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No benefit of adding metformin to chemoradiotherapy in locally advanced lung cancer

Journal
JAMA Oncology
Reuters Health - 05/08/2021 - Two studies have found no benefit of adding metformin to chemoradiotherapy in non-diabetic patients with inoperable locally advanced non-small-cell lung cancer (NSCLC).

"The findings of both studies are surprising and particularly more so those of the Canadian trial (OCOG-ALMERA)," which found worse outcomes and increased toxicity in the metformin group, Dr. Theos Tsakiridis of Juravinski Cancer Center, McMaster University, in Hamilton, Canada, told Reuters Health by email.

However, "we believe that the association of metformin with inferior outcomes in OCOG-ALMERA is a chance finding that is influenced by the small sample size in this trial. We do not think that metformin is toxic to patients with NSCLC. This was demonstrated in NRG-LU001 trial," Dr. Tsakiridis said.

Both studies were published in JAMA Oncology.

The NRG-LU001 trial compared taxane-based chemoradiotherapy and consolidation chemotherapy alone (control) or with metformin (2,000 mg/d) in 167 non-diabetic patients with unresectable stage-III NSCLC.

At a median follow-up of 28 months, one-year progression-free survival (PFS), the primary outcome, was not significantly different in the control group and the metformin group (60.4% and 51.3%; HR 1.15; 95% confidence interval: 0.77 to 1.73).

Metformin also did not improve one-year overall survival, which was 80.2% in the control group and 80.8% in the metformin group. Rates of local-regional recurrence and distant metastasis were similar between the two groups.

"The addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC," Dr. Tsakiridis and colleagues conclude.

Therefore, adding metformin to chemoradiotherapy is "not warranted" in these patients.

In the OCOG-ALMERA trial, non-diabetic patients with stage-III locally advanced NSCLC were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy, with or without consolidation chemotherapy (control) or the same treatment plus metformin (2,000 mg/d) during chemoradiotherapy and afterward for up to 12 months.

The trial was stopped early due to slow accrual, when 54 patients had been randomized (28 to the control group and 26 in the metformin group).

The primary outcome was the proportion of patients who suffered a treatment-failure event (locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months).

This happened more often in the metformin group than the control group (69.2% vs. 42.9%).

The one-year PFS rate was also lower in the metformin group (34.8% vs. 63.0%), as was overall survival (47.4% vs. 85.2%). More patients in the metformin group reported at least one grade-3-or-higher adverse event (53.8% vs. 25.0%).

Based on the OCOG-ALMERA study results, "metformin is not recommended in patients with locally-advanced NSCLC who are candidates for chemoradiotherapy," Dr. Tsakiridis and colleagues conclude.

He emphasized that both trials enrolled non-diabetic patients. "We are indeed concerned that the findings of these trials may be misinterpreted as evidence of detrimental effects of metformin in diabetic patients treated with chemoradiotherapy," he told Reuters Health.

"It is important to re-state the well-described metabolic benefits of metformin in metabolic disorders and clarify that NRG-LU001 and OCOG-ALMERA did not study diabetic patients. Results of these two trials do not provide a basis for modification of metformin treatment of diabetics diagnosed with NSCLC who receive treatment with chemotherapy and radiotherapy," he added.

In an editorial, Dr. Chukwuka Eze and colleagues from University Hospital LMU Munich, in Germany, say, "Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted."

"There might yet be a role for metformin in selected patients with NSCLC patients: KRAS/LKB1-mutated tumors or tumors with elevated fluorodeoxyglucose metabolism," they say.

"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," they add.

"Future trial designs should aim to clarify a potential effect of metformin on the characteristics of lymphocyte populations, including proliferation, cytotoxicity, and tumor infiltration. Currently, a number of trials investigating metformin with immune checkpoint inhibitors are ongoing," the editorial writers say.

SOURCE: https://bit.ly/37fk4aI, https://bit.ly/3ym4u9i and https://bit.ly/3A8mMuY JAMA Oncology, online July 29, 2021.

By Megan Brooks



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