NEW YORK — A greater understanding of disease biology has led to the development of novel immunotherapies and targeted therapies that hold promise to improve outcomes for patients with advanced uveal melanoma, according to a speaker at HemOnc Today Melanoma and Cutaneous Malignancies.
Fifty percent of all patients with uveal melanomas — which represent about 5% of all melanomas — develop metastases, Richard D. Carvajal, MD, associate professor of medicine and director of experimental therapeutics and of the melanoma service at Columbia University Medical Center, said during his presentation.
“Once it recurs, outcomes are quite poor,” Carvajal said. “The reasons for that in part are one, because it is a rare disease, and it is challenging to manage. And two, the therapies that we have that have shown dramatic efficacy in cutaneous melanoma just don’t seem to work as well in ocular melanoma.”
Richard D. Carvajal
Across trial data, it appears about 5% of patients achieve a response with ipilimumab (Yervoy, Bristol-Myers Squibb) and the 3-month disease control rate is only 38%.
The differences in outcome with uveal melanoma compared with cutaneous melanoma may relate to the underlying biology of the disease, Carvajal said. The mutational burden of the uveal melanoma is much less than that of cutaneous melanoma.
One potential target in uveal melanoma is gp100, which appears to have greater expression in this disease compared with cutaneous melanoma. IMCgp100 (Immunocore) targets gp100 and has shown promise in a phase 1 trial, Carvajal said.
Other genes frequently mutated in uveal melanoma are GNAQ or GNA11. Because this pathway may be affected by MEK inhibition, Carvajal and colleagues evaluated selumetinib (AstraZeneca) vs. chemotherapy in 96 patients with uveal melanoma. Selumetinib demonstrated superior PFS, the study’s primary endpoint (15.9 weeks vs. 7 weeks; HR = 0.46; 95% CI, 0.3-0.71).
“I will point out that the different was 7 weeks to 15.9 weeks, which was an improvement from bad to a little less bad,” Carvajal said. “But, there still was a signal of activity.”
Based on these data, researchers initiated a phase 3 trial evaluating the addition of selumetinib to dacarbazine chemotherapy; however, the combination yielded no improvement in PFS or response rate.
“This was a disappointing finding, and does lead one to ask what the role of MEK inhibition is in this disease,” Carvajal said.
MEK inhibition might be enhanced through the optimization of single-agent MEK inhibition, a vertical pathway blockade or a dual pathway blockade, he said.
Researchers are evaluating the concurrent targeting of PKC and PI3Kalpha with AEB071 (Novartis) and BLY719 (Novartis) for metastatic uveal melanoma, and there are a few other MEK and PKC-based trials ongoing for uveal melanoma, Carvajal said.
“There are a number of other clinical trials specifically being developed for this disease,” he said. “If I had put up a list of trials for uveal melanoma 5 years ago, the list would be about five trials. This is very exciting for our patients that there is so much interest now.
“Clinical trials do remain the priority for these patients,” he added. – by Alexandra Todak
Carvajal RD. What’s new in uveal melanoma? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 18-19, 2016; New York.
Disclosure: Carvajal reports consultant/advisory roles with Aura Biosciences, AstraZeneca, Janssen, Merck, Novartis, Rgenix and Thomson Reuters.