Uveal Melanoma Therapy on the Horizon?

Encouraging results from a phase II trial of selumetinib (AstraZeneca) offer the first hope of an effective treatment for patients with metastatic uveal melanoma, a rare and fatal cancer of the eye.

Investigators across the United States and Canada randomized 101 patients with metastatic uveal melanoma to selumetinib, a selective inhibitor of MEK, or standard chemotherapy. Median progression-free survival among selumetinib patients was 15.9 weeks compared with 7 weeks in the chemotherapy group, and almost half of the patients who took selumetinib experienced tumor regression compared with none in the chemotherapy group. The results were published in The Journal of the American Medical Association in June.

“This is the first time that a MEK inhibitor was ever tested in this type of cancer, for which there is no established treatment,” says the study's senior author, Gary Schwartz, MD, chief of hematology/oncology at New York Presbyterian–Columbia University Medical Center in New York City. “This will be the building block of future clinical trials in patients with metastatic uveal melanoma.”

There was no significant improvement in overall survival, but because patients who started on chemotherapy were allowed to switch to selumetinib if their tumors progressed, any improvement in overall survival was masked, says Schwartz. Toxicity was common among the treatment group but effects were reversible and manageable, he adds.

Most patients with uveal melanoma have GNAQ or GNA11 mutations, which activate the MAPK pathway. Earlier, Schwartz and other researchers showed that blocking the activation of MEK, a key enzyme in the MAPK pathway, could inhibit growth of uveal melanoma cells in the lab, and Schwartz's lab was the first to demonstrate this with selumetinib.

The phase II trial may never have happened without funding from the NCI, because industry is sometimes hesitant to invest in therapies for rare diseases, says Schwartz. AstraZeneca developed selumetinib and allowed the NCI to add the drug to its research pipeline for study in conditions such as uveal melanoma that the company didn't want to pursue on its own. The NCI also provided access to a national network of clinical trial centers.

With the phase II success, AstraZeneca has decided to conduct a phase III randomized trial of selumetinib in patients with uveal melanoma, says Schwartz. “The MEK story is emerging as a target, and uveal melanoma is a unique niche for this drug.”