Reinhard Dummer, MD

KEYNOTE-022’S invited discussant, Reinhard Dummer, MD, Professor of Dermatologic Oncology at the University Hospital Zurich Skin Cancer Center in Switzerland, told attendees, “We’ve been waiting for this small prospective randomized phase II trial, and the initial results appear very promising.”

In the first-line setting, the addition of pembrolizumab (Keytruda) to dabrafenib (Tafinlar) and trametinib (Mekinist) in a BRAF-mutant population produced “a very high response rate,” an encouraging duration of response, and promising progression-free and overall survival hazard ratios, he said. “It’s a very appealing concept…. The results meet the expectation we would have for a triple combination.”

More Frequent Adverse Events

HOWEVER, THE study population was small and the follow-up, at less than 10 months, is too short to draw firm conclusions on long-term efficacy, noted Dr. Dummer. In addition, there were “drawbacks” for the triplet in terms of more frequent and more severe adverse events. Although some were life-threatening, it is difficult to know whether such rates are really increased with pembrolizumab. Information about nonresolving toxicity was lacking, he added.

The adverse events included more severe pyrexia, rash, and transaminitis, “a pattern that seems to be consistent and treatable,” Dr. Dummer suggested. He has observed an inflammatory picture of sorts in some of his own patients. “I’d like to say it’s cytokine-release syndrome that occurs with anti–PD-1 [programmed cell death protein 1] plus targeted therapy.”

Triplet therapies also may be activating different compartments of the immune system, based on changes seen in interferon-gamma, C-reactive protein, and other inflammatory markers of the innate immune response. “Strategies should reduce side effects and support the effector function of immunotherapies…. We have a well-defined set of anti-inflammatory tools that may reduce toxicity and maybe increase efficacy,” he said.

“These are interesting data,” Dr. Dummer concluded. “But we don’t know whether adding pembrolizumab is better than dabrafenib and trametinib alone. We have to wait for other clinical trials.” ■

DISCLOSURE: Dr. Dummer reported personal financial interests with Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Amgen, Takeda, and Pierre Fabre.