A Phase 2 Feasibility Study Combining Pembrolizumab and Metformin in patients with Metastatic Head and Neck Cancer

BACKGROUND: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this Phase 2 clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK cell activity. METHODS: Eligible patients were randomized 1:1 into two arms: (1) metformin ER dose escalation to 2000 mg over 14 days followed by combination with pembrolizumab 200 mg q3 weeks or (2) pembrolizumab 200 mg q3 weeks followed by combination with metformin ER 2000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated by CTCAE v5.0. The distribution, activation, and cytotoxic function of NK cells was analyzed by flow cytometry. RESULTS: Twenty-one patients were enrolled. 76% were male, 52% smokers, and median age was 64. Ten patients had oropharyngeal tumors, of which 9 were p16 positive. Eighteen patients were evaluable for response, including 4 complete and 5 partial responses for an ORR of 50% (95%CI [29,71]). Combination therapy was well tolerated with no unexpected adverse events (AEs). Five Grade 3 AEs occurred, including nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK cell maturation and cytotoxic ability. CONCLUSION: The combination of metformin and pembrolizumab was well tolerated with mild GI-associated AEs and promising activity warranting further investigation in a randomized trial.