Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: A phase 2 randomized clinical trial

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dc.contributor.authorArrieta, Oscar
dc.contributor.authorBarrón, Feliciano
dc.contributor.authorSalinas Padilla, Miguel-Ángel
dc.contributor.authorAvilés-Salas, Alejandro
dc.contributor.authorRamírez Tirado, Laura Alejandra
dc.contributor.authorArguelles Jiménez, Manuel Jesús
dc.contributor.authorVergara, Edgar
dc.contributor.authorZatarain Barrón, Zyanya Lucia
dc.contributor.authorHernández-Pedro, Norma
dc.contributor.authorCardona-Mendoza, Andrés Felipe
dc.contributor.authorCruz-Rico, Graciela
dc.contributor.authorBarrios-Bernal, Pedro
dc.contributor.authorYamamoto Ramos, Masao
dc.contributor.authorRosell, Rafael
dc.contributor.orcidCardona-Mendoza, Andrés Felipe [0000-0002-6697-5471]
dc.date.accessioned2020-05-12T21:54:45Z
dc.date.available2020-05-12T21:54:45Z
dc.date.issued2019
dc.description.abstractenglishImportance Metformin hydrochloride is emerging as a repurposed anticancer drug. Preclinical and retrospective studies have shown that it improves outcomes across a wide variety of neoplasms, including lung cancer. Particularly, evidence is accumulating regarding the synergistic association between metformin and epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs). Objective To assess the progression-free survival (PFS) in patients with advanced lung adenocarcinoma who received treatment with EGFR-TKIs plus metformin compared with those who received EGFR-TKIs alone. Design, Setting, and Participants Open-label, randomized, phase 2 trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lung adenocarcinoma with an activating EGFR mutation. Interventions Patients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plus metformin hydrochloride (500 mg twice a day) or EGFR-TKIs alone. Treatment was continued until occurrence of intolerable toxic effects or withdrawal of consent. Main Outcomes and Measures The primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety. Results Between March 31, 2016, and December 31, 2017, a total of 139 patients (mean [SD] age, 59.4 [12.0] years; 65.5% female) were randomly assigned to receive EGFR-TKIs (n = 70) or EGFR-TKIs plus metformin (n = 69). The median PFS was significantly longer in the EGFR-TKIs plus metformin group (13.1; 95% CI, 9.8-16.3 months) compared with the EGFR-TKIs group (9.9; 95% CI, 7.5-12.2 months) (hazard ratio, 0.60; 95% CI, 0.40-0.94; P = .03). The median OS was also significantly longer for patients receiving the combination therapy (31.7; 95% CI, 20.5-42.8 vs 17.5; 95% CI, 11.4-23.7 months; P = .02). Conclusions and Relevance To our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1001/jamaoncol.2019.2553
dc.identifier.issn2374-2437
dc.identifier.urihttps://hdl.handle.net/20.500.12495/2656
dc.language.isoeng
dc.publisherAmerican Medical Associationspa
dc.publisher.journalJAMA oncologyspa
dc.relation.ispartofseriesJAMA oncology, 2374-2437, 2019spa
dc.relation.urihttps://jamanetwork.com/journals/jamaoncology/article-abstract/2749256
dc.rights.creativecommons2019
dc.rights.localAcceso cerradospa
dc.subject.decsAnticolesterolemiantesspa
dc.subject.decsMetforminaspa
dc.subject.decsMiastenia gravisspa
dc.titleEffect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: A phase 2 randomized clinical trialspa
dc.title.translatedEffect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone in patients with epidermal growth factor receptor-mutated lung adenocarcinoma: A phase 2 randomized clinical trialspa
dc.typearticlespa
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localartículospa

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