Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.
Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.
Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.
The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.
Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.
He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.
Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
No Survival Benefit
In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.
Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.
The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.
With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
Not Recommended
The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.
They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.
The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.
The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.
The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.
With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
Future Research Directions
Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?
Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.
In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”
For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.
They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.
Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
Better-Than-Expected Outcomes
Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.
In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”
The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.
On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.
They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.
However, Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.
“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.
Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”
He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”
Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”
NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial.
Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Eze declares no relevant relationships.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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