Paclitaxel with or without trametinib or pazopanib in advanced wild-type braf melanoma (pacmel): A multicentre, open-label, randomised, controlled phase II trial

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.