy in patients with previously untreated, advanced KRAS G12C-mutated non–small cell lung cancer (NSCLC), according to results from the phase 2 KRYSTAL-7 trial (NCT04613596).1
Findings from KRYSTAL-7 were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The trial evaluated 150 patients who received oral adagrasib at 400 mg twice a day plus 200 mg of intravenous pembrolizumab every 3 weeks.
"The rationale for this study was that adagrasib is an approved agent in the second-line setting for advanced or metastatic KRAS G12C-mutant NSCLC. In the first-line setting, standard treatment for these patients typically involves a PD-(L)1 inhibitor with or without chemotherapy. This study aimed to explore how the combination of adagrasib and pembrolizumab performs in this same context—as a potential chemotherapy-free, first-line treatment strategy for previously untreated patients," explained Pasi A. Jänne, MD, PhD, in an interview with Targeted OncologyTM.
The primary end point was overall response rate (ORR) per investigator assessment, and secondary end points were duration of response, progression-free survival (PFS) per investigator assessment, overall survival (OS), and safety.
Efficacy Findings
Among all patients, the ORR was 44% (95% CI, 36%-53%). This included complete responses in 1% of patients, partial responses in 43%, stable disease in 37%, and progressive disease in 8%. Eleven percent of patients were not evaluable (NE). The disease control rate was 81% (95% CI, 74%-87%). The ORR in the biomarker-evaluable population was 36% (90% CI, 23%-50%) for patients with a PD-L1 tumor proportion score (TPS) of less than 1%, 41% (90% CI, 25%-58%) for patients with a PD-L1 TPS from 1% to 49%, and 61% for patients with a PD-L1 TPS of 50% or more (90% CI, 46%-74%).
The median PFS was 11.0 months (95% CI, 5.8-14.0). At 12 and 18 months, PFS rates were 48% and 38%, respectively. Median OS was 18.3 months (95% CI, 14.3-NE) with OS rates of 62% at 12 months and 52% at 18 months. The median duration of follow-up was 22.8 months. Approximately 30% of patients went on to receive additional anticancer therapy following progression, including chemotherapy alone (n = 21) or chemotherapy combined with a checkpoint inhibitor (n = 9).
"In an unselected patient population receiving pembrolizumab monotherapy, the median PFS is typically around 7 to 8 months in those with a PD-L1 TPS ≥50%. However, in this selected KRAS G12C-mutant population, the addition of adagrasib resulted in a significantly longer PFS,” explained Jänne, the 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, in the interview.
When stratified by PD-L1 TPS, median PFS was 8.2 months (95% CI, 2.7-13.6) in patients with TPS of less than 1%, 13.5 months (95% CI, 2.3-NE) for TPS between 1% and 49%, and 27.7 months (95% CI, 9.6-NE) for TPS 50% or more. Corresponding 12-month PFS rates were 38%, 53%, and 65%, while 18-month rates were 29%, 37%, and 51%, respectively.
Median OS by PD-L1 expression was 15.5 months (95% CI, 9.6-NE) for TPS <1%, 14.3 months (95% CI, 8.3-NE) for TPS 1-49%, and not reached (95% CI, 19.4-NE) for TPS ≥50%. OS rates at 12 months were 58%, 57%, and 78%, respectively, and at 18 months were 42%, 48%, and 69%.
“These findings suggest that, in this molecularly selected population, combining pembrolizumab with adagrasib leads to improved response rates and extended PFS compared with pembrolizumab monotherapy in an unselected first-line setting,” stated Jänne.
Safety Data
Treatment-related adverse events (TRAEs) were common across PD-L1 subgroups, with 95% of all patients experiencing any-grade TRAEs and 58% experiencing grade ≥3 events. The most frequent TRAEs included nausea (56%), diarrhea (47%), and elevated liver enzymes (alanine transaminase [ALT] 40%, aspartate aminotransferase [AST] 36%). Serious TRAEs (grade ≥3) most commonly involved elevated AST (14%), lipase (13%), and ALT (11%).
Dose interruptions and reductions of adagrasib were frequent (67% and 48%, respectively), while discontinuation rates remained relatively low (adagrasib 7%, pembrolizumab 17%, both agents 7%).
Immune-related AEs occurred in 22% of patients overall, with pneumonitis (12%) and hypothyroidism (7%) being most common. Safety profiles were broadly consistent across PD-L1 subgroups, though grade 5 TRAEs occurred only in the PD-L1 <50% group (3%).
Next Steps
In December 2022, the FDA granted accelerated approval to adagrasibfor use in patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC treated with at least 1 prior systemic therapy, including immunotherapy.2 Since then, adagrasib has been approved for use with cetuximab (Erbitux) to treat patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer.3
These findings from KRYSTAL-7 may support future efforts to establish adagrasib as part of a first-line standard of care regimen in KRAS G12C–mutant NSCLC, pending results from the phase 3 trial.
“This promising data underpins the rationale for the ongoing phase 3 portion of the KRYSTAL-7 trial, which is evaluating adagrasib plus pembrolizumab vs pembrolizumab alone as first-line therapy in advanced KRAS G12C-mutant NSCLC with PD-L1 TPS ≥50%, to determine whether the combination is superior to the current standard of care," concluded Jänne.
