Prognostic and predictive value of metformin in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

Autor:	Kennedy OJ; University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom; Christie NHS Foundation Trust, Manchester, Wilmslow Rd, Manchester M20 4BX, United Kingdom. Electronic address: ojk@doctors.org.uk., Kicinski M; EORTC Headquarters, Brussels, Belgium., Valpione S; Division of Immunology, Immunity to Infection and Respiratory Medicine, The University of Manchester, Manchester, United Kingdom., Gandini S; Department of Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy., Suciu S; EORTC Headquarters, Brussels, Belgium., Blank CU; Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands., Long GV; Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals, Sydney, NSW, Australia., Atkinson VG; Princess Alexandra Hospital, Brisbane, QLD, Australia., Dalle S; Hospices Civils de Lyon Cancer Institute, Lyon, France., Haydon AM; Alfred Hospital, Melbourne, VIC, Australia., Meshcheryakov A; NN Blokhin Cancer Research Center, Moscow, Russian Federation., Khattak A; Fiona Stanley Hospital & Edith Cowan University, Perth, WA, Australia., Carlino MS; Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia., Sandhu S; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Larkin J; Royal Marsden Hospital, London, United Kingdom., Puig S; Hospital Clinic de Barcelona, Universitat de Barcelona, IDIBAPS, and Spain &Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain., Ascierto PA; Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', Naples, Italy., Rutkowski P; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland., Schadendorf D; University Hospital Essen, Essen, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr Research Center One Health, Essen, Germany., Boers-Sonderen M; Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands., Di Giacomo AM; Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy., van den Eertwegh AJM; Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands., Grob JJ; Aix Marseille University, Hôpital de la Timone, Marseille, France., Gutzmer R; Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum Campus Minden, Minden, Germany., Jamal R; Centre Hospitalier de l'Université de Montréal (CHUM), Centre de recherche du CHUM, Montreal, QC, Canada., van Akkooi ACJ; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia., Robert C; Gustave Roussy and Paris-Saclay University, Villejuif, France., Eggermont AMM; Princess Máxima Center and University Medical Center Utrecht, 3584 CS Utrecht, the Netherlands; Comprehensive Cancer Center Munich, Technical University Munich & Ludwig Maximiliaan University, Munich, Germany., Lorigan P; Christie NHS Foundation Trust, Manchester, Wilmslow Rd, Manchester M20 4BX, United Kingdom; Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom., Mandala M; University of Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy.
Jazyk:	angličtina
Zdroj:	European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2023 Aug; Vol. 189, pp. 112900. Date of Electronic Publication: 2023 Apr 29.
DOI:	10.1016/j.ejca.2023.04.016
Abstrakt:	Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation. Results: Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52-1.45) and DMFS (HR 0.82, 95% CI 0.47-1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37-1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56-1.69). Conclusions: There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma. Competing Interests: Declaration of Competing Interest Oliver John Kennedy. None declared. Michal Kicinski. Grants or contracts from any entity: BMS, MSD, Pierre Fabre. Sara Valpione None declared. Sara Gandini None declared. Stefan Suciu. Grants or contracts from any entity: MSD. Christian Blank. Grants or contracts from any entity: BMS, Novartis, NanoString, 4SC. Consulting fees - consultant advisor for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre- Payments were made to my institution, Third Rock Venture - Payments were made to me. Stock or stock options: Immagene BV and Signature Oncology - Co-founder. Georgina V Long. Consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme (Australia), Merck Sharpe & Dohme, Novartis, OncoSec Australia, PHMR Ltd, Pierre Fabre, Provectus Australia, Qbiotics, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb - Personal 1 h lecture of my own slides, Pierre Fabre, Personal 1 h lecture of my own slides. Victoria Atkinson. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre- Speakers bureaus fees. Support for attending meetings and/or travel: BMS, Travel support. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche, Limbic - Advisory boards. Stephane Dalle. Grants or contracts from any entity: Bristol Myers Squibb, Merck Sharp & Dohme - My Institution. Support for attending meetings and/or travel: Bristol Myers Squibb, Pierre Fabre, Merck Sharp &. Dohme. Other financial or non-financial interests: Sanofi Pasteur - My wife is an employee of Sanofi Pasteur. Andrew M. Haydon. Payment or honoraria for lectures, presentations, speakers bureaus: BMS, Merck Sharp & Dohme Novartis. Participation to Advisory Board: BMS, Novartis, Pierre Fabre, Merck Sharp & Dohme. Andrey Meshcheryakov. Grants or contracts from any entity: Sanofi, AstraZeneca, Merck Sharp & Dohme - My institution, me. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or. educational events: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, SERVIER, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis - Honoraria for lectures, presentations, speakers bureaus. Support for attending meetings and/or travel: BIOCAD, SERVIER, Merck Sharp & Dohme, Sanofi- Aventis, Merck - Attending meetings and/or travel. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bayer AG, BIOCAD, Bristol Myers Squibb, Eli Lilly, Merck, Servier, Takeda Pharmaceuticals, Eisai, AstraZeneca, Sanofi-Aventis. - Advisory Board. Adnan Khattak None declared. Matteo S. Carlino. Participation on Advisory Board for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp and Dohme, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche. Consulting fees: Bristol Myer Squibb, Merck Sharp & Dohme, Novartis. Shahneen Sandhu. Grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Senwha, Genentech, AstraZeneca - Funding to the institution. Participation on an Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Advanced Accelerators Applications (a Novartis company). - Funding to the institution. James Larkin. Grants or contracts from any entity: Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. Institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. Consulting fees from iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte. Honorariums from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS. Speaker fee from Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs, MSD. Susana Puig. Grants or contracts from any entity: Almirall, ISDIN, La Roche Posay - To My Institution. Consulting fees: ISDIN, Almirall, La Roche Posay, MSD, Sanofi, Sun Pharma, Pfizer, Roche, Regeneron. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche Posay, Leo Pharma, Pfizer, Roche, Regeneron, BMS, Sun Pharma. Support for attending meetings and/or travel: Almirall. Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Sanofi, Sun Pharma, Almirall, ISDIN, Pfizer, Novartis. Paolo A. Ascierto. Grants or contracts from any entity: Bristol Myers Squibb, Roche-Genentech, Pfizer/Array, Sanofi. Consulting fees: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, Sun Pharma, Sanofi, Idera, Sandoz, 4SC, Italfarmaco, Nektar, Pfizer/Array, Lunaphore, Medicenna, Bio-Al Health, ValoTx, Replimmune, Bayer. Support for attending meetings and/or travel: Pfizer, Bio-Al Health, Replimmune. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, Roche- Genentech, Merck Sharp & Dohme, Novartis, AstraZeneca, Immunocore, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos. Piotr Rutkowski. Consulting fees: Amgen, Blueprint Medicine, Bristol Myers Squibb, Merck, MSD, Novartis, Philogen, Pierre Fabre, Sanofi - Advisory Role - Personal fees. Payment or honoraria for lectures: Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Sanofi Pasteur. Dirk Schadendorf. Grants or contracts from any entity: Amgen, Array BioPharma, Novartis. Consulting fees: 4SC, Angenus, Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, EMD Serano, Roche, Genentech, InFlarX, Merck, Nektar, Novartis, Pfizer, Philogen, Pierre Fabre, Regeneron, Sandoz, Sanofi, UltimoVacs. Participation on a Data Safety Monitoring Board: Immunocore. Honoraria for lectures: Amgen, Novartis. Support for attending meetings and/or travel: Amgen, Novartis. Marye Boers-Sonderen. None declared. Anna Maria di Giacomo. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, MSD, Pierre Fabre, Sanofi. Support for attending meetings and/or travel: BMS, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Nektar, Pierre Fabre, Sanofi, GSK, Novartis. Alfonsus J.M. van den Eertwegh. Grants or contracts from any entity: Roche, Sanofi, Bristol Myers Squibb, Idera Consulting fees: Bristol Myers Squibb. Support for attending meetings and/or travel: MSD Oncology, Roche, Pfizer, Sanofi, Pierre Fabre. Participation on a Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, Pierre Fabre. Jean-Jacques Grob. Payment for participation to an advisory board: Amgen, Bristol Myers Squibb, Hoffmann-La Roche. Consulting fees: MSD, Novartis, Philogen, Pierre Fabre, Sanofi Pasteur. Ralf Gutzmer. Grants or contracts from any entity: Pfizer, Novartis, Johnson & Johnson, Amgen, Merck Serono, Sun Pharma Industries, Sanofi. Consulting fees: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Genentech, Novartis, Merck Serono, Almirall, Amgen, Sun Pharma Industries, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, Bayer AG, Immunocore. Support for attending meetings and/or travel: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Industries. Rahima Jamal. Grants or contracts from any entity: Merck Sharp & Dohme, Bristol Myers Squibb, Iovance Biotherapeutics. Consulting fees: Bristol Myers Squibb. Alexander C.J. van Akkooi. Grants or contracts from any entity: Amgen, Merck, Pfizer. Participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, Merck, Pfizer, Pierre Fabre, Provectus, Sanofi, Sirius Medical, 4SC. Caroline Robert. Consulting fees: AstraZeneca, BMS, MSD, Merck, Roche, Novartis, Pfizer, Pierre Fabre, Sanofi. Co-founder: Ribonexus. Alexander Eggermont. Consulting fees: Agenus, BioInvent, BMS, Brenus, CatalYm, Ellipses, Galecto, IO Biotech, IQVIA, ISA Pharmaceuticals, Merck&Co, MSD, Pierre Fabre, Sairopa, Sellas, SkylineDX, TigeTx, Trained Immunity TX. Participation on a Data Safety Monitoring Board: BioNTech, GSK, and Pfizer. Lectures: BMS, MSD. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences, German Cancer Aid. Stock or stock options: IO Biotech, SkylineDx and SaiRoPA. Paul Lorigan. Grants or contracts from any entity: BMS, Pierre Fabre. Consulting fees: Amgen, BMS, MSD, Nektar, Novartis, Pierre Fabre. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, BMS, Merck, MSD, Nektar, NeraCare GmbH, Novartis, Oncology Education, Pierre Fabre, Roche. Support for attending meetings and/or travel: BMS, MSD. Mario Mandala. Participation to Advisory Board: BMS, Merck Sharp & Dohme, Novartis, Pierre Fabre Pharmaceuticals. (Copyright © 2023. Published by Elsevier Ltd.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Full Text from ScienceDirect