Pembrolizumab + lenvatinib (VEGFR/FGFR TKI) hits biomarker-gated ORR in 1L NSCLC, but survival looks broadly similar across groups

Pembrolizumab (anti–PD-1) was combined with lenvatinib (multi-kinase VEGFR/FGFR inhibitor), quavonlimab (CTLA-4 mAb), or favezelimab (LAG-3 mAb) in the biomarker-directed, adaptively randomized Phase 2 KEYNOTE-495/KeyImPaCT trial in previously untreated advanced NSCLC (n=243; NCT03516981; data cutoff July 30, 2025). Across four prespecified subgroups defined by T-cell–inflamed GEP (low vs non-low) and TMB (<5 vs ≥5 mut/Mb), the “GEP non-low/TMB non-high” subgroup on pembrolizumab+lenvatinib met the Bayesian ORR threshold (posterior probability of true ORR >20% ≥95%); observed outcomes varied widely by subgroup (e.g., ORR 12.0%–57.1% and median PFS 5.4–17.8 months for pembrolizumab+lenvatinib), while OS was reported as comparable across biomarkers and regimens with long follow-up (median 66.5 months) and no new safety signals. Versus current 1L SOC pembrolizumab+chemo in metastatic NSCLC—median OS ~16 months in squamous disease in KEYNOTE-407 (15.9 vs 11.3 months vs chemo alone) and sustained long-term benefit at 5 years—these chemo-free combinations don’t clearly show superior survival here, especially given small subgroup Ns and broad CIs.