Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma

John M. Kirkwood*, Lars Bastholt, Caroline Robert, Jeff Sosman, James Larkin, Peter Hersey, Mark Middleton, Mireille Cantarini, Victoria Zazulina, Karin Kemsley, Reinhard Dummer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

Purpose: To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma. Experimental Design: This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100mg oral selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m 2/d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival. Results: Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86-1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide. Conclusions: No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors.

Original languageEnglish (US)
Pages (from-to)555-567
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number2
DOIs
StatePublished - Jan 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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