Combination of KRAS G12C inhibitor adagrasib with immune checkpoint inhibitor pembrolizumab showed preliminary efficacy in patients with KRAS G12C-mutated NSCLC
Abstract: The phase 1b KRYSTAL-1 and phase 2 KRYSTAL-7 studies demonstrated that the combination of adagrasib (the second KRAS G12C inhibitor to receive FDA accelerated approval) and pembrolizumab (an immune checkpoint inhibitor) had antitumor activity in patients with NSCLC.
Adagrasib follows sotorasib in receiving accelerated FDA approval on December 12, 2022. Preclinical studies also support the combination of adagrasib with immunotherapy. It was found that adagrasib plus an anti-PD1 checkpoint inhibitor showed enhanced immune responses and efficacy in preclinical models, and that adagrasib trigged increased CD8-T cell responses in post-treatment patient tumor biopsies. Phase 1b KRYSTAL-1 and phase 2 KRYSTAL-7 were presented at the ESMO Immuno-Oncology Annual Meeting in 2022. The KRYSTAL-1 study, with a median follow-up of 19.3 months, confirmed preliminary safety and efficacy data recommending the concomitant use of adagrasib 400 mg and pembrolizumab in first-line treatment. The phase 2 KRYSTAL-7 study enrolled 2 cohorts: PD-L1 TPS < 1% and TPS ≥ 1%. With the median follow-up of 3.5 months, the combination's efficacy was ORR 49% and DCR 89% among 53 patients. Higher response rates were observed in the PD-L1 TPS ≥ 1% group, with ORR 59% in PD-L1 TPS > 50%, 48% PD-L1 TPS 1-49%, and 30% PD-L1 TPS < 1%. Adagrasib plus pembrolizumab showed promising results with a manageable safety profile in KRAS G12C-mut first-line NSCLC patients. The pharmaceutical manufacturer is planning a phase 3 study based on these findings.
Pasi A. Jänne presented at ESMO IMMUNO-ONCOLOGY 2022, LBA4.
Pasi et al.,N Engl J Med 2022; 387:120-131