Expert Point of View: Reinhard Dummer, MD, and Jeffrey Weber, MD, PhD

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Reinhard Dummer, MD

Reinhard Dummer, MD

Jeffrey Weber, MD, PhD

Jeffrey Weber, MD, PhD

ASSUMING THE regimens evaluated in COMBI-AD and CheckMate 238 are both approved by the U.S. Food and Drug Administration for the treatment of high-risk resected melanoma, clinicians may be faced with a tough choice. ESMO experts and the study’s investigators weighed in on this issue in a lively discussion during the press briefing. 

Interstudy Comparisons Difficult 

REINHARD DUMMER, MD, Professor of Dermatology at the University of Zurich in Switzerland, commented, “The good news is that we have two positive clinical trials. The two options have been investigated carefully, and the results are extremely encouraging. Both results will change our current practice.” 

Unfortunately, treatment selection cannot be informed by a side-by-side look at efficacy results. A direct comparison of CheckMate 028 and COMBI-AD is difficult, if not impossible, melanoma experts agreed. 

As Dr. Dummer pointed out, the studies enrolled different populations. CheckMate 238 included stage III to IV patients, whereas COMBI-AD included stage IIIA, IIIB, and IIIC patients, and there were other inclusion/exclusion differences. CheckMate 028 had an active comparator, whereas COMBI-AD was placebo-controlled. COMBI-AD was restricted to patients with BRAF mutations, whereas CheckMate 238 included both those with BRAF-mutated melanoma and those with BRAF wild-type disease. 

Speculation as to which is the optimal strategy is useless at this point, Dr. Dummer said. “We have two good options, and the future will show which is the more beneficial.” 

Jeffrey Weber, MD, PhD, who presented CheckMate 238, agreed that any comparison would be “apples to oranges” and would require “non-Kosher” and “sleight-of-hand statistical arguing.” He added, “After cutting and slicing and making assumptions, … at the end of the day, you’d have two great choices.” 

It is possible, he suggested, that immunotherapy will ultimately produce a greater “tail on the curve,” as it has done in the metastatic setting, and this would score points for the checkpoint inhibitors. He also predicted that many physicians will prefer to prescribe nivolumab (Opdivo), even in BRAF-mutated patients. 

Patient Perspective 

AXEL HAUSCHILD, MD, who presented the COMBI-AD data, countered: “The patient perspective might be different.” 

“Immunotherapy needs to be infused every 2 weeks, whereas the targeted therapy is oral, and they have completely different toxicity profiles. There are patients who are not good candidates for one or the other. There are practical considerations. As for treatment in stage IV disease, it’s a bit of a gut feeling,” he said. 

In Europe, he added, chances are that BRAF-mutated patients will initially receive the dabrafenib (Tafinlar)/trametinib (Mekinist) combination, since ipilimumab (Yervoy) has not even been approved in those countries. 

“We can speculate whether one treatment is superior to the other, but I think this would be unfair,” Dr. Hauschild concluded. “Let’s say they are equivalent, and the choice is based on the discussion between physician and patient as to whether they prefer a kinase inhibitor or immunotherapy.” 

Now, investigators will be turning their attention to the next big questions: how to treat patients with disease progression on adjuvant therapy, and whether immunotherapy combinations will pack a bigger punch than nivolumab alone. ■

DISCLOSURE: Dr. Dummer has been a consultant and/or advisor for Novartis, Merck Sharp & Dhome, BMS, Roche, Amgen, Takeda, and Pierre Fabre outside the submitted work. Dr. Weber reported no conflict of interest. Dr. Hauschild has received clinical trial support from Amgen, BMS, MerckSerono, MSD, Novartis, Philogen, Pierre Fabre, Provectus, Regeneron, Roche; honoraria from Amgen, BMS, MSD, Novartis, Pierre Fabre, Provectus, Roche; and consultant fees from Amgen, BMS, MerckSerono, MSD, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron, Roche.

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