Expert Point of View: Michael B. Atkins, MD

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Michael B. Atkins, MD

My view is that nivolumab plus ipilimumab should be the preferred treatment for patients who need a response and who are perceived as being able to tolerate the combination regimen.

—Michael B. Atkins, MD

Michael B. Atkins, MD, Deputy Director, Lombardi Cancer Center of Georgetown University, Washington, DC, discussed CheckMate 067 at the Plenary Session. Pending overall survival data, he concluded, “Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab. These treatments (along with pembrolizumab) are a new standard for advanced melanoma therapy.”

“The principal take-home message is that, in my opinion, ipilimumab can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma,” Dr. Atkins said. “This clearly has important implications for the field and for our patients.”

He also noted that the combination was more effective than nivolu­mab alone, based on the exploratory analysis showing a 26% reduction in progression and higher overall response rate, but he maintained that biomarker-based selection of patients for single-agent vs combination therapy “is not ready for prime time.”

Many Questions Remain

Discussing toxicity, Dr. Atkins’ slide read, “Toxicity was severe,” as 55% of the combination arm experienced grade 3/4 adverse events; however, the occurrence of adverse events did not appear to impact efficacy, he pointed out. “There seems to be a margin of safety. If one stops treatment and initiates immunomodulatory drugs when significant immune-related adverse events appear, toxicity can be controlled without eliminating efficacy,” he observed.

Dr. Atkins cautioned that while the results are “resoundingly” positive for the combination and for nivolumab alone vs ipilimumab, many questions remain. “A new combination immunotherapy platform has been established on which to explore…. Much work remains to be done,” he said.

One question on the minds of many researchers and clinicians is how nivolumab compares to pembrolizumab. From the available data on the two anti–PD-1 agents, in Dr. Atkins’ opinion, “there is no clear-cut distinction in therapeutic index” between the agents. Therefore, he believes, lacking a head-to-head comparison, treatment decisions will likely be based on other factors, such as dosing schedule, clinical experience, marketing, cost, and predictability of biomarkers.

Utility of PD-L1 as a biomarker, in fact, is a sticking point, in Dr. ­Atkins’ opinion. He noted that only 27% of CheckMate 067 patients were positive by the trial’s assay, while 80% of patients in the KEYNOTE-006 trial of pembrolizumab were PD-L1–positive by Merck’s assay. “In fact, in CheckMate 067, the biomarker failed to identify roughly two-thirds of the nivolumab monotherapy responders,” he indicated.

Biomarker Refinement

Taking these and other observations into consideration, he maintained, “PD-L1 expression is a weak biomarker,” at least at this point. “Biomarker refinement and standardization are needed for clinical decision-making.”

Finally, Dr. Atkins said it is too early to judge the true efficacy of this regimen. “It behooves us to wait for critical survival data,” he said, before concluding the combination is the winner.

Meanwhile, he suggested, “especially if overall survival follows the tumor response data, my view is that nivolu­mab plus ipilimumab should be the preferred treatment for patients who need a response and are perceived as being able to tolerate the combination regimen. Nivolu­mab alone and pembrolizumab alone are acceptable treatment alternatives, irrespective of PD-L1 status, where toxicity is a concern for the patient.” ■

Disclosure: Dr. Atkins reported no potential conflicts of interest.


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