ASCO: Paclitaxel Bests New Drugs in Breast Cancer
By Charles Bankhead, Staff Writer, MedPage Today|
Published: June 04, 2012
· Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
· Patients with metastatic breast cancer did just as well -- and maybe better -- with paclitaxel-based chemotherapy compared with two newer and more expensive agents: nanoparticle albumin-bound paclitaxel (nab-paclitaxel or Abraxane) and ixabepilone (Ixempra), all combined with bevacizumab (Avastin).
· Note that patients who received paclitaxel also had less peripheral neuropathy than with either of the other drugs, and less hematologic toxicity than those who received nab-paclitaxel.
CHICAGO -- Patients with metastatic breast cancer did just as well -- and maybe better -- with paclitaxel-based chemotherapy compared with two newer, more expensive agents, results of a randomized trial showed.
First-line treatment with weekly paclitaxel and bevacizumab (Avastin) resulted in a median progression-free survival (PFS) of 10.6 months compared with 9.2 months with nanoparticle albumin-bound paclitaxel (nab-paclitaxel or Abraxane) and 7.6 months with ixabepilone (Ixempra), each paired with bevacizumab.
The ixabepilone arm had significantly worse PFS at an interim analysis and was dropped from the trial.
Patients who received paclitaxel also had less peripheral neuropathy than with either of the other drugs, and less hematologic toxicity than those who received nab-paclitaxel, Hope Rugo, MD, reported here at the American Society of Clinical Oncology meeting.
"Neither weekly nab-paclitaxel nor ixabepilone is superior to weekly paclitaxel," Rugo, of the University of California San Francisco, said during an ASCO press briefing. "Weekly paclitaxel appears to offer better progression-free survival than ixabepilone."
"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," she added.
During the discussion that followed her presentation, Rugo described cost issues surrounding cancer therapies as "enormously complicated," but said that generic drugs such as paclitaxel will always be less expensive than newer drugs that are not available as generics.
Funded by the National Cancer Institute (NCI), the trial came about as a result of recent developments in the treatment of metastatic breast cancer.
Weekly paclitaxel demonstrated superiority over a 3-week dosing schedule. Ixabepilone has shown evidence of activity in metastatic breast cancer that has developed resistance to microtubule inhibitors, which include paclitaxel. Additionally, nab-paclitaxel has shown promise as therapy for metastatic beast cancer.
The drugs were paired with bevacizumab as a result of findings from a trial that showed a PFS benefit in metastatic breast cancer when added to conventional chemotherapy. The three-arm, NCI-sponsored trial began enrolling patients before the FDA revoked bevacizumab's conditional approval for metastatic breast cancer, Rugo said.
Investigators randomized patients with metastatic breast cancer and no prior chemotherapy to weekly paclitaxel, nab-paclitaxel, or ixabepilone, all at standard doses, plus bevacizumab. The primary endpoint was PFS, defined as the time from randomization to disease progression or death from any cause.
Bevacizumab became optional in March 2011, following the FDA decision, but 98% of all patients included in the primary analysis received bevacizumab, according to Rugo.
The trial had an accrual target of 900 patients, but ended early with a total accrual of 799 patients. A futility analysis in June 2011 showed that patients in the ixabepilone arm had significantly worse PFS compared with the paclitaxel arm, and accrual to that arm stopped.
A second futility analysis in November 2011 showed that the nab-paclitaxel arm had met its futility threshold versus paclitaxel, and all patient accrual ended. The trial had an accrual target of 900 patients and ended with 799 patients. Median follow-up of all surviving patients with was 12 months.
The primary analysis showed that the ixabepilone arm had a 53% increased risk of progression versus paclitaxel (P<0.0001). The nab-paclitaxel arm had a 19% greater risk of progression compared with paclitaxel, but the difference did not achieve statistical significance.
Examination of adverse events showed that 21% of patients in the paclitaxel arm had grade 3-plus hematologic toxicity, 51% of patients in the nab-paclitaxel group (P<0.0001 versus paclitaxel), and 12% in the ixabepilone arm (P=0.004 versus paclitaxel).
Grade 3-plus nonhematologic toxicity occurred in 60% of nab-paclitaxel patients (P=0.0002), 56% of ixabepilone-treated patients (P=0.005), and 44% of the paclitaxel arm.
During the discussion, Rugo said the study is the first direct comparison of paclitaxel and nab-paclitaxel in patients with previously untreated metastatic breast cancer. In an earlier study involving previously treated patients, nab-paclitaxel demonstrated a PFS advantage over paclitaxel.
This trial had been "flying under the radar," commented Lisle M. Nabell, MD, of the University of Alabama at Birmingham. However, the implications might reverberate throughout the field of breast cancer.
"I actually think this could be a practice changer," Nabell, who was not involved in the study, told MedPage Today. "Many of us have been using nab-paclitaxel in the metastatic setting as a go-to regimen. In fact, it didn't quite hold up, and its toxicity profile was slightly worse."
"This study will [quietly] make a big splash in terms of how we practice medicine," she said. "Doctors are going to look at this study and see that patients treated with paclitaxel did as well or better than the other two groups, and then they're going to look at the toxicity and the cost, both of which favor paclitaxel."
"And it's going to look like a clear win for paclitaxel," Nabell added.
The increased toxicity seen with nab-paclitaxel was associated with a 150 mg/m2 weekly dose, which is higher than the approved dose for the agent, officials representing drug distributor Celgene said in a statement. The information provides guidance that will be useful in future clinical development of nab-paclitaxel in metastatic breast cancer.
"However, 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 of a head-to-head comparison with paclitaxel monotherapy," the officials added.
The statement referenced a publication related to the phase III trial, whose authors concluded that nab-paclitaxel "demonstrated greater efficacy and a favorable safety profile compared with standard paclitaxel in this patient population (J Clin Oncol 2005; 23:7794-7803)."
The earlier trial differed from the three-arm trial in several respects, Rugo said during the press briefing in response to a question about the previously reported favorable results.
In particular, the earlier trial used the every-3-weeks cycle of paclitaxel, which has been shown to be inferior to the weekly regimen she and her colleagues used. Additionally, she said, the study population included previously treated patients and patients who had received paclitaxel in the adjuvant setting. In contrast, the three-arm trial limited enrollment to patients with previously untreated metastatic breast cancer.
The study was supported by the National Cancer Institute.
Rugo disclosed relationships with Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb. Co-investigators disclosed relationships with Bristol-Myers Squibb, Celgene, and Genentech/Roche.
Nabell had no relevant conflicts of interest.
Primary source: American Society of Clinical Oncology
Rugo HS, et al. "CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel, compared to weekly nanoparticle albumin bound nab-paclitaxel, or ixabepilone with or without bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer" ASCO 2012; Abstract CRA1002.