MEK Inhibitor Improves Outcomes in Metastatic Uveal Melanoma 



For the first time, a drug has proven effective in the treatment of uveal (ocular) melanoma that has metastasized, according to a randomized multicenter phase II study presented at the 2013 ASCO Annual Meeting.1

“This study is the first to demonstrate an improved clinical outcome with any systemic therapy in patients with metastatic uveal melanoma. MEK inhibition with selumetinib resulted in a median progression-free survival that was double that achieved with chemotherapy,” said Richard D. Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, who presented the findings.

Dr. Carvajal noted that effective treatments are lacking for metastatic uveal melanoma. Therefore, the current standard of care is clinical trial participation.

Selumetinib is a non-ATP competitive inhibitor of MEK1/2. It was evaluated in 98 patients with metastatic uveal melanoma, 84% of whom harbored the GNAQ or GNA11 (GNAQ/11) genetic alterations that are common in ocular melanoma and that are known to activate the MAP kinase pathway, promoting tumor growth. The MEK protein is a key component of this pathway.

GNAQ/11 mutations are early oncogenic events found in uveal melanoma and result in susceptibility to treatment with MEK inhibition,” Dr. Carvajal explained. Studies have shown that selumetinib decreases the viability of uveal melanoma in a mutation-dependent fashion, he said.

Study of 98 Patients

The multicenter study enrolled 98 patients, most with metastatic disease involving the liver, who had received no more than one prior treatment for metastatic disease, including prior ipilimumab (Yervoy) in approximately 20%. Patients were randomly assigned to selumetinib at 75 mg twice daily or temozolomide at 150 mg/m2 daily for 5 days in 28-day cycles (four patients received dacarbazine at 1,000 mg/m2 every 21 days).

The response patterns were very different between the treatment arms. With the MEK inhibitor selumetinib, 50% of patients had tumor regression and 15% had a response by RECIST criteria. “This is quite remarkable, because radiographic tumor shrinkage is uncommon in this disease,” he said. With temozolomide, in contrast, tumor shrinkage was 11% with no major RECIST responses observed.

Clinical outcomes corresponded with the significantly different response patterns observed. With selumetinib, 35 of 46 (76%) patients achieved stable disease. Another 7 (15%) achieved a RECIST response. The median duration of response was 23 weeks (range, 7.9–40.3).

Survival Rates

Progression-free survival was improved with selumetinib, in both the overall and mutation-only populations. For the overall population, median progression-free survival was 15.9 weeks with selumetinib and 7.0 weeks with temozolomide—a 54% reduction in risk that was highly significant (P = .0005). In the 84% of patients who had mutations in exon 5 GNAQ/11, it was 15.4 vs 7.0 weeks—a 45% reduction in risk (P = .011), he reported.

The progression-free survival rates for the overall population were 43.1% vs 8.5% at 4 months and 22.9% vs 5.7%, respectively, at 6 months. The 16 patients with wild-type GNAQ/11 had similar outcomes, he noted.

Despite an 80% crossover rate, a trend toward an improvement in overall survival was also observed, with median survival times of 10.8 and 9.4 months, respectively, or a 21% nonsignificant reduction in risk (P = .4).

Adverse Events

Selumetinib was associated with more anemia (30% vs 14%), CPK elevations (49% vs 0%), diarrhea (40% vs 8%), elevations in liver enzyme tests (49% vs 12%), edema (40% vs 2%), and muscle weakness (8% vs 0%). However, most side effects were grade 1 or 2, he said.

Dr. Carvajal called the treatment “promising” and said the MEK inhibitor provides a platform for the development of combinatorial therapeutic approaches. ■

Disclosure: Dr. Carvajal reported no potential conflicts of interest.

Reference

1. Carvajal RD, Sosman JA, Quevedo F, et al: Phase II study of selumetinib versus temozolomide in gnaq/Gna11 mutation uveal melanoma. 2013 ASCO Annual Meeting. Abstract CRA9003. Presented June 1, 2013.


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