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).
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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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