Metformin in Advanced Lung cancer

Results of the safety run-in part of the METAL (METformin in Advanced Lung cancer) study: a multicentre, open-label phase I–II study of metformin with erlotinib in second-line therapy of patients with stage IV non-small-cell lung cancer
Floriana Morgillo, Morena Fasano, Carminia Maria Della Corte, Ferdinando Carlo Sasso, Federica Papaccio, Giuseppe Viscardi, Giovanna Esposito, Raimondo Di Liello, Nicola Normanno, Annalisa Capuano, Liberato Berrino, Giovanni Vicidomini, Alfonso Fiorelli, Mario Santini, Fortunato Ciardiello
DOI: 10.1136/esmoopen-2016-000132 Published 2 May 2017


Abstract

Purpose Our previous works demonstrated the ability of metformin to revert resistance to gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in non-small-cell lung cancer (NSCLC) EGFR/LKB1 wild-type (WT) cell lines. However, the optimal dose of metformin to be used in non-diabetic patients still remains to be defined. The phase I–II trial METformin in Advanced Lung cancer (METAL) was designed to identify the maximum tolerated dose and to evaluate safety and activity of metformin combined with erlotinib in second-line treatment of patients with stage IV NSCLC, whose tumours harbour the WT EGFR gene.

Patients and methods
We report results from the safety run-in part designed to detect acute toxicities, to study pharmacokinetics and to identify the recommended phase II dose (RPD) to be used for the following phase of the study. In the run-in phase, metformin treatment was administered according to a dose escalation scheme and, subsequently, combined with erlotinib.

Results
Twelve patients were enrolled. Common adverse events were diarrhoea, decreased appetite, abdominal pain, vomiting and skin toxicity, mostly reversible with symptomatic medical treatment. Dose-limiting toxicities were vomiting and diarrhoea registered in the initial cohort receiving metformin 2000 mg plus erlotinib at 150 mg die, which was declared the maximum administered dose. Only one of nine patients treated at the next lower dose of 1500 mg of metformin plus erlotinib at 150 mg experienced G3 gastrointestinal toxicity. Metformin plasma-concentration profile confirmed the trend already observed in non-diabetic population. Glycemic profiles showed stability of the blood glucose level within the physiological range for non-diabetic subjects. At a follow-up of 30 weeks, six (50%) patients experienced a disease control (5 SD and 1 partial response).

Conclusions
The RP2D of metformin dose was defined at 1500 mg/day to be combined with erlotinib 150 mg.

Trial registration number EudraCT number: 2014-000349-59.
Key messages

What is already known about this subject?

A series of epidemiological evidences suggested a reduced incidence of cancer in patients treated with metformin compared with those taking other therapies.

In our preclinical model, the combination of metformin with an epidermal growth factor receptor (EGFR) inhibitor resulted synergistic in terms of inhibition of proliferation and induction of apoptosis, in particular in those cell lines harbouring wild-type LKB1 gene.

What does this study add?

This phase I/II dose-escalation study evaluated the combination of metformin and erlotinib in second line treatment of stage IV non-small-cell lung cancer EGFR wild type.

The safety profile was clinically acceptable and maximum tolerated dose was identified.

Preliminary activity data were obtained.

How might this impact on clinical practice?

This clinical experience demonstrated a therapeutic role of metformin in non-diabetic people affected by non-small-cell lung cancer.

The phase II of the trial, by enrolling a higher number of patients, will probably provide more information on the activity of the combination and more instruments for the identification of patient to be treated.