Metformin disappoints in two phase 2 lung cancer trials

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, Dr. 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.

Dr. 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.”

Dr. 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. Dr. 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. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.