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05-08-2021 | Oncology | News | Article

Add-on metformin fails to improve locally advanced NSCLC outcomes

Author:
Shreeya Nanda

medwireNews: Nondiabetic patients with stage III non-small-cell lung cancer (NSCLC) do not benefit from the addition of metformin to chemoradiotherapy, suggest results from two phase 2 trials.

“Metformin, an antidiabetic drug, has demonstrated a broad spectrum of antitumor activity in preclinical studies,” explain the authors of a commentary accompanying the research in JAMA Oncology.

But the NRG-LU001 and OCOG-ALMERA trials did not show a significant improvement in outcomes with metformin use, and the latter study “reported increased toxic effects” in the metformin arm, say Chukwuka Eze and fellow commentators from University Hospital LMU Munich in Germany.

The open-label NRG-LU001 trial – conducted by Heath Skinner (UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA) and colleagues – included 170 diabetes-free individuals with unresectable stage IIIA or IIIB NSCLC.

The findings were initially presented at the 2019 ASCO Annual Meeting, and as previously reported by medwireNews, showed comparable progression-free survival (PFS) and overall survival (OS) regardless of whether metformin 2000 mg/day was given alongside chemoradiotherapy and consolidation chemotherapy.

There was also no difference between the metformin and control arms with respect to the rates of grade 3 or worse adverse events (AEs), at 65.8% and 68.0%, respectively.

In the open-label OCOG-ALMERA study, which terminated prematurely due to slow accrual, 54 nondiabetic patients with inoperable stage IIIA or IIIB NSCLC were randomly assigned to receive chemoradiotherapy, with or without consolidation chemotherapy, or the same regimen with metformin 2000 mg/day given alongside chemoradiotherapy and as consolidation for up to 12 months.

The primary endpoint of treatment failure at the 1-year mark was observed in 69.2% of patients in the metformin group, compared with 42.9% of those in the control group.

Accordingly, the 1-year PFS and OS rates were lower among participants who did versus did not receive metformin, at 34.8% versus 63.0% and 47.4% versus 85.2%, respectively, and corresponding hazard ratios of 2.42 and 3.80.

And a higher proportion of patients in the metformin than control group experienced an AE of at least grade 3, at 53.8% versus 25.0%, a finding that the researchers describe as “unexpected” given that metformin “is generally well tolerated.”

They speculate whether “the increased toxic effects observed in metformin patients limited their ability to receive the prescribed doses of chemoradiotherapy,” thereby leading to the increased incidence of failure events in the group.

“Based on these findings, metformin is not recommended in patients with [locally advanced]-NSCLC who do not have diabetes and are candidates for chemoradiotherapy,” conclude Theodoros Tsakiridis (McMaster University, Hamilton, Ontario, Canada) and collaborators.

The commentary authors suggest that “[d]espite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For instance, there could still be a role for metformin in selected NSCLC patients, such as those with KRAS/LKB1-mutated tumors, they write, adding that “special attention to the immunomodulatory effects of metformin in the host and tumor [is] pertinent” in the current era of immuno-oncology.

Eze and co-authors continue: “Future trial designs should aim to clarify a potential effect of metformin on the characteristics of lymphocyte populations, including proliferation, cytotoxicity, and tumor infiltration.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Oncol 2021; doi:10.1001/jamaoncol.2021.2318
JAMA Oncol 2021; doi:10.1001/jamaoncol.2021.2328
JAMA Oncol 2021; doi:10.1001/jamaoncol.2021.2316

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