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Adding Sorafenib to Chemo Combo Fails to Improve Metastatic Melanoma Survival

Adding Sorafenib to Chemo Combo Fails to Improve Metastatic Melanoma Survival

No improvement in overall survival was seen in patients with metastatic melanoma who were assigned treatment with sorafenib in combination with carboplatin/paclitaxel for the treatment of their disease, according to the results of a double-blind, phase III study published in the Journal of Clinical Oncology.

Ball-and-stick model of sorafenib

“The main result was that sorafenib did not improve outcomes when added to chemotherapy for melanoma,” said Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center. Flaherty added that the results were surprising given the researchers initial expectations, but that negative results from a smaller second-line phase III trial testing this regimen tempered their expectations.

The study included 823 patients with metastatic melanoma who were chemotherapy-naive. Patients were randomly assigned to treatment with carboplatin/paclitaxel with (n = 410) or without (n = 413) the addition of sorafenib 400 mg twice a day.

No difference in overall survival was observed between the treatment arms with a median overall survival of 11.3 months in the carboplatin/paclitaxel alone arm vs 11.1 months for the combination arm.

Only 779 patients had progression-free survival data available. Median progression-free survival was 4.2 months for carboplatin/paclitaxel arm vs 4.9 months for the combination arm.

In addition, patients assigned to combined treatment with sorafenib had higher rates of grade 3 or higher toxicities (84% vs 78%; P = .027), including rash, thrombocytopenia, and hand-foot syndrome.

“To our surprise, the carboplatin/paclitaxel backbone explored in this clinical trial has more antitumor and disease-controlling activity than we had anticipated based on the very limited data available when we proposed this large randomized trial,” Flaherty said.

Based on data from another smaller randomized trial with sorafenib/carboplatin/paclitaxel, as well as data from this study, the carboplatin/paclitaxel regimen has become a standard therapy for metastatic melanoma and is incorporated in current NCCN guidelines.

“The negative results from this trial with regard to the contribution of sorafenib suggests that we do not have an adequate understanding of what type of antiangiogenic therapy might be optimal in melanoma and these results suggest that more selective antagonists of VEGF receptors or agents that target other proangiogenic cytokines should be considered,” Flaherty said.

Flaherty also acknowledged that the field of melanoma treatment looks very different than it did in 2003 when this trial was proposed and initiated. Since that time, a new generation of immunotherapies has begun to displace the use of conventional chemotherapy in metastatic melanoma.

“Our emphasis has shifted largely to understanding how to further develop molecularly targeted therapy in combination with BRAF inhibitors, or with other targeted therapy backbones for other genetically defined subpopulations,” Dr. Flaherty said. “We continue to explore novel immunotherapy strategies that appear far more effective, tolerable, and safer than the older generation of cytokine-based immunotherapies.”

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