601 A phase 2 feasibility study combining pembrolizumab and metformin to harness the natural killer cytotoxic response in metastatic head and neck cancer patients

Background

Recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC) has dismal survival rates. Immunotherapy has revolutionized treatment, but response rates remain low. Treatment with metformin is associated with decreased risk of HNSCC in diabetic patients. It has been shown that metformin increases CD8+ tumor infiltrating lymphocytes and inhibits PD-L1 membrane localization. Furthermore, metformin increases peripheral and tumor infiltrating NK cells, which harbor PD-1. Therefore, we hypothesized that combination therapy with metformin and anti-PD-1 may enhance NK cell function and the tumor cytotoxic response, leading to improved survival. In this phase II feasibility study (NCT04414540), we combined metformin and pembrolizumab to test the overall response rate (ORR) in R/M HNSCC, evaluate the possible mechanism of their synergistic effect, and determine the importance of NK cell infiltration and activation.

Methods

Eligible patients were randomized to one of two arms: metformin ER dose escalation to 2000 mg over 14 days followed by combination with pembrolizumab 200 mg q3 weeks (Arm 1) or pembrolizumab 200 mg lead-in followed by combination with metformin ER dose escalation to 2000 mg daily thereafter (Arm 2). The primary endpoint was ORR including complete response (CR) and partial response (PR) using RECIST 1.1 and iRECIST. Twenty patients with goal of 19 evaluable were planned to estimate the proportion of approximately 32% ORR. The first 9 patients were enrolled as the lead-in population to evaluate dose limiting toxicity (DLT). Safety was evaluated by CTCAE v5.0. The distribution, activation, and cytotoxic ability of NK cells was analyzed using flow cytometry.

Results

At time of data cutoff, 21 patients were enrolled. 71% were male, 48% were smokers, and median age was 64. Eight patients were p16+, 7 were p16-, and p16 status was unknown for 6 patients. Fifteen patients were evaluable for overall response (OR). Two were unevaluable and 4 were pending scan confirmation. The best OR was 1 CR, 4 PR, 5 stable disease, and 5 progressive disease. Combination therapy was tolerated well with no unexpected AEs or DLTs. Four Grade 3 AEs occurred including nausea, diarrhea, fatigue, and weight loss, resulting in metformin dose reduction. Metformin increased peripheral NK cell cytotoxic ability.

Conclusions

Combination of metformin and pembrolizumab is preliminarily estimated at an ORR of 33%, meeting the primary endpoint. The regimen was well tolerated with mild GI associated AEs. NK cell studies showed an increase in cytotoxic effects. The data suggest further investigation into a Phase II/III trial is warranted.

Trial Registration

NCT04414540.

Ethics Approval

It complied with the Declaration of Helsinki and GCP, was approved by the IRB at the participating site, and monitored by the University of Cincinnati Cancer Center Data Safety Monitoring Board. All participants were required to sign an informed consent.