Nick Mulcahy

June 05, 2012

June 5, 2012 (Chicago, Illinois) — The old is just as good as the new in the first-line treatment of either locally advanced or metastatic breast cancer, according to a new study.

In a phase 3 randomized trial involving 799 patients, the efficacy of paclitaxel, which was approved in this setting in 1992, was comparable to 2 newer and more expensive agents — nanoparticle albumin-bound (nab)-paclitaxel (Abraxane, Celgene) and ixabepilone (Ixempra, Bristol-Myers Squibb).

Median progression-free survival was 10.6 months for paclitaxel, 9.2 months for nab-paclitaxel, and 7.6 months for ixabepilone. Ixabepilone was significantly less effective than paclitaxel (P < .0001), and nab-paclitaxel was not superior to paclitaxel (P = .12). Median follow-up in survivors was 12 months (as of April 2012).

"There was no difference in overall survival in the 3 arms," said lead author Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. She spoke at a press conference here at the 2012 Annual Meeting of the American Society of Clinical Oncology.

Dr. Rugo noted that the patients, who were enrolled from 2008 to 2011, were chemotherapy-naïve at study entry, and most received bevacizumab (Avastin, Roche) as part of their treatment.

She also said that paclitaxel demonstrated significantly fewer grade 3/4 hematologic and nonhematologic toxic events than nab-paclitaxel.

However, Nicholas Vogelzang, MD, from the Comprehensive Cancer Centers of Nevada in Henderson, who moderated the press conference, endorsed all of the therapies. "All 3 of the agents are clearly active. I want all 3 of these agents on my team when treating breast cancer," he told reporters.

Dr. Rugo endorsed the primary use of nab-paclitaxel for some patients. "Very good data" indicate that the newer drug is well suited for patients who have an allergic reaction to paclitaxel, she said.

Another breast cancer expert attending the meeting said that which of the 3 agents to choose might be clarified by not-yet-completed correlative biomarker studies. The studies will likely "provide a better understanding of which patients are best suited for which drug," Sylvia Adams, MD, from New York University School of Medicine in New York City, told Medscape Medical News.

Dr. Adams pointed out that the study was sponsored by 2 cooperative groups: the Cancer and Leukemia Group B (CALGB) and the North Central Cancer Treatment Group (NCCTG). Such government-sponsored studies allow a head-to-head comparison of therapies, which are less likely to be undertaken by industry, and exemplify the importance of maintaining National Institutes of Health funding for such efforts, she said.

All 3 drugs are approved by the US Food and Drug Administration for metastatic breast cancer.

Celgene, the marketer of nab-paclitaxel, issued a statement about the trial results, saying that "the data presented…do not impact the body of breast cancer data for nab-paclitaxel monotherapy, which has demonstrated significantly superior efficacy and an acceptable safety profile, compared to paclitaxel, in a randomized phase 3 clinical study [J Clin Oncol. 2005;23:7794-7803] that was the basis for nab-paclitaxel approvals."

The dosing for nab-paclitaxel in the study presented is "significantly higher" than the approved dose intensity. "The 150 mg/m² weekly dose is targeted to have a 30% higher weekly dose intensity than the approved dose of 260 mg/m² every 3 weeks," according to the Celgene statement.

The study results are complicated by the fact that paclitaxel has been one of the cancer drugs in short supply in the United States. But Dr. Rugo pointed out that major centers do not have a supply problem. The shortage woes are restricted to "smaller" centers, she said, which might have problems because of the limited number of suppliers.

Adverse Events Matter

In this open-label trial, participants were randomized to weekly treatment with paclitaxel 90 mg/m² (control group; n = 283), nab-paclitaxel 150 mg/m² (n= 271), or ixabepilone 16 mg/m² (n =245). Each cycle consisted of 3 weeks of treatment followed by a 1-week break.

Dr. Rugo explained that the trial was motivated by a desire to learn about more than just efficacy. "We wanted to know whether giving these newer microtubule agents on a weekly schedule would result in similar or superior effectiveness with improved toxicity profiles over the standard weekly paclitaxel regimen," she said in a press statement.

The majority of patients also received bevacizumab (10 mg/kg every 2 weeks). The targeted therapy was part of study design before the "bevacizumab controversy"; it became optional in March 2011. Adding bevacizumab has been shown to improve progression-free survival, she said, citing the E2100 trial.

Patients with stable or responding disease after 6 cycles of chemotherapy could discontinue chemotherapy and continue with bevacizumab therapy.

Dr. Rugo noted at the press conference that grade 3/4 nonhematologic toxic events were lowest with paclitaxel. Specifically, they were 44% for paclitaxel, 56% for ixabepilone (P = .005), and 60% for nab-paclitaxel (P = .0002).

In the study abstract, the authors flesh out the data for one nettlesome nonhematologic toxic event in particular — sensory neuropathy. Grade 2 or higher sensory neuropathy was 48% for nab-paclitaxel, 44% for ixabepilone, and 37% for paclitaxel.

Grade 3/4 hematologic toxic events were lower with ixabepilone (12%; P = .004) than with paclitaxel (21%), and higher with nab-paclitaxel (51%; P < .0001).

Dr. Adams was encouraged by the trial's focus on both efficacy and adverse events.

"The study shows that investigators are striving not only to look at efficacy, but at the side-effect profile as well," she said.

The primary end point of progression-free survival was defined as time from randomization to disease progression or all-cause death. The trial had a target of 900 patients, and was powered to detect a hazard ratio of 1.36 (median progression-free survival, 10.0 vs 13.6 months). However, at the first interim analysis (165 events), the comparison of ixabepilone and paclitaxel crossed the futility boundary and accrual to ixabepilone was closed. At the second interim analysis (236 events), the comparison of nab-paclitaxel and paclitaxel crossed the futility boundary; the study was closed in November 2011.

"This study demonstrates that we should not simply assume that newer drugs are better than the standard therapies. In metastatic breast cancer, we are constantly examining and refining dosing schedules, testing new therapies, and looking closely at the molecular characteristics of patients' tumors to find the right treatment for the right patient with the fewest toxicities," said Dr. Rugo.

Dr. Rugo reports receiving research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb. Other investigators report multiple relationships with industry, as does Dr. Vogelzang. Dr. Adams reports financial ties to GlaxoSmithKline.

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract CRA1002. Presented June 5, 2012.


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