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 language | English |
|---|---|
| Pages (from-to) | e413-e417 |
| Journal | Clinical Lung Cancer |
| Volume | 20 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - May 2019 |
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Keywords
- Cancer metabolism
- LKB1 inactivation
- Overall survival
- Progression-free survival
- Safety
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
- Cancer Research
Cite this
Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma : The FAME Trial. / Vernieri, Claudio; Signorelli, Diego; Galli, Giulia; Ganzinelli, Monica; Moro, Massimo; Fabbri, Alessandra; Tamborini, Elena; Marabese, Mirko; Caiola, Elisa; Broggini, Massimo; Hollander, Lital; Gallucci, Rosaria; Vandoni, Giulia; Gavazzi, Cecilia; Triulzi, Tiziana; Colombo, Mario Paolo; Rizzo, Angela Maria; Corsetto, Paola Antonia; Pruneri, Giancarlo; de Braud, Filippo; Sozzi, Gabriella; Torri, Valter; Garassino, Marina Chiara.
In: Clinical Lung Cancer, Vol. 20, No. 3, 05.2019, p. e413-e417.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma
T2 - The FAME Trial
AU - Vernieri, Claudio
AU - Signorelli, Diego
AU - Galli, Giulia
AU - Ganzinelli, Monica
AU - Moro, Massimo
AU - Fabbri, Alessandra
AU - Tamborini, Elena
AU - Marabese, Mirko
AU - Caiola, Elisa
AU - Broggini, Massimo
AU - Hollander, Lital
AU - Gallucci, Rosaria
AU - Vandoni, Giulia
AU - Gavazzi, Cecilia
AU - Triulzi, Tiziana
AU - Colombo, Mario Paolo
AU - Rizzo, Angela Maria
AU - Corsetto, Paola Antonia
AU - Pruneri, Giancarlo
AU - de Braud, Filippo
AU - Sozzi, Gabriella
AU - Torri, Valter
AU - Garassino, Marina Chiara
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Cancer metabolism
KW - LKB1 inactivation
KW - Overall survival
KW - Progression-free survival
KW - Safety
UR - http://www.scopus.com/inward/record.url?scp=85059455131&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059455131&partnerID=8YFLogxK
U2 - 10.1016/j.cllc.2018.12.011
DO - 10.1016/j.cllc.2018.12.011
M3 - Article
C2 - 30617039
AN - SCOPUS:85059455131
VL - 20
SP - e413-e417
JO - Clinical Lung Cancer
JF - Clinical Lung Cancer
SN - 1525-7304
IS - 3
ER -