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

Abstract

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 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.

Trial registration: ClinicalTrials.gov identifier: NCT03071705.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Arrieta reported receiving grants or personal fees from the National Council for Science and Technology in Mexico (CONACyT), Pfizer, AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Bristol-Myers Squibb, and Roche. Dr Vergara reported receiving grants from CONACyT. Dr Zatarain-Barrón reported receiving grants from CONACyT. Dr Cardona reported receiving grants or personal fees from Roche, Boehringer Ingelheim, AstraZeneca, Pfizer, Celldex, Bristol-Myers Squibb, Merck Sharp & Dohme, and AbbVie and reported being cofounder of the Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia. No other disclosures were reported.

Figures

Figure 1.. Trial CONSORT Diagram

CONSORT indicates Consolidated Standards of Reporting Trials; ECOG, Eastern Cooperative Oncology Group; and EGFR-TKIs, epidermal growth factor receptor–tyrosine kinase inhibitors.

Figure 2.. Kaplan-Meier Curves of Study Outcomes for Comparison Between Therapy With EGFR-TKIs vs EGFR-TKIs Plus Metformin

A, Median progression-free survival is 9.9 (95% CI, 7.5-12.2) months for EGFR-TKIs vs 13.1 (95% CI, 9.8-16.3) months for EGFR-TKIs plus metformin (HR, 0.60; 95% CI, 0.40-0.94; P = .03). B, Median progression-free survival is 9.7 (95% CI, 5.1-14.3) months for EGFR-TKIs vs 11.8 (7.3-20.6) months for EGFR-TKIs plus metformin (HR, 0.64; 95% CI, 0.41-0.99; P = .049). C, Median objective response rate is 54.3% (38 of 70) for EGFR-TKIs vs 71.0% (49 of 69) for EGFR-TKIs plus metformin (P = .04). D, Median overall survival is 17.5 (95% CI, 11.4-23.7) months for EGFR-TKIs vs 31.7 (95% CI, 20.5-42.8) months for EGFR-TKIs plus metformin (HR, 0.50; 95% CI, 0.28-0.90; P = .02). EGFR-TKIs indicates epidermal growth factor receptor–tyrosine kinase inhibitors; HR, hazard ratio; and RECIST, Response Evaluation Criteria in Solid Tumors guideline (version 1.1).