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‘Major need’ exists for more effective mucosal melanoma treatments
NEW YORK — Although immunotherapy and targeted agents have demonstrated some promise for mucosal melanoma, outcomes in this patient population remain poor, according to a presenter at HemOnc Today Melanoma and Cutaneous Malignancies.
“There is a major need to increase our understanding of the biology in order to increase the number of responders and, in particular, the duration of responses,” Axel Hauschild, MD, PhD, professor of dermatology and head of dermato-oncology at University Hospital in Kiel, Germany, said during his presentation. “This is clearly a very high unmet clinical need.”
Mucosal melanoma — prevalent in Asia — accounts for only 1.3% of all melanomas in the Western population. This incidence rate appears stable.
Median age at diagnosis is 70 years, and incidence is more common among black and Asian individuals.
The majority of cases occur in on the head or neck (55%), anorectum (24%) or vulvovaginal region (18%). Other sites include the bronchial region, esophagus, stomach, small intestine, cervix and gallbladder. Outcomes are not affected by primary site.
Disease etiology remains unclear. Approximately one-third of oral cavity tumors are preceded by melanosis. Vulvovaginal tumors may be associated with chronic inflammation, and cases in the anorectal region are more common among HIV–positive individuals, Hauschild said.
Mucosal melanoma is associated with a poorer prognosis than cutaneous melanoma. An estimated 50% to 90% of patients who undergo surgery experience recurrence. Only 25% of those with localized disease survive 5 years.
“Because these melanomas are not on the surface of the skin, they often are diagnosed when patients develop symptoms, so they are detected late,” Hauschild said.
Because circumscribed melanosis is a precursor of mucosal melanoma, these patients require close clinical observation and possibly biopsy, Hauschild said.
A study by Carvajal and colleagues, published in 2011 in JAMA, showed approximately 23% of patients in the Western world with mucosal melanoma harbor KIT mutations, 12% have NRAS mutations and 9% have BRAF mutations.
“You need to investigate mucosal melanomas for BRAF mutations because they might be sensitive to BRAF and MEK inhibitors,” Hauschild said.
Kalinsky and colleagues conducted a phase 2 study of dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) on metastatic acral or mucosal melanomas with or without CKIT mutations. A second stage of the trial included 22 evaluable patients with mucosal melanoma.
Results, published last year in Journal of Clinical Oncology, “were not as good as expected,” Hauschild said.
No patients achieved complete responses, 18.2% achieved partial response, 31.8% demonstrated stable disease and 25% had progressive disease. Researchers reported median PFS of 2.7 months and median OS of 11.8 months.
“This reminds us of the old times of chemotherapy for metastatic melanoma,” Hauschild said. “It certainly doesn’t make us very enthusiastic.”
Twelve percent of patients discontinued therapy due to grade 3 or grade 4 fatigue or other adverse events.
Hauschild also presented results of an analysis of six trials that evaluated three immunotherapy regimens for patients with melanoma. Of these, about 10% (n = 157) had mucosal melanoma.
Eighty-six patients received monotherapy with 3 mg/kg nivolumab (Opdivo, Bristol-Myers Squibb); 35 patients received combination therapy with 1 mg/kg nivolumab plus3 mg/kg ipilimumab (Yervoy, Bristol-Myers Squibb); and 36 patients received ipilimumab monotherapy dosed at 3 mg/kg.
Researchers reported significantly longer PFS among patients treated with the combination (median, 5.9 months; HR = 0.42; 95% CI, 0.23-0.75) or nivolumab monotherapy (median, 3 months; HR = 0.61; 95% CI, 0.39-0.96) compared with ipilimumab monotherapy (median, 2.7 months).
Six patients — five (5.8%) who received nivolumab monotherapy and one (2.9%) who received the combination — achieved complete response. Thirty patients — 15 (17.4%) who received nivolumab alone, 12 (34.3%) who received the combination and three (8.3%) who received ipilimumab alone — achieved partial response.
“Immunotherapy, for me, is the new standard of care,” Hauschild said. “At our center, if possible, we bring all patients with metastatic mucosal melanoma to ipilimumab plus nivolumab. … Targeted therapies might have a role, but new German guidelines on melanoma say they are for second-line treatment only. First-line is immunotherapy.” – by Mark Leiser
Reference:
Hauschild A. Mucosal melanomas: Different disease or different biology? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 24-25, 2017; New York.
Disclosure: Hauschild reports consultant roles or speakers fees from Amgen, BMS, Merck Serono, Merck Sharp & Dohme, Novartis, Oncosec, Philogen, Pierre Fabre, Provectus, Regeneron and Roche.