Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active?

Background/Aim: Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients. Patients and Methods: Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination. Results: We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate. Conclusion: The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination.