Journal Article

Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study

Spencer, Stuart, Kim, Kevin B, Arance, Ana, Robert, Caroline, Gutzmer, Ralf, Cantarini, Mireille, Liszkay, Gabriella, Nyakas, Marta, Schadendorf, Dirk, Dummer, Reinhard, Lorigan, Paul, Middleton, Mark R

2013

Overview

Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m2 on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13·9 months, 80% CI 10·2–15·6, in the selumetinib plus dacarbazine group and 10·5 months, 9·6–14·7, in the placebo plus dacarbazine group; hazard ratio [HR] 0·93, 80% CI 0·67–1·28, one-sided p=0·39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0·63, 80% CI 0·47–0·84, one-sided p=0·021), with a median of 5·6 months (80% CI 4·9–5·9) versus 3·0 months (2·8–4·6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3–4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). Selumetinib plus dacarbazine showed clinical activity in patients with BRAF-mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. AstraZeneca.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adult / Aged / Antineoplastic Agents, Alkylating - administration & dosage / Antineoplastic Agents, Alkylating - adverse effects / Antineoplastic Agents, Alkylating - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Benzimidazoles - administration & dosage / Brazil / Cancer therapies / Chemotherapy / Cytotoxicity / Dacarbazine - administration & dosage / Dacarbazine - adverse effects / Dacarbazine - therapeutic use / Disease-Free Survival / DNA Mutational Analysis / Double-Blind Method / Drug Administration Schedule / Drug dosages / Europe / Female / Genetic Predisposition to Disease / Hematology, Oncology, and Palliative Medicine / Humans / Kaplan-Meier Estimate / Logistic Models / Male / Melanoma / Melanoma - drug therapy / Melanoma - enzymology / Melanoma - genetics / Melanoma - mortality / Melanoma - secondary / Metastasis / Middle Aged / Mutation / Neoplasms, Unknown Primary - drug therapy / Neoplasms, Unknown Primary - enzymology / Neoplasms, Unknown Primary - genetics / Neoplasms, Unknown Primary - mortality / Neoplasms, Unknown Primary - pathology / Phenotype / Proportional Hazards Models / Protein Kinase Inhibitors - administration & dosage / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Skin cancer / Skin Neoplasms - drug therapy / Skin Neoplasms - enzymology / Skin Neoplasms - genetics / Skin Neoplasms - mortality / Skin Neoplasms - pathology / Survival analysis / Time Factors / Treatment Outcome / Tumors / United States