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Clinical Trial
. 2025 Aug;30(8):1537-1544.
doi: 10.1007/s10147-025-02786-2. Epub 2025 May 28.

Phase-Ib dose-finding and pharmacokinetic trial of metformin combined with nivolumab for refractory/recurrent solid tumors

Toshio Kubo  1   2 , Hironari Kato  3 , Shigeru Horiguchi  3 , Toshiyuki Kozuki  4 , Akinori Asagi  5 , Michihiro Yoshida  6 , Heiichiro Udono  7 , Katsuyuki Kiura  1 , Katsuyuki Hotta  8   9
Affiliations
Clinical Trial

Phase-Ib dose-finding and pharmacokinetic trial of metformin combined with nivolumab for refractory/recurrent solid tumors

Toshio Kubo et al. Int J Clin Oncol. 2025 Aug.

Abstract

Background: Our previous findings showed that the addition of metformin to nivolumab resulted in remarkable tumor regression and increased the number of tumor-infiltrating T cells in mouse models. Therefore, we conducted a phase Ib study using combination therapy with nivolumab and metformin in patients with refractory/recurrent solid tumors.

Methods: This study consisted of two parts: 1, evaluating the maximum tolerated dose (MTD), safety, pharmacokinetics in solid tumors, and 2, principally investigating the safety at the recommended dose limited to thoracic and pancreatic cancers. Metformin and nivolumab were administered orally at doses of 750-2,250 mg/day and biweekly at a fixed intravenous dose of 3 mg/kg, respectively. Dose-limiting toxicity was evaluated within the first 4 weeks. Both metformin and nivolumab were continued until disease progression or discontinued because of toxicity.

Results: In total, 17 and 24 patients were enrolled in parts 1 and 2, respectively. One patient experienced increased pancreatic enzyme levels (grade 4) and lactic acidosis (grade 3). No Grade 5 adverse events were observed. MTD was not reached up to 2,250 mg/day of metformin, 2,250 mg/day was selected for part 2. An objective response was observed in 4 of 41 patients. One-year progression-free and overall survival rates were 9.8% and 56.8%, respectively. Two patients remained alive without disease progression for more than three years.

Conclusions: Nivolumab and metformin combination therapy was well-tolerated and showed preliminary signals of efficacy in a subset of patients. Further verification of the underlying mechanism in cases where treatment is effective is required.

Trial registration numbers: UMIN registration number 000028405 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031915 .

Keywords: Anti-PD-1 antibody; Metformin; Nivolumab; Pancreatic cancer; Phase Ib; Thoracic tumors.

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Conflict of interest statement

Declarations. Conflict of interest: TK received a research grant outside the current work from Chugai. KH received personal fees from AZ, Chugai, Lilly, MSD, BMS, Ono, Boehringer-Ingelheim, Nippon Kayaku, Amgen, Taiho, and Merck, and grants from MSD, AZ, Chugai, Lilly, BMS, Abbvie, and Ono. KK received honoraria from Chugai, AZ, Lilly, Taiho, BMS, Ono, MSD, Pfizer, Beohringer Ingelheim, Merck, Daiichi-Sankyo, Bayer, AMGEN, Eisai, Kyowa Hakko Kirin, Abbvie, Sanofi, LaboCorp Japan, IQVIA, and Gilead Sciences, and Research funding from Chugai, AZ, Lilly, Taiho, BMS, Ono, MSD, Pfizer, Beohringer Ingelheim, Merck, Nippon Kayaku, Novartis, Daiichi-Sankyo, Takeda, Bayer, Sawai, AMGEN, Eisai, and Abbvie. KK received research funding from Ono pharmaceutical. The authors declare no conflicts of interest regarding this study. Ethics approval statement: This study was approved by the institutional review board of each participating hospital in accordance with the Declaration of Helsinki. The protocol summary, including participant and intervention details, has been previously described.

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