RT Journal Article SR Electronic T1 Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e007235 DO 10.1136/jitc-2023-007235 VO 11 IS 10 A1 Akce, Mehmet A1 Farran, Batoul A1 Switchenko, Jeffrey M A1 Rupji, Manali A1 Kang, Sandra A1 Khalil, Lana A1 Ruggieri-Joyce, Amanda A1 Olson, Brian A1 Shaib, Walid L A1 Wu, Christina A1 Alese, Olatunji B A1 Diab, Maria A1 Lesinski, Gregory B A1 El-Rayes, Bassel F YR 2023 UL http://jitc.bmj.com/content/11/10/e007235.abstract AB Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study.Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry.Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475).Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.Data are available upon reasonable request.