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DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.

DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.
DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.
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/m2 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).
1569-8041
968-974
Gupta, A.
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Love, S.
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Schuh, A.
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Shanyinde, M.
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Larkin, J.M.
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Plummer, R.
f2c58c6f-1a6d-468b-b69f-1b925b632065
Nathan, P.D.
becd56a6-1824-4aff-8ea9-0846f8879a91
Danson, S.
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Ottensmeier, C.H.
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Lorigan, P.
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Collins, L.
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Wise, A.
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Asher, R.
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Lisle, R.
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Middleton, M.R.
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Gupta, A.
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Love, S.
de3ec24d-be42-4ca4-967d-b05436b6adc9
Schuh, A.
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Shanyinde, M.
3961b20d-bc3a-448c-9f98-1c038bb37b37
Larkin, J.M.
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Plummer, R.
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Nathan, P.D.
becd56a6-1824-4aff-8ea9-0846f8879a91
Danson, S.
b4c0141d-7282-490a-a147-e0a22d534b49
Ottensmeier, C.H.
42b8a398-baac-4843-a3d6-056225675797
Lorigan, P.
42f0a90b-b129-4d62-aa8a-0463046f563b
Collins, L.
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Wise, A.
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Asher, R.
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Lisle, R.
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Middleton, M.R.
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Gupta, A., Love, S., Schuh, A., Shanyinde, M., Larkin, J.M., Plummer, R., Nathan, P.D., Danson, S., Ottensmeier, C.H., Lorigan, P., Collins, L., Wise, A., Asher, R., Lisle, R. and Middleton, M.R. (2014) DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. Annals of Oncology, 25 (5), 968-974. (doi:10.1093/annonc/mdu054). (PMID:24567366)

Record type: Article

Abstract

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/m2 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).

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Accepted/In Press date: 4 February 2014
Published date: May 2014
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 396344
URI: http://eprints.soton.ac.uk/id/eprint/396344
ISSN: 1569-8041
PURE UUID: 0f2254cd-0b9d-4283-9942-9d46ae6458c4

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Date deposited: 08 Jun 2016 13:44
Last modified: 15 Mar 2024 00:52

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Contributors

Author: A. Gupta
Author: S. Love
Author: A. Schuh
Author: M. Shanyinde
Author: J.M. Larkin
Author: R. Plummer
Author: P.D. Nathan
Author: S. Danson
Author: P. Lorigan
Author: L. Collins
Author: A. Wise
Author: R. Asher
Author: R. Lisle
Author: M.R. Middleton

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