Alirocumab Plus Cemiplimab in Immunorefractory NSCLC: A Single Arm Phase 2 Study

In preclinical models, PCSK9 mediates cancer immunotherapy resistance and may serve as a novel immuno-inhibitory target. Herein, we report the results from a multi-center, single arm, phase II study evaluating the clinical activity and safety of the PCSK9 inhibitor alirocumab, in combination with the anti-PD1 antibody cemiplimab, in non-small cell lung cancer (NSCLC) patients with disease progression after previous immune checkpoint blockade. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR) and safety, and an exploratory objective was to analyze potential biomarkers of response. Sixty patients were enrolled, and 58 were evaluable for ORR. The ORR was 14.78% (90% CI, 5.30, 25.43), the median PFS was 2.5 months (95% CI, 1.5-3), and the median OS was 7.3 months (95% CI, 5.4 - 12.3). The most common treatment related adverse events (all grades) were anemia and fatigue. Grade 3 adverse events occurred in seven (12%) patients and were anemia, Guillain-Barre Syndrome and elevated amino transferase. There were no treated related adverse events of grade 4 or greater in the study population. Biomarker analysis identified superior outcomes in NSCLC harboring PIK3CA, PTEN, or AKT1 alterations. The ORR in patients with PIK3CA, PTEN, or AKT1 alterations (n=17) was 29.4% (95% CI, 10.3% - 56.0%). No objective responses were observed in the absence of PIK3CA, PTEN or AKT1 alterations (n=39). The presence of PIK3CA, PTEN or AKT1 alterations was significantly associated with response, p 0.0032 (two-sided, Fisher's exact test). Further translational studies revealed the impact of PIK3CA, PTEN or AKT1 alterations on intratumoral PCSK9, providing a biological rationale for the pattern of response and clinical benefit. These findings provide clinical proof-of-principle that PCSK9 inhibition can overcome immunotherapy resistance in a subset of patients and suggest that PIK3CA/PTEN/AKT1 pathway plays a significant role in PCSK9 mediated immune evasion and could be a biomarker of response. These findings warrant further investigation in larger confirmatory studies.