Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma: The FAME Trial

Claudio Vernieri, Diego Signorelli, Giulia Galli, Monica Ganzinelli, Massimo Moro, Alessandra Fabbri, Elena Tamborini, Mirko Marabese, Elisa Caiola, Massimo Broggini, Lital Hollander, Rosaria Gallucci, Giulia Vandoni, Cecilia Gavazzi, Tiziana Triulzi, Mario Paolo Colombo, Angela Maria Rizzo, Paola Antonia Corsetto, Giancarlo Pruneri, Filippo de BraudGabriella Sozzi, Valter Torri, Marina Chiara Garassino

Research output: Contribution to journalArticle

Abstract

Advanced lung adenocarcinoma with inactive liver kinase B1 (LKB1)tumor suppressor protein is associated with poor response to immune checkpoint inhibitors and molecularly targeted agents, and with dismal patient prognosis. LKB1 is a central orchestrator of cancer cell metabolism, and halts tumor growth/proliferation during metabolic stress. Recent preclinical evidence suggests that LKB1-inactive lung adenocarcinoma is highly sensitive to metformin, a safe and low-cost antidiabetic compound that inhibits mitochondrial oxidative phosphorylation. The effects of metformin can be enhanced by nutrient deprivation (ie, glucose, amino acids), which reduces intracellular levels of ATP and anabolic precursors and can be achieved by the fasting mimicking diet (FMD). Noticeably, metformin also prevents resistance to cisplatin in preclinical in vitro and in vivo models of LKB1-inactive lung adenocarcinoma. Based on such preclinical evidence, the phase II FAME trial was designed to test the hypothesis that the addition of metformin, with or without cyclic FMD, to standard platinum-based chemotherapy improves the progression-free survival of patients with advanced, LKB-1 inactive lung adenocarcinoma. Enrolled patients will be randomized in a 1:1 ratio to receive cisplatin/carboplatin and pemetrexed with the addition of metformin alone (Arm A)or metformin plus FMD (Arm B). The FAME study will use a “pick-the-winner” design with the aim of establishing which of the 2 experimental treatments is superior in terms of antitumor efficacy and safety. The primary assumption of the study is that the combination of the 2 experimental treatments shall improve median progression-free survival from 7.6 months (historical data with chemotherapy alone)to 12 months. Secondary study endpoints are: objective response rate, overall survival, treatment tolerability, and compliance to the experimental treatment.

Original languageEnglish
Pages (from-to)e413-e417
JournalClinical Lung Cancer
Volume20
Issue number3
DOIs
Publication statusPublished - May 2019

Keywords

  • Cancer metabolism
  • LKB1 inactivation
  • Overall survival
  • Progression-free survival
  • Safety

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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