Phase III Trial of Carboplatin and Paclitaxel With or Without Sorafenib in Metastatic Melanoma

Abstract

A B S T R A C T PurposeThe primary objective of this study was to determine whether carboplatin, paclitaxel, and sorafenib (CPS) improve overall survival (OS) compared with carboplatin and paclitaxel (CP) in chemotherapynaive patients with metastatic melanoma. Patients and MethodsIn this double-blind, randomized, placebo-controlled phase III study, all patients received carboplatin at area under the [concentration-time] curve 6 and paclitaxel 225 mg/m 2 intravenously once every 21 days with random assignment to sorafenib 400 mg orally twice per day on days 2 through 19 every 21 days or placebo. The primary end point was OS, and secondary end points included progression-free survival, objective tumor response, and toxicity. ResultsIn all, 823 patients were enrolled over 34 months. At final analysis, the median OS was 11.3 months (95% CI, 9.8 to 12.2 months) for CP and 11.1 months (95% CI, 10.3 to 12.3 months) for CPS; the difference in the OS distribution was not statistically significant by the stratified log-rank test, stratified on American Joint Committee on Cancer (AJCC) stage, Eastern Cooperative Oncology Group (ECOG) performance status, and prior therapy (P ϭ .878). Median progressionfree survival was 4.9 months for CPS and 4.2 months for CP (P ϭ .092, stratified log-rank test). Response rate was 20% for CPS and 18% for CP (P ϭ .427). More patients on the CPS arm had grade 3 or higher toxicities (84% v 78%; P ϭ .027), with increased rash, hand-foot syndrome, and thrombocytopenia accounting for most of the difference. ConclusionSorafenib does not improve OS when given in combination with CP for chemotherapy-naive patients with metastatic melanoma. This study establishes benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.

Targeted Therapy for Cutaneous Melanoma: Beyond BRAF...

“…This hypothesis is supported by a recent analysis of the results of the ECOG 2603 trial, which was a randomized trial of paclitaxel and carboplatin (TC) with or without sorafenib in treatment-naïve metastatic melanoma patients. 21 The analysis of the entire treatment population demonstrated that sorafenib did not significantly improve the overall response rate (ORR), PFS, or overall survival (OS), similar to the results reported in a randomized trial in previously-treated metastatic melanoma patients. 22 However, among the 39 patients with activating NRAS mutations, the ORR was 5.6% for patients treated with TC, while the ORR for patients who also received sorafenib was 22.7% (odds ratio 4.26, 95% confidence interval 0.…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Initial attempts to block BRAF via non-RAF-isoform-selective inhibitors were unsuccessful 47 ; however, subsequent structure-guided drug-discovery efforts facilitated the development of clinically active BRAF inhibitors 48 . The first-in-class agent was vemurafenib, a selective inhibitor of V600-mutant BRAF.…”

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

“…Others have shown that dasatinib, nilotinib, and imatinib are competitive inhibitors of P-glycoprotein and BCRP, meaning that they are substrates at low concentrations, while they inhibit transport function at high concentrations [24]. Although these data indicate the potential for kinase inhibitors to be used as tools to overcome chemoresistance through ABC efflux transporter inhibition in vitro, several clinical trials employing kinase inhibitors for mitigation of chemoresistance have been unable to definitively demonstrate improvements in progression free survival and/or overall survival of patients [25][26][27][28].…”