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DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced
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 II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes.
Results:
Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (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 versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect 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).
Insights
This study investigated selumetinib plus docetaxel for advanced melanoma. While the combination showed a higher response rate, it did not significantly improve progression-free survival and was less well tolerated than docetaxel alone.
Area of Science:
- Oncology
- Medical research
- Clinical trials
Background:
- Limited treatment options exist for wild-type BRAF melanoma.
- Selumetinib, a MEK 1/2 inhibitor, targets pERK signaling.
- Combination therapy with docetaxel showed preclinical synergy.
Purpose of the Study:
- To evaluate the efficacy and safety of selumetinib plus docetaxel as a first-line treatment for advanced wild-type BRAF melanoma.
- To assess progression-free survival (PFS) as the primary endpoint.
- To explore the correlation of NRAS mutation status with treatment outcomes.
Main Methods:
- A double-blind, multicenter, randomized phase II trial.
- Patients with wild-type BRAF melanoma received docetaxel with either selumetinib or placebo.
- Primary endpoint was progression-free survival; NRAS mutation status was analyzed retrospectively.
Main Results:
- No significant difference in PFS between the selumetinib combination and placebo groups (HR 0.75, P=0.130).
- Median PFS was 4.23 months with selumetinib versus 3.93 months with placebo.
- Objective response rate was higher with selumetinib (32% vs 14%), but the combination was less well tolerated.
Conclusions:
- The combination of docetaxel and selumetinib did not significantly improve PFS in wild-type BRAF advanced melanoma.
- While response rates were higher, the combination therapy was associated with increased toxicity.
- Tumor NRAS mutation status did not appear to be a predictive biomarker for this combination therapy.
