Metformin Plus TKI Use in Patients With Non-Small Cell Lung Carcinoma

Summary

Treatment for patients with mutation in the epidermal growth factor receptor (EGFR) with specific domain tyrosine kinase inhibitors (TKIs) has given place to objective clinical response, increase in progression-free survival (PFS) compared to cytotoxic chemotherapy. However, despite clinical success with different TKIs, most patients eventually develop acquired resistance to these agents after an average period of time of 10 months. Recently metformin, an oral hypoglycemic agent, has been associated with reduction in the global risk of incidence and mortality of different types of cancer, by exercising anti-tumor properties. Its role as a chemo-preventive and adjuvant drug in overcoming acquired resistance to chemotherapy, target therapy and immunotherapy in NSCLC is still under discussion. However, preclinical data support the role as an adjuvant drug in the treatment of NSCLC in combination with chemotherapy or EGFR-TKIs. This evidence led to examine the effects of metformin in combination with EGFR-TKIs in a NSCLC cellular line panel, obtaining a different sensibility to the unique use with EGFR-TKIs. The combination of metformin and TKIs reduced the colony forming capacity and proliferation, and induced a huge pro-apoptotic effect in NSCLC cellular lines and resistance in EGFR-TKIs. This suggests that metformin may reduce the resistance to TKIs. A retrospective study in patients from our institution from 2008 to 2014, showed significant clinical benefit in patients who used metformin, improving the global survival. Based on these considerations, we propose a phase II randomized study to assess the effect and safety of metformin in combination with TKIs as second line therapy in patients with NSCLC in advanced stages with EGFR mutation. The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone.

Timeline

Start

2016-03

Primary completion

2017-04

Completion

2017-12

Publications

• Background Arrieta O, Varela-Santoyo E, Soto-Perez-de-Celis E, Sanchez-Reyes R, De la Torre-Vallejo M, Muniz-Hernandez S, Cardona AF. Metformin use and its effect on survival in diabetic patients with advanced non-small cell lung cancer. BMC Cancer. 2016 Aug 12;16:633. doi: 10.1186/s12885-016-2658-6.
• Background Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005 Mar 2;97(5):339-46. doi: 10.1093/jnci/dji055.
• Background Goodarzi MO, Bryer-Ash M. Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab. 2005 Nov;7(6):654-65. doi: 10.1111/j.1463-1326.2004.00448.x.
• Background Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005 Dec 9;310(5754):1642-6. doi: 10.1126/science.1120781. Epub 2005 Nov 24.
• Background Morgillo F, Sasso FC, Della Corte CM, Vitagliano D, D'Aiuto E, Troiani T, Martinelli E, De Vita F, Orditura M, De Palma R, Ciardiello F. Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3508-19. doi: 10.1158/1078-0432.CCR-12-2777. Epub 2013 May 21.
• Arrieta O, Barron F, Padilla MS, Aviles-Salas A, Ramirez-Tirado LA, Arguelles Jimenez MJ, Vergara E, Zatarain-Barron ZL, Hernandez-Pedro N, Cardona AF, Cruz-Rico G, Barrios-Bernal P, Yamamoto Ramos M, 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 Nov 1;5(11):e192553. doi: 10.1001/jamaoncol.2019.2553. Epub 2019 Nov 14.

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