Modest Improvement in Progression-Free but Not Overall Survival With Selumetinib vs Chemotherapy

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Patients with uveal melanoma treated with selumetinib had modestly improved progression-free survival and response rate compared to patients treated with chemotherapy, but no improvement in overall survival, according to results of a randomized, open-label, phase II trial. “Improvement in clinical outcomes was accompanied by a high rate of adverse events,” Richard D. Carvajal, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in The Journal of the American Medical Association.

“Arising from melanocytes within the choroid layer of the eye, uveal melanoma “is biologically distinct from cutaneous melanoma,” the investigators noted. Oncogenic mutations of the GNAQ and GNA11 genes “are observed in more than 80% of primary uveal melanomas and activate signaling pathways including the mitogen-activated protein kinase (MAPK) pathway. We and others demonstrated the genotype-dependent antitumor effects of inhibition of the MAPK pathway at the level of the mitogen-activated protein kinase (MEK) enzymes MEK1 and MEK2 in preclinical models.”

Study Background

Selumetinib is a selective, non–adenosine triphosphate competitive inhibitor of MEK1 and MEK2. In a subset analysis of 20 patients with advanced uveal melanoma, progression-free survival time with selumetinib was double that achieved with chemotherapy. At last year’s ASCO Annual Meeting, Dr. Carvajal reported data on 96 patients showing that median progression-free survival was significantly improved for patients treated with selumetinib (15.9 weeks) vs temozolomide (7 weeks) and that there was a trend toward improved overall survival.

As described in the JAMA article, patients recruited at 15 academic oncology centers in the United States and Canada were randomly assigned to receive selumetinib at 75 mg orally twice daily (n = 50), or chemotherapy (n = 51) with the investigator’s choice of temozolomide (Temodar), 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine 1,000 mg/m2 intravenously every 21 days) until disease progression, death, intolerable adverse effects, or withdrawal of consent.

Eligible patients could not have received prior treatment with a MEK inhibitor, temozolmide, or dacarbazine. “After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression,” the researchers noted. A total of 99 patients were ultimately treated, with 98 stopping therapy by December 2013.

While no objective responses were observed with chemotherapy, 49%. of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Median progression-free survival was 7 weeks in the chemotherapy group (median treatment duration, 8 weeks) and 15.9 weeks in the selumetinib group (median treatment duration, 16.1 weeks). “The hazard ratio for progression-free survival was 0.46 [95% confidence interval = 0.30–0.71, P < .001] in favor of selumetinib,” the authors reported.

Safety Profile

Treatment-related adverse events were observed in 65 patients (97%) treated with selumetinib, with 25 patients (37%) experiencing grade 3/4 treatment-related adverse events vs 2 patients (4%) in the chemotherapy group. The treatment-related adverse events in the selumetinib group “were consistent with those observed with other inhibitors of MEK, including rash, creatinine kinase elevation, edema, and visual changes,” the authors stated. In the selumetinib group, 25 patients required at least one dose reduction vs 1 patient in the chemotherapy group.

“In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival time and rate of response; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.” the authors conclude.

The clinical identifier is NCT01143402. ■

Carvajal RD, et al: JAMA 311:2397-2405, 2014.