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Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF Melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial

Urbonas, V; Schadendorf, D; Zimmer, L; Danson, S; Marshall, E; Corrie, P; Wheater, M; ... Middleton, MR; + view all (2018) Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF Melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial. Annals of Oncology , Article mdy500. 10.1093/annonc/mdy500. (In press). Green open access

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Abstract

Backround: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the MAPK pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised, open-label trial. Patients and Methods: Patients were randomised (1:1:1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of 6 cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and objective response rate (ORR). Results: Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS; (time ratio (TR), 1.47; 90% confidence interval (CI): 1.08 to 2.01, P = 0.04) and ORR (42% versus 13%; P = 0.01), but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR, 1.36; 90% CI: 0.96 to 1.93, P = 0.14), ORR, or OS. Toxicity increased in both combination arms. Conclusion: In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS. This study was registered with the EU Clinical Trials Register, number EudraCT 2011-002545-35, and with the ISRCTN registry, number 43327231.

Type: Article
Title: Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF Melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/annonc/mdy500
Publisher version: https://doi.org/10.1093/annonc/mdy500
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
Keywords: phase II, melanoma, RAF wild type, pazopanib, trametinib
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
URI: https://discovery.ucl.ac.uk/id/eprint/10062375
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