[Skip to Navigation]
Sign In
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.

Add or change institution
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    ×