Breast Cancer Trial Results Spin a Cautionary Tale

Neil Osterweil

June 18, 2015

In the care of patients with metastatic breast cancer, the next new thing is the same old thing: paclitaxel (multiple brands).

Results of the CALGB 40502/NCCTG N063H (Alliance) trial, first reported at the American Society of Clinical Oncology annual meeting in 2012 and published online June 8 in the Journal of Clinical Oncology, show that patients with advanced breast cancer had better median progression-free survival (PFS) with once-weekly paclitaxel than with ixabepilone (Ixempra, Bristol-Myers Squibb Company), a newer agent.

In the third arm of the trial, paclitaxel was equivalent in its effect on PFS to its newer, more water-soluble cousin, nanoparticle alubimun-bound paclitaxel (nab-paclitaxel), and plain old paclitaxel was less toxic than either of its comparators.

The patients in all three arms also received bevacizumab (Avastin, Genentech, Inc) and were treatment-naïve at the start of the trial.

"Both newer agents were associated with increased overall toxicity, possibly inferior effectiveness, and reduced palliation of disease-related symptoms," write the study authors, led by Hope S. Rugo, MD, from the Helen Diller Comprehensive Cancer Center at the University of California, San Francisco.

The results are a bit of surprise, say the authors. That is because earlier studies had suggested that either of the two agents under investigation, particularly nab-paclitaxel, might be more efficacious than standard once-per-week paclitaxel.

"Paclitaxel once per week remains the preferred palliative chemotherapy in this setting," the authors state.

Look Before You Leap

Beyond the clinical findings, an important lesson from the study is that first impressions can be deceiving, the investigators caution. Some oncologists incorporated the newer drugs into clinical practice before solid, level I evidence in the form of randomized, controlled trial results became available.

"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, and support the cooperative group mechanism for assessing both better and less expensive therapies," Dr Rugo and colleagues write.

Kathy D Miller, MD, a breast medical oncologist at Indiana University, in Indianapolis, who was not involved in the study, commented that breast cancer therapy is "a delicate balance" between efficacy and toxicity and that the study offers important reminders that are not unique to the trial.

"First, preclinical data can't adequately model the delicate balance our patients seek. Mice don't complain of fatigue and neuropathy, but both can be limiting to patients. Second, phase 2 trials are just that," she said in an audio commentary that accompanied the study on the Journal of Clinical Oncology website.

Dr Miller explained that previous randomized phase 2 trials comparing paclitaxel to nab-paclitaxel provided justification for conducting CALGB 40502, but "nothing more." Phase 2 trials are prone to error and limitations, she said.

Tubulin Inhibitors

The therapeutic rationale for the trial was that paclitaxel, nab-paclitaxel (a formulation that does not need to be delivered with the solvent Kolliphor EL, as paclitaxel does), and ixabepoline all inhibit cancer cell replication by binding to beta-tubulin.

In a randomized phase 3 trial, nab-paclitaxel at a dose of 260 mg/m2 given once every 3 weeks was associated with higher response rates and longer time to progression than paclitaxel 175 mg/m2, with lower hematologic toxicity but increased peripheral neuropathy.

Ixabepilone has been shown to have superior efficacy in combination with capecitabine (Xeloda, F. Hoffman–LaRoche, Ltd) than capecitabine alone in patients with taxane-resistant metastatic breast cancer and as a single agent against multidrug-resistant disease, Dr Rugo and colleagues note.

In the CALGB 40502 study, 783 patients with advanced breast cancer were randomly assigned to receive once weekly for 3 of 4 weeks each cycle of bevacizumab with either paclitaxel 90 mg/m2 (arm A), nab-paclitaxel 150 mg/m2 (arm B), or ixabepilone 16 mg/m2. Arm A was halted for futility after the first interim analysis, and arm B was stopped after the second interim analysis for the same reason.

After continued follow-up for all patients, the median PFS for paclitaxel was 11 months, compared with 7.4 months for ixabepilone, which met the study criterion for inferiority (hazard ratio [HR] for ixabepilone, 1.59; P < .001). The median PFS for nab-paclitaxel was 9.3 months, clearly not meeting the prespecified criterion for superiority (HR = 1.20; P =.054).

Nab-paclitaxel was associated with significantly more hematologic and nonhematologic toxicities, including peripheral neuropathy, than paclitaxel (P < .001). Ixabepilone had significantly lower hematologic toxicity than paclitaxel (P = .0037) but showed a nonsignificant trend toward higher nonhematologic toxicity.

The study was funded by the National Cancer Institute. Dr Rugo has received honoraria and serving on the speaker's bureau for Genomic Health. Dr Miller has disclosed no relevant financial relationships.

J Clin Oncol. Published online June 8, 2015. Abstract


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