Portal de investigación
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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Autores organización
Autores
- Arrieta, O
- Barrón, F
- Padilla, MAS
- Avilés-Salas, A
- Ramírez-Tirado, LA
- Jiménez, MJA
- Vergara, E
- Zatarain-Barrón, ZL
- Hernández-Pedro, N
- Cruz-Rico, G
- Barrios-Bernal, P
- Ramos, MY
- Rosell, R
Unidades de investigación
Resumen
IMPORTANCE 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 Institute Nacional de Cancerologia (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; 653% 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, 9.8-163 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.
Datos de la publicación
- ISSN/ISSNe:
- 2374-2437, 2374-2445
- Tipo:
- Article
- Páginas:
- -
- PubMed:
- 31486833
- Enlace a otro recurso:
- www.scopus.com
Jama Oncology American Medical Association
Citas Recibidas en Web of Science: 112
Citas Recibidas en Scopus: 151
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Keywords
- afatinib; epidermal growth factor receptor; erlotinib; gefitinib; metformin; adult; advanced cancer; anorexia; Article; asthenia; cancer control; cancer patient; cancer staging; cancer survival; constipation; controlled study; diarrhea; drug dose reduction; drug effect; drug response; drug safety; drug withdrawal; EGFR gene; female; gene mutation; histopathology; human; intention to treat analysis; lung adenocarcinoma; major clinical study; male; Mexico City; middle aged; mucosa inflammation; nausea; neuropathy; objective response rate; open study; overall survival; paronychia; phase 2 clinical trial; progression free survival; prospective study; randomized controlled trial; rash; vomiting; xerophthalmia; xerostomia
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Citar la publicación
Arrieta O,Barrón F,Padilla M,Avilés A,Ramírez LA,Jiménez M,Vergara E,Zatarain ZL,Hernández N,Cardona AF,Cruz G,Barrios P,Ramos MY,Rosell R. 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. JAMA Oncol. 2019. 5. (11):e192553. IF:24,799. (1).