Two Newer Breast Cancer Therapies Not Superior to Standard Paclitaxel, Study Suggests

Hope S. Rugo, MD

The newer and more expensive breast cancer treatments nab-paclitaxel (Abraxane, Celgene) and ixabepilone (Ixempra, Bristol-Myers Squibb), failed to demonstrate superior efficacy versus standard care with weekly paclitaxel, according to the authors of a phase III trial presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting.

The randomized, open-label phase III CALGB 40502/NCCTG N063H study comparing the three therapies was a National Cancer Institute-supported cooperative trial. The researchers randomized the majority (98%) of 799 accrued patients with chemotherapy-naïve, metastatic breast cancer 1:1:1 to 10 mg/kg of bevacizumab (Avastin, Genentech) every 2 weeks plus weekly treatment with either nab-paclitaxel (150 mg/m²), ixabepilone (16 mg/m²), or paclitaxel (90 mg/m²).

The chemotherapy was administered on a 3 weeks on/1 week off cycle to give patients time to recover from toxicities. After six cycles, patients who were stable or had responding disease could discontinue chemotherapy and continue with bevacizumab monotherapy.

Contrary to the authors’ expectations, the data revealed that at these doses and schedules, ixabepilone is significantly inferior to paclitaxel and nab-paclitaxel is not superior to paclitaxel.

At 12 months’ follow-up, progression-free survival was 10.6 months, 9.2 months, and 7.6 months for patients receiving paclitaxel, nab-paclitaxel, and ixabepilone, respectively. The hazard ratios were 1.19 (95% CI, 0.96-1.49; P=.12) with nab-paclitaxel and 1.53 (95% CI, 1.24-1.90; P<.0001) with ixabepilone when comparing the two therapies to paclitaxel. There was no difference in overall survival across the treatment arms.

The safety profiles for the treatment arms were also favorable for paclitaxel. Both nab-paclitaxel (60%) and ixabepilone (56%) had worse incidence rates of non-hematologic malignancies compared to paclitaxel (44%). The incidence rate of hematologic toxicities was worse with nab-paclitaxel (51%), compared to paclitaxel (21%) and ixabepilone (12%).

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Dr. Rugo on Paclitaxel Superiority in Advanced Breast Cancer

As part of the safety analysis, the trial also specifically evaluated peripheral neuropathy as a secondary endpoint. “We saw increased peripheral neuropathy in the experimental arms compared to the control arm,” said lead study author Hope S. Rugo, MD, in a press conference at ASCO. Rugo is professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, California. “We are continuing to follow the impact of peripheral neuropathy on patient assessment and life as part of our substudies in this trial,” Rugo added.

Both Celgene, which manufactures nab-paclitaxel, and Bristol-Myers Squibb, which manufactures ixabepilone, issued statements addressing the study’s results.

An official at Celgene noted that a dose of 150 mg/m² weekly is “significantly higher than the approved dose of nab-paclitaxel.” He said the data generated by the increased dose will factor into future decisions regarding the development of the drug.

He also added, “This study does not impact the body of breast cancer data for nab-paclitaxel monotherapy, which has demonstrated significantly superior efficacy, including an overall survival benefit and an acceptable safety profile in the definitive randomized phase III clinical study [J Clin Oncol. 2005;23(31):7794-7803] of a head-to-head comparison with paclitaxel monotherapy.”

In her statement, the Bristol-Myers Squibb official said, “CALGB 40502/NCCTG N063H, an investigator-sponsored trial, did not use the FDA-approved dose and schedule for Ixempra. The recommended dose of Ixempra is 40 mg/m² every three weeks.”

At the ASCO press session, Rugo specifically addressed questions about the selection of treatment doses in the trial. “The intent of the study was to evaluate doses of the experimental chemotherapy agents that had previously been studied in clinical trials that were suggested to be superior to our standard treatment with paclitaxel,” Rugo said. She added, “What we learned is that paclitaxel at the standard dose we are using is a good drug and it’s as good or better than the two comparators, at least at these doses and given weekly.”

Rugo HS, Barry WT, Moreno-Aspitia A. CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2012;30(suppl; abstr CRA1002).

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