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.
Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma : the FAME Trial / C. Vernieri, D. Signorelli, G. Galli, M. Ganzinelli, M. Moro, A. Fabbri, E. Tamborini, M. Marabese, E. Caiola, M. Broggini, L. Hollander, R. Gallucci, G. Vandoni, C. Gavazzi, T. Triulzi, M.P. Colombo, A.M. Rizzo, P.A. Corsetto, G. Pruneri, F. de Braud, G. Sozzi, V. Torri, M.C. Garassino. - In: CLINICAL LUNG CANCER. - ISSN 1525-7304. - 20:3(2019), pp. e413-e417. [10.1016/j.cllc.2018.12.011]
Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma : the FAME Trial
C. Vernieri;G. Galli;A.M. Rizzo;P.A. Corsetto;G. Pruneri;F. de Braud;
2019
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.File | Dimensione | Formato | |
---|---|---|---|
1-s2.0-S1525730418303358-main.pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
381.12 kB
Formato
Adobe PDF
|
381.12 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.