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.

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).