Sorafenib Active in Metastatic Breast Cancer

San Antonio, TX—The multi-targeted kinase inhibitor sorafenib (Nexavar), approved to treat kidney and liver cancer, may also benefit patients with metastatic breast cancer, according to a phase IIb study presented at the 32nd annual San Antonio Breast Cancer Symposium. “We saw a signal of potential activity,” said principal investigator William S. Gradishar, MD, Professor of Medicine at Northwestern University School of Medicine, Chicago. The principal endpoint, progression-free survival (PFS), showed a trend favoring sorafenib combined with paclitaxel versus single-agent paclitaxel in patients with locally advanced or metastatic breast cancer.

The double-blind randomized placebo-controlled phase IIb trial included 237 patients from the United States, India, and Brazil. It is the second in a series of four worldwide phase IIb clinical trials testing the use of sorafenib in advanced HER2-negative breast cancer in a program called TIES (Trials to Investigate the Effects of Sorafenib in Breast Cancer).

To evaluate the benefit of sorafenib when paired with chemotherapy, the study randomized 119 patients to paclitaxel (90 mg/m2 weekly) plus oral sorafenib (400 mg twice daily) and 118 patients to the same dose of paclitaxel plus placebo.

Median PFS was 6.9 months with the combination and 5.6 months with single-agent paclitaxel, for a 21% relative reduction in risk of death or progression (P = .0857). The lack of statistical significance may have been due, according to Dr Gradishar, to the excess number of deaths in the sorafenib arm, none believed to be related to treatment; out of 20 deaths, 17 occurred in patients receiving sorafenib. Most of the deaths occurred among the 170 patients from India who died from malaria, tuberculosis, and other conditions not typical of patients treated in the United States, he explained.

“We think these deaths skewed the PFS,” he said at a press briefing. “Time to progression, which does not include deaths, showed a 3-month spread that looks more impressive.”

Time to progression was reduced by 33% with sorafenib. Median duration of response was 5.6 months with sorafenib and 3.7 months in the control arm (P = .0079), and objective response rates were 67% versus 54%, respectively (P = .0234), he reported.

Press briefing moderator Kent Osborne, MD, professor of Medicine at Baylor College of Medicine, Houston, Texas, and director of the Dan L. Duncan Cancer Center at Baylor, explained that the purpose of a phase IIb trial is to obtain “a hint of activity.” This does not require the number of patients needed to show statistical significance at the .05 level, he said, noting, “This study did meet the statistical guidelines” needed to show activity, which was a 20% improvement over the control arm. No unexpected toxicities were observed, though ~30% of patients receiving sorafenib developed serious hand-foot syndrome, he said.

Dr Osborne said to use sorafenib effectively, “we need to find a dose that will lower the side effects, and to do an expanded trial showing definitively that the addition of this oral drug to chemotherapy is advantageous.” SABCS Abstract 44.