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Alirocumab Plus Cemiplimab in Immunorefractory NSCLC: A Single Arm Phase 2 Study
Eziafa Oduah1, Jhanelle Gray2, Thomas Stinchcombe3
1Duke Cancer Institute, Duke University School of Medicine.
Research Square
|July 3, 2026
Summary
PCSK9 inhibition with alirocumab and cemiplimab shows promise in non-small cell lung cancer (NSCLC) resistant to immunotherapy. Patients with PIK3CA, PTEN, or AKT1 alterations responded significantly better, suggesting these as biomarkers for treatment success.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in mediating resistance to cancer immunotherapy.
- PCSK9 inhibition presents a potential novel strategy to overcome treatment resistance in cancer.
- Non-small cell lung cancer (NSCLC) patients often develop resistance to immune checkpoint blockade therapies.
Purpose of the Study:
- To evaluate the clinical activity and safety of PCSK9 inhibitor alirocumab combined with anti-PD1 antibody cemiplimab in NSCLC patients.
- To assess response rates, survival outcomes, and safety profiles in patients with prior immunotherapy failure.
- To explore biomarkers predictive of response to this combination therapy.
Main Methods:
- A multi-center, single-arm, phase II clinical trial was conducted.
- Sixty patients with advanced NSCLC and disease progression after immune checkpoint blockade were enrolled.
- Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were primary and secondary endpoints. Biomarker analysis was exploratory.
Main Results:
- The ORR was 14.78% in the evaluable population (n=58). Median PFS was 2.5 months and median OS was 7.3 months.
- Anemia and fatigue were the most common adverse events. Grade 3 adverse events included anemia and Guillain-Barre Syndrome in 12% of patients.
- Patients with PIK3CA, PTEN, or AKT1 alterations (n=17) showed a significantly higher ORR of 29.4% (p=0.0032) compared to those without (0%).
Conclusions:
- PCSK9 inhibition combined with anti-PD1 therapy demonstrates clinical activity in a subset of NSCLC patients resistant to immunotherapy.
- Alterations in the PIK3CA/PTEN/AKT1 pathway are associated with superior response and may serve as predictive biomarkers for this combination.
- These findings provide a proof-of-principle for targeting PCSK9 to overcome immunotherapy resistance, warranting further investigation in larger studies.
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