Skin reactions may affect up to 42% of patients treated with pembrolizumab (Keytruda, Merck & Co, Inc) and could indicate better progression-free survival, according to a retrospective review published online July 29 in JAMA Dermatology.
"Cutaneous adverse events are frequent but mild during pembrolizumab treatment. The development of cutaneous adverse events, especially of hypopigmentation, in patients affected by melanoma, could point toward better treatment response," commented first author Martine Sanlorenzo, MD, of the University of California, San Francisco.
Pembrolizumab is an anti–programmed death-1 drug that has shown promise in treating melanoma, non–small cell lung cancer, and renal cell cancer. The drug is a monoclonal antibody that targets the programmed death–1 (PD-1) receptor on T lymphocytes, which functions in immune inactivation. Tumor cells that express the programmed death ligand–1 (PDL-1) take advantage of the PD-1 receptor to evade the immune response.
The US Food and Drug Administration recently approved pembrolizumab and another anti-PD-1 drug, nivolumab (Opdivo, Bristol-Myers Squibb Company), for the treatment of advanced melanoma. Because pembrolizumab is so new, not much is known about skin reactions related to treatment.
In the single-institution study, researchers reviewed medical records of 83 patients with cancer treated with pembrolizumab at the University of California, San Francisco, between March 2011 and May 2014.
The study included 31 women and 52 men (median age, 66 years) who had received at least one dose of pembrolizumab and had at least one follow-up visit. Researchers categorized patients into the following groups: those receiving 10 mg/kg every 3 weeks (n = 43); those receiving 10 mg/kg every 2 weeks (n = 24); and those receiving 2 mg/kg every 3 weeks (n = 16). Sixty-six patients had melanoma, 15 had lung cancer, one had prostate cancer, and one had Merkel cell lymphoma. The patients' median follow-up time was 15 weeks; they underwent a median of six treatment cycles.
Results showed that 35 patients (42%) experienced skin reactions to pembrolizumab, the most common of which were macular popular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All seven patients who developed hypopigmentation had melanoma.
Compared with patients who did not experience skin reactions to pembrolizumab, patients who developed skin reactions had significantly longer progression-free survival (10 mg/kg every 3 weeks: P = .001; 10 mg/kg every 2 weeks: P = .003; 2 mg/kg every 3 weeks: P = .009).
Patients who developed skin reactions received more treatment cycles than those who did not (10 mg/kg every 3 weeks: 17 vs 4.5 cycles, P < .001; 10 mg/kg every 2 weeks: 10 vs 6 cycles, P = .02; 2 mg/kg every 3 weeks: 18 vs 4 cycles, P = .05).
No patients developed grade 4 skin reactions; two patients developed grade 3 reactions.
"Pembrolizumab has a favorable cutaneous safety profile," explained Dr Sanlorenzo. "Macular papular eruptions were more frequent on photo-exposed areas of the body, and they usually responded to topical steroid treatment. Pruritus can occur without skin lesions and was typically treated with moisturizing creams. The use of oral antihistamine was reserved for persistent cases. We observed hypopigmentation only in patients affected by melanoma."
The fact that hypopigmentation occurred only in patients with melanoma may suggest that these patients had stronger immune activation, according to the authors. Hypopigmentation is a "well- known positive prognostic factor" in melanoma, they point out. Melanocytes and melanoma share common antigens. Lymphocytes directed at the tumor could have cross-reacted with normal melanocytes, resulting in skin hypopigmentation, they explain.
It is important, though, to put this research into the right context, according to Patrick Ott, MD, PhD, clinical director of the Center for Immuno-Oncology at the Dana-Farber Cancer Institute, Harvard Medical School, in Boston. Dr Ott was not involved in the study.
Skin reactions to pembrolizumab could be "potentially very valuable" for assessing treatment response, but it is too soon to know for sure, he said.
"You don't want to overemphasize the findings. It's an interesting observation, but we don't really know if it's actually going to pan out," he commented. "It clearly needs to be confirmed in larger data sets and prospective studies, and maybe in more homogeneous patient groups."
It should also be borne in mind that patients who responded may have had more exposure to the drug, he added.
"If somebody doesn't respond, they may get three or four doses and not even have the chance to develop side effects. Somebody who responds will have a higher chance to develop toxicity," he explained. "The question is whether the observation in this study just reflects whether the patient has been on drug for longer."
That said, because pembrolizumab belongs to a very new drug class, the study deserves recognition as the first analysis looking at a consistent, relatively large data set of PD-1 inhibitors.
"The field in general is something that's new and very promising. This immune therapy has changed the field of oncology quite a lot in the past couple of years," Dr Ott highlighted, "so anything that's associated with it is something that's new and potentially valuable."
One or more authors report research support to their institution, advisory board membership, stock ownership, and/or consulting for one or more of the following companies: AbbVie, Celgene, Genentech/Roche, Novartis, Celgene, Pfizer, BMS, GlaxSmithKline, OncoSec, Amgen, Median Technologies, and AstraZeneca. Dr Ott reports no relevant financial relationships.
JAMA Dermatol. Published online July 29, 2015. Abstract
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