ASCO 2013: Selumetinib Significantly Improves Progression-free Survival for Patients with Advanced Melanoma of the Eye
Progression-free survival was significantly improved for patients with metastatic melanoma of the eye (uveal melanoma) treated with selumetinib, according to the final analysis of data from a phase II crossover study presented at the 2013 ASCO Annual Meeting (Abstract CRA9003). Progression-free survival was 15.9 weeks in the selumetinib arm vs 7 weeks in the temozolomide arm.
“This was highly statistically significant, with a hazard ratio of 0.46. That’s a 54% reduction in the risk of progression or death,” noted the study’s lead author Richard D. Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York.
“This study is the first to ever demonstrate efficacy of any systemic therapy in patients with uveal melanoma,” Dr. Carvajal said. As a result, “selumetinib could be considered a new standard for patients with uveal melanoma.” He said that the trial also provides a platform for the development of new therapeutic approaches.
‘Orphan Cancer’
Melanoma of the eye is “an orphan disease,” Dr. Carvajal said. “It is quite rare. There are less than 2,500 cases diagnosed each year in the United States.” While most patients are diagnosed with early-stage disease, about half eventually develop metastatic disease, with survival ranging from 9 to 12 months.
Uveal melanoma “is distinct biologically from cutaneous melanoma,” Dr. Carvajal explained. “There are no effective systemic chemotherapies for metastatic uveal melanoma. The current standard of care for these patients therefore is clinical trial participation.”
Of 157 patients treated over the past decade on eight different clinical trials testing potential new therapies for this cancer, including chemotherapy, targeted therapy, and immunotherapy, only two patients experienced major tumor shrinkage. In the current trial, tumor shrinkage occurred in 50% of patients treated with selumetinib, with major shrinkage occurring in 15%. None of the patients in the temozolomide group achieved significant shrinkage.
Unique Molecular Subset
“Ours is the largest randomized study of patients with melanoma of the eye. It proves that inhibiting the MAPK pathway in this unique molecular subset of melanoma, which is commonly characterized by mutations in Gnaq and Gna11, is effective, more than doubling progression-free survival,” Dr. Carvajal said.
Gnaq and Gna11 alterations activate the MAPK pathway, which fuels cancer cell growth. These alterations occur in greater than 85% of patients with uveal melanoma. Selumetinib blocks the MEK protein, a key component of the MAPK pathway. The drug is also being investigated for the treatment of other cancers, including cancers of the thyroid and lung.
Among the 98 patients with metastatic melanoma of the eye participating in the study, 47% had Gna11 alterations in their tumors and 37% had Gnaq alterations. The remainder of the patients did not have alterations in either of those genes. “Greater than 90% of the cases in both arms had advanced disease,” Dr. Carvajal reported.
Trend Toward Improved Overall Survival
Participants were randomly assigned to receive selumetinib (48 patients) or temozolomide (50 patients). “The selumetinib was administered orally twice daily on a continual basis,” Dr. Carvajal reported.
“It is a challenging situation to have to conduct a randomized trial for a disease in which there is no standard,” Dr. Carvajal noted. “Temozolomide is a standard drug commonly used for cutaneous melanoma, and it was felt that that would be a reasonable choice for a standard here in the absence of any true standard of care and that it would be well tolerated by patients without any undue risk. We did include the crossover design to allow everyone to get the investigational drug.”
Median survival was 10.8 months in the selumetinib arm and 9.4 months in the temozolomide arm. “Despite the crossover in our design, where more than 80% of the patients initially randomized to chemotherapy crossed over to selumetinib, there was a trend toward improved survival,” Dr. Carvajal said.
This study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge. Dr. Carvajal had nothing to disclose.
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