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Invited Commentary
July 29, 2021

Forging a Path for Metformin Use in Inoperable Locally Advanced Non–Small Cell Lung Cancer

Author Affiliations
  • 1Department of Radiation Oncology, University Hospital LMU Munich, Munich, Germany
  • 2German Cancer Consortium, partner site Munich, Munich, Germany
  • 3German Cancer Research Center, Heidelberg, Germany
  • 4Comprehensive Pneumology Center Munich, Munich, Germany
JAMA Oncol. 2021;7(9):1341-1342. doi:10.1001/jamaoncol.2021.2316

Metformin, an antidiabetic drug, has demonstrated a broad spectrum of antitumor activity in preclinical studies: mechanistic effects include inhibition of complex I of the mitochondria oxidative phosphorylation chain, activation of AMPK, suppression of the IGF-1R and PI3K/AKT/mTORC1 pathways, and stimulation of the immune system.1

The NRG-LU0012 and Ontario Clinical Oncology Group Advanced Lung Cancer Treatment with Metformin and Chemoradiotherapy (OCOG-ALMERA)3 studies reported in this issue of JAMA Oncology represent 2 phase 2 randomized clinical trials that compared concurrent chemoradiotherapy (CRT) alone vs CRT and metformin in nondiabetic inoperable locally advanced non–small cell lung cancer (NSCLC). The NRG-LU0012 trial assessed concurrent and consolidation taxane-based CRT alone vs the same treatment plus metformin, 2000 mg/d, administered during the concurrent and consolidation cytotoxic treatment. The study was powered to detect a 15% improvement in 1-year progression-free survival (PFS) from 50% (control arm) to 65% in the experimental (metformin) arm (1-year PFS was 49.2% in the 60-Gy arm of RTOG 06174). At a median follow-up of 27.7 months, the primary end point of 1 year PFS in the control arm vs metformin arm of NRG-LU001 was higher than anticipated (60.4% vs 51.3%). One-year overall survival was similar in the control (80.2%) and metformin (80.8%) arms. In comparison, in the durvalumab arm of the PACIFIC trial,5 1-year PFS was 55.9%. Overall survival rates were consistent with RTOG 06174 and slightly better and worse than the control (75.3%) and experimental (83.1%) arms in the PACIFIC trial.5 An important difference was, 65.9% of patients presented with more favorable stage IIIA disease vs 53% in PACIFIC.5 In addition, use of intensity-modulated radiation (76% of patients in the control arm vs 46% in the 60-Gy arm of RTOG 06174) was more predominant and more-specific heart constraints were used in NRG-LU001.2 In total, 52 of 86 (63.4%) patients completed metformin treatment per protocol, which is to be expected in clinical trials. Furthermore, in the intention-to-treat analysis, the overall concurrent and consolidation chemotherapy dose was slightly lower in the metformin arm and 12 of 86 (vs 6 of 81 in the control arm) patients in the metformin arm did not receive radiotherapy. The authors provide a detailed rationale for their findings. Post hoc analyses including additional imaging and biological biomarker analyses could potentially decipher subcohorts of patients who might yet derive survival benefit.

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