A phase II study of metformin plus pemetrexed and carboplatin in patients with non-squamous non-small cell lung cancer (METALUNG).

Immune checkpoint inhibitors (ICIs) ± chemotherapy is the standard treatment for driver mutation-negative non-small cell lung cancer (NSCLC). However, accessibility to ICIs in LMICs is limited due to high cost, and platinum-based chemotherapy remains the mainstay of treatment. Metformin has anticancer properties, and studies suggest synergism between metformin and pemetrexed. Based on preclinical evidence, this combination may be more beneficial for STK11-mutated NSCLC, a subgroup, inherently resistant to ICIs. In this Simon two-stage, single-arm phase 2 trial, we investigated metformin with pemetrexed-carboplatin (PC) in patients with treatment-naive stage IV non-squamous NSCLC. The primary outcome was 6-month progression-free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK11 mutation, and effect of STK11 mutation on 6-month PFS rate. The study was terminated for futility after interim analysis. The median follow-up was 34.1 months. The 6-month PFS rate was 28% (95% CI 12.4-0.46). The median PFS and OS were 4.5 (95% CI 2.2-6.1) and 7.4 months (95% CI 5.3-15.3), respectively. The ORR was 72%. Gastrointestinal toxicities were the most common. No grade 4/5 toxicities were reported. Targeted sequencing was possible in nine cases. Two patients had STK11 mutation and a poor outcome (PFS < 12 weeks). We could not demonstrate the benefit of metformin with CP in terms of improvement in 6-month PFS rate; however, the combination was safe (CTRI/2019/02/017815).