Alirocumab (PCSK9 inhibitor) + cemiplimab (anti–PD-1) shows biomarker-enriched activity in ICI-refractory metastatic NSCLC

Alirocumab is a monoclonal antibody PCSK9 inhibitor (approved for hypercholesterolemia) being repurposed here to counter immunotherapy resistance, combined with the anti–PD-1 antibody cemiplimab in a first-in-class, multi-center, single-arm Phase 2 study in metastatic NSCLC previously resistant to immune checkpoint blockade (NCT05553834). Among 58 evaluable patients (enrolled May 2023–Aug 2025; n=60 total), ORR was 14.98% (90% CI 5.45–25.52), median OS was 7.2 months (95% CI 5.3–13.6), and median DOR was not estimable; as a rough benchmark in the post–PD-(L)1 setting, docetaxel+ramucirumab historically delivers ORR 23% and mOS 10.5 months in REVEL (pre-ICI era), with some real-world post-ICI series reporting higher response rates but variable generalizability. Safety was described as having no new signals, mostly ≤G2 AEs, with two G3 events. A prespecified(?) correlative signal stood out: tumors with PIK3CA/AKT1/PTEN alterations had ORR 31.5% (95% CI 13.9–68.4) with a significant association to response (p=0.0008), while no responses occurred without these alterations; OS was numerically longer in the altered group (13.64 months; 95% CI 3.1–NR) vs unaltered (7.2 months; 95% CI 5.2–12.8). Take Home: If this alteration-defined “on-switch” for benefit holds up, PCSK9 inhibition could become a genuinely rational salvage immunotherapy re-challenge strategy—otherwise, the all-comers ORR (15%) looks more “in-range” than practice-changing against common post-ICI chemotherapy benchmarks.