Adagrasib + Pembrolizumab Posts 44% ORR and 26-Month DoR as Chemo-Free First-Line Option for KRAS-G12C NSCLC

In the Phase 2 KRYSTAL-7 study (NCT04613596), 149 untreated metastatic KRAS-G12C NSCLC patients received adagrasib (KRAS G12C inhibitor) 400 mg BID plus pembrolizumab (PD-1 checkpoint inhibitor) Q3W. About 13% of NSCLC cases are KRAS G12C mutants. Investigator-assessed ORR was 44.3% (59% in PD-L1 ≥50%, 36% in PD-L1 <50%). Median PFS reached 11.0 months (27.7 mo vs 6.9 mo by PD-L1 strata) and median OS reached 18.3 months. Median DoR hit 26.3 months overall. Grade 3–4 TRAEs occurred in 68% of patients—mostly transaminase elevations (ALT 11%, AST 14%). Three grade 5 events (2 pneumonia, 1 pneumonitis) were reported, and hepatic toxicity led to permanent discontinuation in 2% (adagrasib) and 7% (pembrolizumab) of patients. In comparison, pembrolizumab monotherapy in PD-L1 ≥50% tumors delivers an ORR of ~45% and mPFS of 10.3 monthswhile pembrolizumab + platinum/pemetrexed in unselected nonsquamous disease yields mPFS ~8–9 mo with higher myelosuppression.