Two newly developed agents, nab-paclitaxel and ixabepilone, both proved inferior to standard once-weekly paclitaxel and caused more toxicities in a phase III trial involving 783 patients with advanced chemotherapy-naive breast cancer, which was reported online June 8 in Journal of Clinical Oncology.
“On the basis of our data, once-per-week paclitaxel should remain the preferred microtubule inhibitor for patients with metastatic breast cancer in the first-line setting,” said Dr. Hope S. Rugo of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center and her associates.
Dr. Hope S. Rugo
Nab-paclitaxel is a novel, solvent-free formulation of paclitaxel in albumin-bound nanoparticles, which precludes the need for premedication to prevent hypersensitivity reactions. Ixabepilone is a semisynthetic analog of epothilone B that binds to the same beta-tubulin site as does paclitaxel.
In phase II studies, both agents appeared to be more potent than paclitaxel and to have similar or superior toxicity profiles. In this trial, patients with metastatic or recurrent breast cancer not amenable to local therapy were randomly assigned to receive nab-paclitaxel (267 participants), ixabepilone (241 participants), or standard paclitaxel (275 participants) as well as bevacizumab; they were followed for a median of 25 months (maximum, 50 months).
The trial was halted early when interim analyses showed that both of the new agents crossed the futility boundary for superiority. The primary endpoint, progression-free survival, was 11 months with paclitaxel. Ixabepilone was clearly inferior, with a median progression-free survival of 7.4 months (HR, 1.59), and nab-paclitaxel trended toward inferiority, with a median progression-free survival of 9.3 months (HR, 1.20). Overall survival rates followed the same pattern. In addition, treatment response rates were lower with both new agents than with paclitaxel, as was palliation of disease-related symptoms.
Both hematologic and nonhematologic toxicities were more severe with the novel drugs than with paclitaxel. These included neutropenia, anemia, sensory neuropathy, fatigue, hypertension, motor neuropathy, pain, and nausea, the investigators said (J. Clin. Oncol. 2015 June 8 [doi:10.1200/JCO.2014.59.5298]).
Unfortunately, before these negative findings were published, the promising results of the phase II studies “led to widespread use of more costly and higher-dose nab-paclitaxel in many clinical practices,” Dr. Rugo and her associates noted.
“Our trial illustrates the importance of adequately powered prospective trials to confirm phase II reports. In addition, these results remind clinicians to be cautious when incorporating new agents, particularly those that are more expensive and potentially more toxic,” they added.
This study was supported by grants from the National Cancer Institute, the Alliance for Clinical Trials in Oncology’s Statistics and Data Center, and the Breast Cancer Research Foundation. Dr. Rugo reported ties to Genomic Health, Plexxikon, MacroGenics, OBI Pharma, Eisai, Pfizer, Novartis, Eli Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, Merck, Roche, OBI Ontology, and Mylan; her associates reported ties to some of those companies and to Myriad Genetics, Amgen, Celgene, and Verastem.