DOC-MEK: A double blind randomized phase 2 trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma
Mené sur 83 patients atteints d'un mélanome avancé ne présentant pas de mutation du gène BRAF, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du selumétinib en complément du docétaxel
Background Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma. Patients and methods In this double blind multicentre phase 2 trial patients with wild-type BRAF melanoma were randomised (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m2 was administered intravenously every three weeks up to 6 cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes. Results Eighty-three patients were randomised to docetaxel plus selumetinib (N=41) or docetaxel plus placebo (N=42). The PFS hazard ratio (selumetinib:placebo) was 0.75 (90%CI: 0.50-1.14; P=0.130), with a median PFS of 4.23 months (90%CI: 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90%CI: 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib vs 14% with placebo (P=0.059). In a retrospective subset analysis NRAS mutation status did not impact significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone. Conclusions The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy.Clinical Trial DOC-MEK (EudraCT no: 2009-018153-23).