Selumetinib Yields Modest Benefits in Rare Eye Cancer

Megan Brooks

June 17, 2014

The investigational MEK inhibitor selumetinib (AstraZeneca) continues to show promise in patients with uveal melanoma, a rare form of melanoma that affects the eye.

In the first randomized controlled trial of selumetinib in uveal melanoma, tumor responses were better and progression-free survival (PFS) time longer with selumetinib than with chemotherapy.

However, overall survival (OS) did not improve, and the modest improvement in clinical outcomes was accompanied by a high rate of adverse events.

Nonetheless, "this is the first study to show that a systemic therapy provides significant clinical benefit in a randomized fashion to patients with advanced uveal melanoma, a population of patients who have very limited treatment options. This clinical benefit has never previously been demonstrated with other agents, both conventional or investigational," Richard D. Carvajal, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center, New York City, who worked on the study, told Medscape Medical News.

The study, which is from a phase 2 trial, appears in the June 18 issue of JAMA.

Uveal melanoma arises from melanocytes within the choroid layer of the eye. Each year, roughly 1500 new cases of uveal melanoma are diagnosed.

Selumetinib inhibits the mitogen-activated protein kinase (MAPK) pathway. Uveal melanoma is characterized by GNAQ and GNA11 mutations, which activate this pathway, leading to uncontrolled cell growth, and so blocking the pathway in these patients was hoped to lead to clinical benefits.

In the current trial, 101 patients with metastatic uveal melanoma were randomly allocated to selumetinib, 75 mg orally twice daily, on a continuous basis or chemotherapy with temozolomide (150 mg/m2 orally daily for 5 of every 28 days) or dacarbazine (1000 mg/m2 intravenously every 21 days) until disease progression, death, intolerable adverse effects, or withdrawal of consent. Choice of chemotherapy was left up to individual investigators. After analysis of the primary outcome, 19 additional patients were registered and 18 treated with selumetinib without randomization, to complete the planned 120-patient enrollment.

Median PFS was 7 weeks with chemotherapy (95% confidence interval [CI], 4.3 - 8.4 weeks; median treatment duration, 8 weeks) vs 15.9 weeks with selumetinib (95% CI, 8.4 - 21.1 weeks; median treatment duration, 16.1 weeks), the researchers report.

The 4-month PFS rate was 8.5% with chemotherapy compared with 43.1% with selumetinib. There was no statistically significant difference in median OS (9.1 months with chemotherapy and 11.8 months with selumetinib, as of December 31, 2013).

No objective tumor responses were seen with chemotherapy, whereas 49% of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to the drug.

This is not the first time that selumetinib has demonstrated efficacy in this setting.

An unplanned subgroup analysis from an earlier trial that included 20 patients with uveal melanoma suggested favorable results with selumetinib (Clin Cancer Res. 2011;17:2087-2100). In that earlier trial, median PFS was 16.3 weeks in 7 patients randomly assigned to selumetinib vs 7.1 weeks in 13 patients randomly assigned to temozolomide, findings similar to the results reported in JAMA this week.

The new study "confirms that this drug does have activity in uveal melanoma; however, we need to continue to make clinical advances to improve outcomes in these patients," Tara Gangadhar, MD, a melanoma expert from the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, who wasn't involved in the study, told Medscape Medical News.

Treatment-related adverse events occurred in 97% of patients treated with selumetinib, including rash, creatine kinase elevation, edema, and visual changes. "The high rate of adverse events is similar to that seen with other targeted therapies; the toxicities were mild and were manageable in most patients," Dr. Gangadhar said.

Phase 3 Trials Underway

On the heels of this "hypothesis-generating" phase 2 study, "accrual to SUMIT, an international phase 3 trial of selumetinib in combination with DTIC [dacarbazine] versus chemotherapy alone has recently begun," Dr. Carvajal told Medscape Medical News. "We hope that this study will confirm the efficacy of MEK inhibition observed in our current trial."

Dr. Carvajal also noted that preclinical data demonstrate that the efficacy of MEK inhibition can be enhanced with the addition of AKT inhibition or PKC inhibition. Based on this, he said a study of trametinib (Mekinist, GlaxoSmithKline) alone or in combination with the experimental AKT inhibitor GSK2141795; a study of the MEK inhibitor MEK162 and the PKC inhibitor AEB071 are also underway.

"Each of these 3 trials have been designed to try to build upon the efficacy observed with single-agent MEK inhibition utilizing distinct combinatorial strategies," Dr. Carvajal said.

Selumetinib is also being investigated in other cancers, including thyroid cancer and lung cancer.

The study was sponsored by Cancer Therapy Evaluation Program. Financial support was provided by the National Cancer Institute, the Conquer Cancer Foundation, Cycle for Survival, and the Fund for Ophthalmic Knowledge. The Division of Cancer Treatment and Diagnosis at the National Cancer Institute provided selumetinib for the trial. The authors and Dr. Gangadhar have disclosed no relevant financial relationships.

JAMA. 2014;311:2397-2405. Abstract


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