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
Open accessAbstract
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.
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Metformin may exert beneficial effects on body weight and fat composition, as well as extra metabolic ancillary effects.
“Metformin, the most widely prescribed drug to treat T2DM, especially when associated with obesity, may exert beneficial effects on body weight and fat composition, as well as extra metabolic ancillary effects that are clinically very interesting [155].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [155]
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The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms
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- Authors
- Morgillo, F., Fasano, M., Della Corte, C. M., Sasso, F. C., Papaccio, F., Viscardi, G., Esposito, G., Di Liello, R., Normanno, N., Capuano, A., Berrino, L., Vicidomini, G., Fiorelli, A., Santini, M., & Ciardiello, F.
- Affiliations
- University of Campania "Luigi Vanvitelli" (IT)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Corresponding author
- Morgillo, Floriana
- ORCID
- Venue
- ESMO Open
- Publisher
- Elsevier BV
- Published
- 2017
- Volume
- 2
- Issue
- 2
- Pages
- e000132
- ISSN
- 2059-7029 (ISSN-L)
- PMC
- PMC5519802
- OpenAlex
- W2611153764
- Cited by
- 76
- References
- 21
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 16 · 2021: 25 · 2020: 8 · 2019: 7 · 2018: 8
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ESMO Open (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- metformin, erlotinib, non-small cell lung cancer, EGFR tyrosine kinase inhibitor resistance, gefitinib resistance, second-line therapy, stage IV lung cancer, maximum tolerated dose, recommended phase 2 dose, dose-limiting toxicity, gastrointestinal toxicity, pharmacokinetics, blood glucose, disease control
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