Metformin ‘Not Recommended’ For Locally Advanced NSCLC Patients Undergoing Chemoradiation

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: The phase II OCOG-ALMERA trial has ruled out the use of metformin alongside chemotherapy and chest radiation for nondiabetic patients with unresected stage IIIA or IIIB non-small-cell lung cancer (NSCLC), finding poorer efficacy and greater toxicity with use of the oral diabetes agent.

The results are published in JAMA Oncology alongside the similarly negative findings for the phase II NRG-LU001 trial of metformin in patients undergoing chemoradiotherapy for unresectable stage III NSCLC, which were previously reported at 2019 ASCO Annual Meeting.

The OCOG-ALMERA trial included 54 patients with unresected locally advanced NSCLC who were given platinum-based chemotherapy with concurrent 60–63 Gy of chest radiotherapy, with or without consolidation chemotherapy.

Treatment failure, defined as locoregional disease progression, distant metastases, death or trial discontinuation, occurred in 69.2% of 26 patients who were randomly assigned to receive metformin 2000 mg/day during treatment and for up to 12 months after and 42.9% of the 28 patients who were not.

Patients given metformin also had significantly poorer outcomes than controls for both the 1-year rate of progression-free survival (34.8 vs 63.0%, hazard ratio [HR]=2.42) and overall survival (47.4 vs 85.2%, HR=3.80).

Of concern, metformin use was associated with a higher rate of grade 3 or more severe adverse events than non-use (53.8 vs 25.0%), with lung infection (23.1 vs 0%), oesophagitis (19.2 vs 3.6%) and decreases in lymphocytes (11.5 vs 3.6%) and neutrophils (11.5 vs 0%) the most commonly reported grade 3 events.

“The observed increased toxic effects in this trial were unexpected” and may have “limited [patient] ability to receive the prescribed doses of chemoradiotherapy”, suggest Theodoros Tsakiridis, from McMaster University in Hamilton, Ontario, Canada, and fellow investigators.

They conclude: “Based on these findings, metformin is not recommended in patients with [locally advanced]-NSCLC who do not have diabetes and are candidates for chemoradiotherapy.”

Nevertheless, the authors of an invited commentary say that “[t]here might yet be a role for metformin in selected patients with NSCLC” despite the results of the OCOG-ALMERA and NRG-LU001 trials.

“In the current era of immuno-oncology and consolidation anti-PD-L1 immunotherapy currently the standard of care and a plethora of further studies assessing concomitant immune checkpoint inhibitors and [chemoradiotherapy] in [locally advanced]-NSCLC, special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent”, suggest Chukwuka Eze and co-commentators from the University Hospital LMU Munich in Germany.

References

• Tsakiridis T, Pond GR, Wright J, et al. Metformin in combination with chemoradiotherapy in locally advanced non–small cell lung cancer. The OCOG-ALMERA randomized clinical trial. JAMA Oncol; Advance online publication 29 July 2021. doi:10.1001/jamaoncol.2021.2328
• Skinner H, Hu C, Tsakiridis T, et al. Addition of metformin to concurrent chemoradiation in patients with locally advanced non-small cell lung cancer. The NRG-LU001 phase 2 randomized clinical trial. JAMA Oncol; Advance online publication 29 July 2021. doi:10.1001/jamaoncol.2021.2318
• Eze C, Belka C, Manapov F. Forging a path for metformin use in inoperable locally advanced non–small cell lung cancer. JAMA Oncol; Advance online publication 29 July 2021. doi:10.1001/jamaoncol.2021.2316