CHICAGO—Newer is not always better. Patients with metastatic breast cancer had equivalent—and in some cases superior—-outcomes when treated with paclitaxel-based chemotherapy than when given two newer, more expensive agents, according to results of a Phase III randomized trial reported here at the ASCO Annual Meeting (Abstract CRA1002).
In the NCI-sponsored trial of patients with chemotherapy-naïve advanced breast cancer receiving bevacizumab, neither weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) nor ixabepilone were superior to weekly paclitaxel, reported Hope S. Rugo, MD, Clinical Professor in the Department of Medicine (Hematology/Oncology) and Director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, Comprehensive Cancer Center.
Moreover, “weekly paclitaxel appears to offer better progression-free survival than ixabepilone,” and said patients who received paclitaxel had less peripheral neuropathy than those in either of the experimental arms and less hematologic toxicity than those who received nab-paclitaxel. The data suggest that similar patients could be appropriately treated with weekly paclitaxel.”
Rugo said there is still a role for nab-paclitaxel in treating certain patients, but that its use will likely be diminished.
Better Outcomes Expected
About 20 to 30 percent of patients with early-stage disease will relapse and develop metastatic cancer, and about five to 10 percent of cases are diagnosed with metastatic disease at first presentation, she noted.
The study was designed with the hypothesis that adding a newer agent to standard of care would improve outcomes, she said, adding that several studies contributed to the design of the current cooperative group trial. A weekly schedule of paclitaxel was chosen because it has demonstrated clear superiority over a three-week dosing schedule in terms of response rate and time to progression (Seidman et al:JCO 2008;26:1642–1649).
In Phase II trials, ixabepilone demonstrated activity in metastatic breast cancer with resistance to taxane (Thomas et al:JCO 2007;25:3399–3406). And nab-paclitaxel has been shown to be effective in the treatment of metastatic breast cancer (Gradishar et al:JCO 2009;27:3611–3619).
Finally, a Phase III trial showed that paclitaxel plus bevacizumab prolongs progression-free survival times, compared with paclitaxel alone (Miller et al:NEJM 2007;357:2666–2676).
The current trial began enrolling patients in November 2008, before the FDA rescinded bevacizumab's conditional approval for metastatic breast cancer, Rugo explained. A total of 98 percent of patients in the primary analysis received the drug.
In the three-arm trial, patients with metastatic breast cancer and no prior chemotherapy were randomized to receive weekly paclitaxel at 90 mg/m2, nab-paclitaxel at 150 mg/m2, or ixabepilone at 16 mg/m2, plus bevacizumab. The primary endpoint was progression-free survival, defined as the time from randomization to disease progression or death from any cause.
In June 2011, a futility analysis demonstrated that progression-free survival times were significantly worse in the ixabepilone arm compared with the paclitaxel arm. Accrual to that arm stopped, and the trial became a two-arm study.
In November 2011, a second futility analysis showed no advantage to administration of nab-paclitaxel compared with paclitaxel. Enrollment was terminated, with 799 of 900 planned patients accrued.
The median follow-up time for all surviving patients was 12 months.
In the primary analysis, patients given ixabepilone were 53 percent more likely to have disease progression, compared with those on paclitaxel, a highly significant difference, she said. Patients taking nab-paclitaxel had a 19 percent greater risk of progression compared with those on paclitaxel, but the difference did not achieve statistical significance.
The median progression-free survival time was 10.6 months for the 283 patients on paclitaxel, 9.2 months for the 271 patients on nab-paclitaxel, and 7.6 months for the 245 patients on ixabepilone.
As for adverse events, 51 percent of patients in the nab-paclitaxel arm experienced Grade 3 or higher hematologic toxicity, compared with 21 percent in the paclitaxel arm and 12 percent in the ixabepilone arm. Grade 3 or higher nonhematologic toxicity occurred in 60 percent of patients taking nab-paclitaxel, 56 percent on ixabepilone, and 44 percent of patients in the paclitaxel arm.
Rugo noted that there was a significant increase in peripheral neuropathy—a secondary safety endpoint—in the experimental arms.
During the question-and-answer period that followed the presentation, she said that costs could not easily be broken down. Still, she added, generic drugs such as paclitaxel will always be less expensive than newer drugs that have not gone off patent.
Rugo also noted that the trial offers the first direct comparison of paclitaxel and nab-paclitaxel in patients with chemotherapy-naïve metastatic breast cancer. In a Phase III trial of previously treated patients, nab-paclitaxel was associated with a longer time to disease progression than paclitaxel was (Gradishar et alJCO 2005;23:7794–7803).
There were several other differences between the two trials, she noted during a news briefing. In the earlier study, the drugs were administered every three weeks—a regimen that has been demonstrated to be inferior to weekly cycles of paclitaxel. Additionally, the drugs could be given as first-, second-, or third-line metastatic breast cancer treatment in the earlier study.
Asked which populations are appropriate for nab-paclitaxel treatment after this trial, Rugo said “there is very good evidence” that the drug can be safely given to previously treated patients and patients who cannot tolerate paclitaxel.
Additionally, nab-paclitaxel should be used if paclitaxel is not available, she said, noting that smaller centers with few suppliers have experienced a shortage.
She also noted that the 150 mg/m2 weekly dose given in the study is higher than the approved dose: “We should be using a 100 mg/m2 dose. It's effective and less toxic,” she said.
“The effect of this study will be to cut the use of nab-paclitaxel. It is not superior to paclitaxel, and it is clearly more toxic. It is not worth [the cost] to use it first-line unless the patient is intolerant to steroids. But if a patient's breast cancer recurs within a year of getting paclitaxel, nab-paclitaxel may have efficacy. Currently nab-paclitaxel is used in about a third of metastatic breast cancer patients. [After this trial], about 25 percent of patients will probably still continue to get it.”
Kimberly L. Blackwell, MD, Professor of Medicine (Oncology) at Duke University Medical Center, said some patients may prefer nab-paclitaxel because steroids are not needed to avoid an allergic reaction, as is the case with paclitaxel. Steroids have their own risks and add an hour to each treatment, she noted.
Thehang H. Luu, MD, Clinical Assistant Professor of Medical Oncology at City of Hope, said, “There will always be a role for nab-paclitaxel in people who are allergic to cremophor [a component of paclitaxel]. Abraxane [nab-paclitaxel] won't go away, but use will go down. Fewer than five percent of people are allergic to cremophor, but 10 to 15 percent more are diabetic or have other complications that preclude use of cremophor.”
And the Chair of ASCO's Cancer Communications Committee, Nicholas G. Vogelzang, MD, Medical Director of the Developmental Therapeutics Committee at Comprehensive Cancer Care Centers of Nevada, said, “All of these agents are clearly active. I want all three of these on my team when I treat breast cancer. We want nab-paclitaxel to continue to be available because we know what it is like not to have enough tools in the real world. Having options allows you to tailor treatment to individual patients.”
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Both Celgene, which manufactures nab-paclitaxel, and Bristol-Myers Squibb, which manufactures ixabepilone, issued statements addressing the study.
Celgene reiterated Dr. Rugo's point that the dose of 150 mg/m2 weekly used in the study is significantly higher than the approved dose of nab-paclitaxel: “The data presented at ASCO does 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 III clinical study that was the basis for nab-paclitaxel approvals in more than 40 countries for the treatment of metastatic breast cancer,” the statement reads. It refers to the pivotal trial comparing paclitaxel and nab-paclitaxel in patients with chemotherapy-naïve metastatic breast cancer (Gradishar et al:JCO 2005;23:7794–7803).
The Bristol-Myers Squibb statement also addressed a dosing issue, pointing out that the trial did not use the FDA-approved dose and schedule of 40 mg/m2 of ixabepilone every three weeks.© 2012 Lippincott Williams & Wilkins, Inc.
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