Cutaneous adverse events may be linked to clinical benefit in metastatic melanoma
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Cutaneous adverse events appeared largely reversible and rarely led to therapy discontinuation among patients with metastatic melanoma treated with combination checkpoint inhibitors, according to a study in Cancer.
Additionally, patients who experienced cutaneous toxicities after treatment with a combination of anti-CTLA-4 and anti-PD-1 therapy had a longer time to next treatment, suggesting a possible clinical benefit, researchers wrote.
“Combination checkpoint inhibitor therapy can indeed have a high incidence of toxicities, specifically dose-limiting toxicities; however, if patients can make it through the combination phase to the maintenance phase of therapy, they have much better compliance,” Anisha B. Patel, MD, FAAD, associate professor of dermatology at The University of Texas MD Anderson Cancer Center and UT Health Science Center at Houston, told Healio. “Further, cutaneous toxicities in these patients are associated with clinical benefit to the tumor response.”
Patel said she and fellow researchers anecdotally noted more toxicities with combination checkpoint inhibitor (CPI) therapy than with CPI monotherapy and set out to investigate whether it caused increased toxicity and how it impacted a patient’s ability to remain on therapy.
“Prior studies had shown that adverse events in CPI monotherapy correlated with improved tumor response, and we suspected that the same trend would carry through for combination CPI therapy. But we also worried that with increased toxicity, patients might not be able to remain on combination CPI therapy long enough to get the clinical benefits we hoped for,” Patel said.
The analysis included 155 patients (median age at combination CPI initiation, 57 years; range, 22-85; 64.5% men) treated with at least one dose of ipilimumab (Yervoy, Bristol Myers Squibb) in combination with either nivolumab (Opdivo, Bristol Myers Squibb; 92.9%) or pembrolizumab (Keytruda, Merck; 7.1%) for stage III or stage IV metastatic melanoma from Jan. 1, 2012, to Dec. 31, 2017. Patel and colleagues calculated time to next treatment from the start of CPI therapy to the start of the next treatment or death and tested the development of cutaneous adverse events in a time-dependent Cox regression to identify associations with time to next treatment.
Results showed 92 cutaneous adverse events in 81 patients (52.3%), including eczematous dermatitis (25%), morbilliform eruption (22.8%), vitiligo (12%), and pruritus without rash (8.7%).
Cutaneous adverse events first occurred at a median 21 days (range, 0-341); resolution took a median 50 days (range, 1-352). Most cutaneous adverse events resolved after patients entered the CPI maintenance phase treatment with oral antihistamines with or without topical steroids.
Among patients definitively treated with CPIs (n = 134), time to next treatment was significantly longer with cutaneous adverse events than without them (HR = 0.567; 95% CI, 0.331-0.972).
Researchers discontinued CPI treatment for four patients (2.6%) because of cutaneous adverse events, for 49 (31.6%) because of other immune-related adverse events and for 20 (12.9%) because of melanoma progression or death.
“We were taken aback at the high rate of early discontinuation due to toxicities in this line of therapy,” Patel told Healio.
Patel and colleagues concluded that early recognition and management of cutaneous adverse events can minimize therapy interruptions or discontinuations, as well as support a patient’s ability to gain the full benefit of CPI therapy. They also stated that it is essential for the oncology and dermatology communities to be aware of common adverse events that develop with this treatment as it quickly becomes the standard of care.
“I think we all found it motivating to pursue prospective research to identify predictive factors or biomarkers for toxicity,” Patel said of future related research.
For more information:
Anisha B. Patel, MD, FAAD, can be reached at Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1452, Houston, TX 77030; email: apatel11@mdanderson.org.
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