LBA65 KRYSTAL-7: Efficacy and safety of adagrasib with pembrolizumab in patients with treatment-naïve, advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation

Adagrasib (ada) is an irreversible KRASG12C inhibitor selected for favorable properties, including long half-life (23 hrs), dose-dependent PK, and CNS penetration. Optimized noncovalent binding affinity and minimized cysteine reactivity associated with ada are hypothesized to limit off-target effects in the liver and other organ sites. Preliminary ada plus pembrolizumab (pembro) data showed a manageable safety profile and encouraging clinical activity. We report updated efficacy and safety in more patients (pts) treated with ada plus pembro in KRYSTAL-7 (NCT04613596). In the phase 2 KRYSTAL-7 study, pts with treatment-naïve KRASG12C-mutated advanced NSCLC received concurrent ada 400 mg orally BID plus pembro 200 mg intravenously Q3W. Study objectives included efficacy (investigator-assessed objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], and overall survival), and safety. As of 19 June 2023, 148 pts had received ada plus pembro (median follow-up 8.7 months). Median age was 67 years, 48% were female, 39%/61% were ECOG PS 0/1. In pts with PD-L1 ≥50% (median follow-up 10.1 months), ORR was 63% (32/51 pts), disease control rate was 84%. Median DOR was not reached (NR; 95% CI 12.6–not estimable [NE]); median PFS was NR (95% CI 8.2–NE). In all pts, treatment-related adverse events (TRAEs) of any grade (gr) occurred in 94% (139/148) of pts; 55% gr3, 9% gr4, 1% gr5. TRAEs led to both ada and pembro discontinuation in 4% of pts (6% discontinued ada alone, 11% discontinued pembro alone). No pt discontinued both drugs due to ALT/AST increase or hepatic TRAEs; 1 pt discontinued ada and 3 pts discontinued pembro due to liver transaminase elevation. Additional efficacy and safety analyses will be presented. After longer follow-up, concurrent ada plus pembro continued to have encouraging preliminary efficacy in pts with PD-L1 ≥50% and a manageable safety profile. These findings support initiation of a phase 3 trial evaluating concurrent ada plus pembro vs pembro for treatment-naïve pts with KRASG12C-mutated NSCLC and PD-L1 ≥50% (NCT04613596).