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Background: The aim of this open label study was to assess the efficacy of paclitaxel alone compared with paclitaxel in combination with either the MEK inhibitor trametinib or the anti-angiogenic agent pazopanib in metastatic melanoma. Methods: Eligible patients aged >=18yrs with wild type BRAF melanoma, NRAS status, unresectable stage 3 or 4 and adequate cardiac function were randomised (1:1:1) to paclitaxel alone or with either trametinib or pazopanib. Paclitaxel was administered intravenously on day 1, 8 and 15 of each 28 day cycle for a maximum 6 cycles at 80 mg/m2 (single agent & trametinib arms) or 65 mg/m2 (pazopanib arm). Trametinib 2 mg and pazopanib 800 mg was administered orally once daily and both treatments were permitted until disease progression or unacceptable toxicity. Patients were stratified by prior therapy, NRAS status and baseline lactate dehydrogenase level. Neither participants nor investigators were blinded. The primary end point was progression free survival (PFS) with secondary endpoints including PFS at 6 months, overall survival (OS), objective response rate (ORR) and safety and tolerability. A one sided p-value of 0.1 was considered significant for the primary analysis and for the secondary analyses a two-sided p-value of 0.05 was used. Results: 111 patients from 26 centres (UK and Germany) were randomised to paclitaxel alone (n=38), paclitaxel plus trametinib (n=36) or paclitaxel plus pazopanib (n=37). All patients were considered in the Intention to treat analysis. The median age was 63 (range, 57) years and the median follow-up was 26.3 months. Median PFS was 3.4, 5.2 and 5.3 months with paclitaxel alone, paclitaxel+trametinib and paclitaxel+pazopanib respectively. Efficacy results show benefit for paclitaxel+trametinib in increasing PFS (Time ratio (TR), 1.47; 90% Confidence interval (CI) 1.08 to 2.01, p=0.02) and with significant benefit in ORR (odds ratio (OR), 4.7; p=0.01) as compared to paclitaxel alone but no differences in OS (p=0.1). There was significant benefit of paclitaxel+pazopanib in increasing PFS (TR, 1.17; 90% CI 0.98 to 1.39, p=0.07) but no difference in the ORR (OR, 1.82; p=0.34) or OS (p=0.20). The frequency of ≥ Gr 3 AEs was significantly higher (p<0.01) when paclitaxel combined with trametinib or pazopanib (75% and 78% vs 24%) and this was also supported by a significantly higher (p<0.01) frequency of SAEs (47% and 68% vs 13%). The pazopanib combination was particularly problematic. Conclusions: Paclitaxel+trametinib and paclitaxel+pazopanib combination improved the efficacy of paclitaxel by increasing PFS and for the trametinib combination also significantly increasing ORR. However, the combination of paclitaxel with either trametinib or pazopanib resulted in higher incidence of AEs and SAEs with the pazopanib combination being particularly problematic.


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