Bittersweet.

Top Line: Does metformin improve treatment outcomes for stage III NSCLC treated with chemoradiation?

The Studies: Two trials have recently been published exploring this question: OCOG-ALMERA and NRG-LU001. So, where did this idea come from? Population studies have linked metformin use with better survival and clinical outcome across several cancer types--including NSCLC. In preclinical studies, metformin has anti-proliferative effects on cancer cells via regulation of the AMPK pathway and inhibition of the mTOR pathway, and it may also be a radiosensitizer. Both ALMERA and LU001 were randomized phase 2 trials of definitive chemoradiation and consolidative chemo +/- metformin (no immunotherapy). LU001 was the larger of the two with 167 eligible patients whereas ALMERA was closed early with only 54 of a planned 96 patients enrolled. In both trials, the target metformin dose was 2000 mg per day. In LU001, the addition of metformin didn’t improve 1-year progression-free survival (51.3 vs 60.4%), overall survival (80.8 vs 80.2%), recurrence patterns, or adverse events. In ALMERA, 1-year PFS was significantly worse with metformin (34.8 vs 63%) and 1-year overall survival was 47.4 vs 85.2%. In addition, grade 3+ adverse events were higher with metformin (53.8 vs 25%).

TBL: Two randomized phase 2 studies show no evidence of improved treatment outcomes when metformin is added to chemoradiation for stage III NSCLC. | Skinner and Tsakiridis, JAMA Oncol 2021