Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT)

Abstract

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.

Oncogenic signaling in uveal melanoma

“…The resulting phase III (SUMIT) clinical trial with 129 patients in treatment naïve metastatic UM, comparing selumetinib + dacarbazine versus dacarbazine, did not meet its primary end point with median PFS 2.8 months vs 1.8 months (HR 0.78, 95% CI 0.48–1.27). The RR of selumetinib + dacarbazine was 3.1% compared to dacarbazine (0%) with no statistically significant benefit in OS (Carvajal et al., ).…”

Decitabine limits escape from MEK inhibition in uveal melanoma

“…In a phase II clinical trial of advanced uveal melanoma, treatment with the single agent MEKi selumetinib was associated with some responses and an increase in the progression‐free survival from 7 to 16 weeks (Carvajal et al, ). Unfortunately, this was not replicated in later studies, and a trial of selumetinib plus dacarbazine failed to show any benefit over dacarbazine alone in a phase III double‐blind clinical trial (Carvajal et al, ). Studies in multiple cancers have shown that tumor cells rapidly adapt to kinase inhibitors through the adoption of a drug‐tolerant state, which is often epigenetically mediated.…”

YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines

“…Most UM tumors harbor the GNAQ or GNA11 mutations; these mutants have been shown to activate oncogenic pathways, including the mitogen-activated protein kinase (MAPK) and Hippo-Yes-associated protein (YAP) pathways [9][10][11] . Based on these studies, phase II/III clinical trials using the MEK1/2 inhibitor, selumetinib, have been conducted, but selumetinib monotherapy or combination therapy with dacarbazine has failed to increase the overall survival of patients with UM 12,13 .…”