Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial. (14th November 2018) - Urbonas, V
Abstract: Background: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF ( BRAF -wt) melanoma. However, the mitogen-activated protein kinase 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 and 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 six 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 end point was progression-free survival (PFS). Key secondary end points 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) 1.08–2.01, 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 0.96–1.93; 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, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.