Hydroxychloroquine Use and Survival in Immune Checkpoint Inhibitor-treated Mucosal Head and Neck Cancer

Introduction: Hydroxychloroquine (HCQ) is an autophagy-inhibiting, immunomodulatory agent used for autoimmune disease. Preclinical studies suggest HCQ may either enhance or attenuate anti-PD-1 efficacy through context-dependent effects on antigen presentation and T-cell function; however, the association between HCQ exposure and outcomes during anti-PD-1 therapy in head and neck squamous cell carcinoma (HNSCC) remains unclear.

Methods: We conducted a retrospective multi-institutional database study using Epic COSMOS (Jan 2015-Oct 2024). Adults with mucosal HNSCC initiating pembrolizumab or nivolumab were included. Concurrent HCQ exposure was defined as ≥2 HCQ medication orders overlapping the peri-ICI window. The primary outcome was overall survival (OS) from index ICI start. We compared unadjusted Kaplan-Meier curves and fit sequential Cox models adjusting for demographics, comorbidity burden, autoimmune history/HCQ indications, tumor characteristics, ICI regimen/era, prior treatments, and (in sensitivity models) recent corticosteroid/immunosuppressant orders.

Results: Among 21,446 patients, 83 (0.4%) received HCQ. Median follow-up was 744 days (IQR, 318-1,424). HCQ-exposed patients had greater comorbidity and autoimmune disease burden and higher baseline healthcare utilization compared with unexposed patients. In unadjusted analysis, concurrent HCQ was associated with worse OS (HR, 1.37; 95% CI, 1.04-1.81; P=.03). After multivariable adjustment for demographics, comorbidity, autoimmune history/HCQ indications, tumor and treatment factors, the association attenuated and was not significant (adjusted HR, 1.02; 95% CI, 0.71-1.47; P=.90).

Conclusions: To our knowledge, this is the first large multi-institutional real-world analysis evaluating HCQ exposure during anti-PD-1 therapy in mHNSCC. We find that concurrent HCQ use was uncommon and was not independently associated with OS after adjustment for baseline health status and treatment factors. Additional prospective and mechanistic studies are needed to better define potential context-specific effects.