The combination of selumetinib with dacarbazine did not offer improved survival outcomes over placebo/dacarbazine in patients with metastatic uveal melanoma.
The combination of the MEK inhibitor selumetinib with dacarbazine did not offer improved survival outcomes over placebo plus dacarbazine in patients with metastatic uveal melanoma, according to a phase III trial.
“Uveal melanoma is biologically distinct from cutaneous melanoma and accounts for approximately 3% to 5% of all melanomas in the United States,” wrote study authors led by Richard D. Carvajal, MD, of Columbia University Medical Center in New York. “There are currently no approved or effective systemic therapies specifically for these patients.”
Preclinical and early clinical data have suggested that the MEK1/2 inhibitor selumetinib may offer benefit in metastatic uveal melanoma patients. The new phase III SUMIT trial was a randomized, international, double-blind, placebo-controlled trial that included 129 patients with metastatic uveal melanoma who had received no prior systemic therapy. They were randomized to receive either selumetinib plus dacarbazine (97 patients) or placebo plus dacarbazine (32 patients). Results were published in the Journal of Clinical Oncology.
The study’s primary endpoint of progression-free survival (PFS) was not met. Eighty-two patients (85%) experienced a PFS event in the selumetinib group, compared with 24 (75%) in the placebo group; the hazard ratio (HR) for PFS was 0.78 (95% CI, 0.48–1.27; P = .32). The median PFS was 2.8 months with selumetinib, and 1.8 months with placebo. The 3-month PFS rate was 38% with selumetinib, compared with 26% with placebo; at 6 months, these rates were 10% and 18%, respectively.
A preliminary overall survival analysis also showed no difference, with an HR of 0.75 (95% CI, 0.39–1.46; P = .40). There were three responses in the selumetinib group (3%), and none in the placebo group (P = .36).
All patients in the study reported at least one adverse event. Grade 3 or higher adverse events occurred in 63% of selumetinib patients and in 53% of placebo patients; 21% of selumetinib patients and 6% of placebo patients had a serious adverse event, and 18% and 6%, respectively, had an event leading to hospitalization. The authors noted that in spite of the relatively high adverse event rate, most patients could be treated with single-dose interruptions or reductions. The primary reason for drug discontinuation was disease progression.
“It remains a possibility that dacarbazine limits the efficacy of MEK inhibitors in this disease, and the exploration of selumetinib as monotherapy or in alternative combinations, other than with alkylating agents, remains of interest,” the authors wrote. “Given the lack of effective treatment options for patients with advanced uveal melanoma, rapid development and testing of novel therapeutic strategies are critical.”