(ChemotherapyAdvisor) – Adding sorafenib to carboplatin and paclitaxel (CPS), compared to carboplatin and paclitaxel (CP) alone, did not improve overall survival (OS), progression-free survival (PFS), or response rate in chemotherapy-naïve patients with metastatic melanoma, a study concluded in the Journal of Clinical Oncology online December 17.

“Despite the promising antitumor activity of sorafenib and chemotherapy combinations in patients with unresectable stage III or stage IV melanoma reported in previous clinical trials, this double-blind randomized phase 3 trial failed to demonstrate statistically significant benefits in OS for CPS therapy compared with CP and placebo therapy,” noted Keith T. Flaherty, MD, of Massachusetts General Hospital, Boston, MA.

When the study was initiated, “sorafenib appeared to be the best available MAP kinase pathway inhibitor,” Dr. Flaherty pointed out. However, “in the intervening years, more active MAP kinase pathway inhibitors (targeting BRAF and MEK) and antiangiogenic drugs have emerged that appear to be of higher priority for further evaluation, particularly in subsets of patients with melanoma.”

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In the study, 823 patients were enrolled over 34 months and were randomly assigned to intravenous (IV) carboplatin area under the [concentration-time] curve (AUC) 6 over 30 minutes on day 1 of each 21-day cycle; plus (IV) paclitaxel 225mg/m2 over 3 hours, once every 21 days; and either oral sorafenib 400mg twice daily days 2 through 19 every 21 days (n=410) or matching placebo (n=413).

Median OS, the primary end point, was 11.3 months (95% CI 9.8–12.2 months) for patients who received CP and 11.1 months (95% CI 10.3–12.3 months) for those who received CPS. Dr. Flaherty noted “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=0.878).”

Median PFS was 4.9 months for patients who received CPS and 4.2 months for CP (P=0.092); response rate was 20.5% and 18.2%, respectively (P=0.427).

Grade 3 or higher toxicities were 84.5% in the CPS arm compared with 78.3% in the CP arm (P=0.027); more patients who received sorafenib had increased rash, hand-foot syndrome, and thrombocytopenia.

Dr. Flaherty noted that these results establish “benchmark end points for the CP regimen in first-line therapy of metastatic melanoma.”