An exploratory study of metformin with or without rapamycin as maintenance therapy after induction chemotherapy in patients with metastatic pancreatic adenocarcinoma

Katherine M. Bever, Erkut H. Borazanci, Elizabeth A. Thompson, Jennifer N. Durham, Kimberly Pinero, Gayle S. Jameson, Amber Vrana, Meizheng Liu, Cara Wilt, Annie A. Wu, Wei Fu, Hao Wang, Yafu Yin, Jeffrey P. Leal, Ana de Jesus-Acosta, Lei Zheng, Daniel A. Laheru, Daniel D. von Hoff, Elizabeth M. Jaffee, Jonathan D. PowellDung T. Le

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Metformin combined with the mTOR inhibitor rapamycin showed potential synergistic anti-tumor activity in preclinical studies in pancreatic ductal adenocarcinoma (PDA). This phase 1b study (NCT02048384) was conducted to evaluate the feasibility and activity of metformin +/– rapamycin in the maintenance setting for unselected patients with metastatic PDA (mPDA) treated with chemotherapy. Materials and Methods: Eligible patients with stable or responding mPDA after ≥ 6 months on chemotherapy were randomized 1:1 to metformin alone (Arm A) or with rapamycin (Arm B), stratified by prior treatment with FOLFIRINOX. Fluorodeoxyglucose (FDG) PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses. Results: 22 subjects (11 per arm) received treatment per protocol. Median PFS/ OS were 3.5 and 13.2 months respectively, with 2 year OS rate of 37%; there were no differences between arms. No responses were observed by RECIST; however, decreases in FDG avidity and/or CA19-9 were observed in several long-term survivors. Treatment related adverse events of Grade ≥ 3 occurred in 0% vs 27% of patients in Arm A vs B and were asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Improved survival was associated with low baseline neutrophil: lymphocyte ratio, baseline lack of assessable disease by PET, and greater expansion of dendritic cells following treatment. Conclusions: Metformin +/– rapamycin maintenance for mPDA was well-tolerated and several patients achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of these agents in the maintenance setting and to enhance patient selection for such approaches.

Original languageEnglish (US)
Pages (from-to)1929-1941
Number of pages13
JournalOncotarget
Volume11
Issue number21
DOIs
StatePublished - May 26 2020

Keywords

  • MTOR inhibition
  • Maintenance therapy
  • Metformin
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology

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