Hope S. Rugo, MD, discusses findings of the CALGB 40502/NCCTG N063H study, which was a randomized phase III trial of paclitaxel compared with nab-paclitaxel or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer.
Hope S. Rugo, MD
In long-term findings of a recent randomized phase III study, nab-paclitaxel (Abraxane) demonstrated improvements in overall survival (OS) and progression-free survival (PFS) compared with paclitaxel for patients with triple-negative breast cancer (TNBC).
Of the 201 patients with TNBC enrolled on the trial, the median OS with nab-paclitaxel was 21.0 months compared with 15.3 months with standard paclitaxel, representing a 26% reduction in the risk of death (HR, 0.74; 95% CI, 0.51-1.07).
A total of 799 patients were enrolled in the CALGB 40502/NCCTGN063H trial and received paclitaxel (n = 283), nab-paclitaxel (n = 271), or ixabepilone (Ixempra) (n = 245). Most patients on the trial also received concurrent bevacizumab (Avastin), which at the time was the standard of care in the first-line setting. Nab-paclitaxel was given at a higher-than-approved dose of 150 mg/m2weekly. Paclitaxel was administered at 90 mg/m2and ixabepilone was administered at 16 mg/m2weekly.
“For hormone receptorpositive (HR+) disease, paclitaxel remains the gold standard. For TNBC, which is more resistant, I would consider nab-paclitaxel as a first option in the first-line metastatic setting…,” said lead investigator Hope S. Rugo, MD, a medical oncologist and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.
In an interview withTargeted Oncologyat the 2017 San Antonio Breast Cancer Symposium (SABCS), Rugo discussed the implications of these findings and the importance of individualizing doses of nab-paclitaxel for each patient.
TARGETED ONCOLOGY: Can you provide an overview of the design of theCALGB 40502/NCCTG N063H study?
Rugo: This is a trial that we started quite a long time ago, and it was designed to evaluate the relative efficacy of novel microtubule inhibitors given in a weekly schedule, compared to the standard of care, which was paclitaxel. At the time, bevacizumab was the standard of care as first-line therapy for metastatic HER2-negative breast cancer, based on the results of ECOG 2100. Our control arm was weekly paclitaxel at 90 mg/m2with bevacizumab, 3 weeks on, 1 week off. If patients had responding or stable disease after 6 cycles of 4 weeks per cycle, they could stop the chemotherapy and continue on with bevacizumab alone.
One of our experimental arms was weekly ixabepilone, which had been approved based on efficacy in taxane-resistant disease, as well as superiority in combination with capecitabine (Xeloda). However, it was given every 3 weeks and was quite toxic. We were evaluating weekly therapy at the same dose16 mg/m2. The second experimental arm was nab-paclitaxel. A randomized phase II trial conducted in Russia and published by William Gradishar, MD, had shown improved efficacy with 150 mg/m2, compared to paclitaxel, every 3-week paclitaxel, and docetaxel (Taxotere). The idea was that we would study that dose. In our study, each experimental arm was compared to the control, rather than to each other.
We planned to enroll 900 patients with a primary endpoint of PFS, but we had interim analyses for futility. At the first interim analysis, the ixabepilone arm was closed for futility, and at the second interim analysis, the entire study was closed due to futility.
TARGETED ONCOLOGY: What were the results of this study?
Rugo: As one would expect, the first time we presented our data at SABCS in 2013, and when it was published in theJournal of Clinical Oncologyin 2015, we showed that neither arm was superior to paclitaxel, and that the nab-paclitaxel arm, in particular, was associated with increased hematologic and non-hematologic toxicity, including both motor and sensory neuropathy. We don’t usually see much motor neuropathy. We also found that the ixabepilone arm was inferior for PFS, and that neither arm showed any difference in OS.
We had an additional 4 years of median follow-up time. We looked at the overall results, which continued to show the inferiority of the ixabepilone arm for PFS, and also now for OS. We also showed similar results for PFS and OS with nab-paclitaxelthere was no superiority, and numerically it was only a little bit less.
TARGETED ONCOLOGY: Was a difference seen in the subset analysis?
Rugo: We also looked at the subsets based on hormone receptor statusHR+, HER2-negative, or TNBC. What we found was a significant test for interaction between nab-paclitaxel and paclitaxel for hormone receptor status, and no significant interaction for ixabepilone for both PFS and OS.
When we looked at the specifics of the subset analysis, we found a trend toward superiority of nab-paclitaxel compared to paclitaxel in the TNBC group only. In the HR+ group, which was a larger group where we have more power to detect significance, we found that both nab-paclitaxel and ixabepilone trended toward being inferior to the paclitaxel arm. The same was true for OS where ixabepilone was inferior, and nab-paclitaxel was trending toward inferiority for OS in the HR+ subset, but was numerically quite superior for PFS in the TNBC group, at 21 months versus 15 months, which was quite intriguing. We continued to show that there were more dose reductions and dose discontinuations for the nab-paclitaxel arm, which was concordant with the increased toxicity.
This was all in the light of the GeparSepto data, which showed that nab-paclitaxel, which they dose-reduced from 150 mg/m2to 125 mg/m2, was superior for event-free survival in both TNBC and HR+ disease. In terms of PFS, we saw a trend toward a differential benefit in TNBC versus HR+ disease. It may be that in disease that has previously seen a taxane and is highly resistant, like TNBC, that there is some advantage to nab-paclitaxel, or that there was an advantage of dose intensity.
I think the take-home message from this is that in certain settings, there might be an advantage for nab-paclitaxel versus paclitaxel, but we don’t know exactly what they are. For HR+ disease, paclitaxel remains the gold standard. For TNBC, which is more resistant, I would consider nab-paclitaxel as a first option in the first-line metastatic setting, keeping in mind that 150 mg/m2should not ever be the dose, because it’s associated with too much toxicity. The highest dose that should be considered is 125 mg. Even at that dose, there was an 8% rate of peripheral neuropathy in the grade 3 range in the GeparSepto study, which is always a difficult toxicity for the patients. As always, we need to balance toxicity versus benefit. At the moment, we don’t have any specific setting where it would be incorrect to give paclitaxel as your first treatment option.
TARGETED ONCOLOGY: How can the results of the GeparSepto trial impact the development of treatment strategies going forward?
Rugo: It’s quite an interesting dataset. They previously published that they were able to markedly reduce the rate of grade 3 or greater peripheral neuropathy by reducing the dose of nab-paclitaxel from 150 mg/m2to 125 mg/m2, but some of the peripheral neuropathy doesn't go away. Even at 3 years, there is persistent peripheral neuropathy, so it's still a big consideration. When they looked at the efficacy with pathologic complete response, it was identical whether they used 150 mg or 125 mg, and more patients actually completed the therapy, which is important.
This has important implications for practice, which is that the higher doses of nab-paclitaxel are associated with more toxicity, and the toxicity isn't always transient, it can be permanent. The dose of 150 mg is not an acceptable dose in any setting. A dose of 125 mg could be used, but you have to keep in mind that it is associated with more toxicity. This is a big quality-of-life issue and we don't actually know if 100 mg/m2, which is much better tolerated, is adequate. It has to be individualized for each patient. Even with the data presented from GeparSepto at this meeting with improved event-free survival, I think we have to be cautious with using the higher doses of nab-paclitaxel in these settings and really individualize treatment for the specific patient. It's certainly not the standard of care at the present time.