Abstract 3482: Correlative analysis of metformin and nivolumab combination in treatment-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC)
Authors: Farran Batoul , Switchenko Jeffrey M. , Khalil Lana , Shaib Walid L. , Olson Brian , Ruggieri Amanda , Wu Christina , Alese Olatunji B. , Diab Maria , Lesinski Gregory B. , El-Rayes Bassel , Akce Mehmet 
Published: June 2022

Background: Preclinical results indicate that metformin can modulate immune cell populations in the tumor microenvironment of solid tumors by diminishing exhaustion of CD8+ tumor infiltrating cells and improving T cell responses. Studies also suggest that metformin could complement PD-1 blockade and potentiate its antitumor activity. Previously we reported the results of a phase II trial with metformin and nivolumab and here we report the findings of correlative analysis of the prospectively collected research samples of 18 patients.

Methods: We conducted a phase II trial with nivolumab and metformin in treatment-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Nivolumab 480 mg IV every 4 weeks and metformin 1000 mg orally twice daily was administered in 28-day cycles following a 14-day metformin only lead-in phase. The primary endpoint was overall response rate (ORR). Secondary endpoints were overall survival (OS) and progression free survival (PFS). Pre-treatment and on-treatment research biopsies and correlative peripheral blood specimens were collected. Paired biopsies obtained at baseline and following treatment with metformin only (n=9) or metformin and nivolumab (n=9) and were stained with a panel of 13 markers using ChipCytometry technology by Canopy Biosciences. Sample was assessed prior to establishing the multiplex assay. 30 out of 36 samples were imaged and analyzed up to 30 Fields of View. Single cell recognition and quantitative biomarker analysis were performed to compare immune cell numbers and population distribution in pre- versus post-treatment samples.

Results: As previously reported, no patients had objective response based on RECIST version 1.1 and the study was stopped after the first stage for futility. Median OS and PFS was 5.1 months [95% CI (2-11.7)] and 2.3 months [95% CI (1.7-2.4)], respectively. Multiplex analysis of tissues from patients receiving lead in with metformin alone revealed fewer effector CD4 T cells and effector and effector memory CD8 T cells after treatment vs. baseline biopsy. Biopsy tissue from patients treated with metformin and nivolumab had lower pAMPK and decreased PDL-1 expression vs. baseline. The combination also increased percentages of leukocytes, effector CD4 T cells, effector and effector memory CD8 T cells as well as levels of PDL1-Tim3+ cells.

Conclusion: In the setting of MSS mCRC, metformin as a single agent did not enhance effector CD4 and CD8 T cell percentages in clinical samples in our patient cohort. Metformin in combination with nivolumab was associated with increased percentages of effector CD4 and CD8 T cells in biopsy specimens, although these improvements did not translate into enhanced clinical endpoints. Analysis of peripheral blood samples are currently underway to corroborate the findings in the tissue samples.

Citation Format: Batoul Farran, Jeffrey M. Switchenko, Lana Khalil, Walid L. Shaib, Brian Olson, Amanda Ruggieri, Christina Wu, Olatunji B. Alese, Maria Diab, Gregory B. Lesinski, Bassel El-Rayes, Mehmet Akce. Correlative analysis of metformin and nivolumab combination in treatment-refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3482.