Metformin (AMPK modulation) + pembrolizumab (PD-1) posts 50% ORR in metastatic HNSCC feasibility Phase 2

Metformin ER (up-titrated to 2000mg daily) was combined with pembrolizumab 200mg q3w in a randomized Phase 2 feasibility study in recurrent/metastatic HNSCC (NCT04414540), with sequencing (metformin lead-in vs pembrolizumab lead-in) and NK-cell immune monitoring. Among 21 enrolled patients, 18 were response-evaluable and achieved 4 CR + 5 PR for an ORR of 50% (95%CI 29–71); 10 had oropharyngeal primaries (9/10 p16+). Grade 3 AEs were limited (5 events total; nausea/diarrhea/fatigue/weight loss) with “no unexpected AEs,” and correlative work suggested increased peripheral NK-cell maturation/cytotoxic potential—an ORR that sits well above typical pembrolizumab monotherapy response rates in R/M HNSCC reported in Phase 3 settings (~15–20% range, depending on line/PD-L1 selection). Take Home: If this 50% ORR holds up in a properly powered randomized study (and isn’t just PD-L1/HPV-enrichment + small-n luck), low-cost metformin could become a surprisingly practical way to “turn up” checkpoint depth of response in a disease where single-agent anti–PD-1 often under-delivers.