Alirocumab plus cemiplimab in immuno-refractory metastatic NSCLC: A single-arm, multi-center, phase 2 study.

2619 Background: Immunotherapy resistance remains a significant unmet clinical need for most non-small cell lung cancer (NSCLC) patients. PCSK9 was shown in preclinical models to mediate cancer immunotherapy resistance and may serve as a novel immuno-inhibitory target. Methods: This is a first-in-class, 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 whose tumors were previously resistant to immune checkpoint blockade. The primary endpoint was objective response rate (ORR). Secondary endpoints were safety, progression free survival (PFS), overall survival (OS), duration of response (DOR) and disease control rate (DCR). The correlative objective was to analyze the biomarkers of response. Results: A total of 60 patients were enrolled between May 2023 and August 2025. In the 58 evaluable patients, the estimated ORR for the two-stage design was 14.98% (90% CI, 5.45, 25.52). The median duration of response was not estimable. The median OS was 7.2 months (95% CI, 5.3 – 13.6). No new safety signals were seen. Non-hematologic adverse events (AEs) were more prevalent than hematologic AEs and were predominantly grade 2 or less. Two grade 3 events were seen. Biomarker analysis identified superior outcomes in NSCLC harboring PIK3CA, AKT1 , or PTEN alterations, with ORR of 31.5% (95% CI,13.9%, 68.4%,), significantly associating with response, p 0.0008 (two-sided, Fisher’s exact). No objective responses were observed in the absence of PIK3CA, PTEN or AKT1 alterations. Median OS was numerically longer in the altered group was 13.64 months (95% CI, 3.1 – NR) compared to 7.2 months (95% CI, 5.2-12.8) in the unaltered group. Analysis of the cancer genome atlas (TCGA) in NSCLC cohorts demonstrated a correlation between PIK3CA, PTEN and AKT1 expression and PCSK9 expression. Preclinical translational studies further elucidated the impact of PIK3CA, PTEN or AKT1 in intratumoral PCSK9 secretion, a novel immune-oncological finding for this pathway, and provided a biological rationale for the observed pattern of response. Conclusions: 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 may play a significant role in PCSK9 mediated immune evasion and could be a biomarker of response. These findings warrant further investigation in a larger confirmatory study. Clinical trial information: NCT05553834 .