Phase 2 feasibility study of pembrolizumab plus metformin in patients with metastatic head and neck cancer

Survival of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, with less than 20% response on immunotherapy. Metformin increases tumor-infiltrating CD8⁺ T and natural killer (NK) cells, which harbor PD-1. A phase 2 trial at the University of Cincinnati (OH) evaluated the combination of metformin and pembrolizumab for R/M HNSCC. Eligible patients were randomized 1:1 in two arms: (i) metformin extended-release (ER) dose escalation to 2000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks, or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2000 mg daily. The primary endpoint was objective response rate (ORR). Twenty-one patients were enrolled (median age 64 years, 76% male, 52% smokers; 10 patients with oropharygeal tumors). Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% (95% CI 29-71). The therapy was well tolerated with no unexpected adverse events. Five grade 3 gastrointestinal adverse events occurred. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability.The authors conclude that the combination of metformin and pembrolizumab was well tolerated and had promising activity in patients with R/M HNSCC.