Expert Point of View: David R. Spigel, MD

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[The relatively small improvement in progression-free survival] leads me to question whether median progression-free survival is the best endpoint for trials of combination immunotherapy.
— David R. Spigel, MD

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“These are outstanding results,” commented formal discussant of this trial David R. Spigel, MD, of the Sarah Cannon Research Institute, Nashville, Tennessee.

In melanoma, the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) vs nivolumab alone vs ipilimumab alone found superior progression-free survival and more frequent complete responses with the combination but also more treatment-emergent adverse events leading to [treatment] discontinuation, Dr. Spigel said.

The strengths of this study include a novel design and less-frequent dosing of ipilimumab. With the combination, PD-L1 (programmed cell death ligand 1) expression appears to select patients who will benefit the most, he continued. Limitations were that 40% of patients had any-grade skin reaction, and the combination appeared to result in higher rates of pneumonitis.

Median progression-free survival was 3.9 months, not as improved as might have been expected given the increase in response rate. “This leads me to question whether median progression-free survival is the best endpoint for trials of combination immunotherapy,” Dr. Spigel commented.

Unanswered Questions

“Does this change anything? Less ipilimumab appears to result in less toxicity. Ipilimumab is currently approved only for the treatment of melanoma. Standard treatment of non–small cell lung cancer (NSCLC) is a platinum doublet. Use of nivolumab in NSCLC is independent of PD-L1 testing,” Dr. Spigel continued.

According to Dr. Spigel, the study raises several questions:

Which is better: upfront chemotherapy followed by immunotherapy or upfront immunotherapy followed by chemotherapy?

Is first-line single-agent immunotherapy safer than the combination and as effective?

Why advance an every-6-week schedule of ipilimumab when the every-12-week schedule had higher overall response rates?

Is PD-L1 testing necessary for first-line treatment?

Multiple phase III first-line NSCLC trials are currently in progress, including CheckMate 227, Mystic, and Neptune. It is hoped that these trials will answer some of these questions, closed Dr. Spigel. ■

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

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