Study Reveals Best of Three Schedules of Nab-paclitaxel/Bevacizumab in Metastatic Breast Cancer
In a phase II study evaluating three dosing regimens of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) given with bevacizumab (Avastin), weekly dosing of nab-paclitaxel resulted in the highest overall response rate and longest progression-free survival. The schedule of nab-paclitaxel given every 2 weeks was not feasible due to high rates of toxicity, investigators found. The study, led by Andrew D. Seidman, MD, of Memorial Sloan-Kettering Cancer Center, New York, was published in Clinical Breast Cancer.
Compared with solvent-based paclitaxel at 175 mg/m2 given every 3 weeks, nab-paclitaxel at 260 mg/m2 every 3 weeks has produced significantly higher overall response rates and time to tumor progression, Dr. Seidman noted for background. Efforts to optimize clinical outcomes with nab-paclitaxel for metastatic breast cancer have focused on different schedules and doses. Bevacizumab was included in the regimen, based on previous trials in which it prolonged progression-free survival when given with taxanes and on preclinical data showing unique antiangiogenic synergy when paired with nab-paclitaxel.
Motivated by these observations, Dr. Seidman and colleagues performed a randomized phase II trial that compared nab-paclitaxel plus bevacizumab given every 3 weeks, every 2 weeks, or weekly as first-line chemotherapy for metastatic breast cancer. The aim was “to optimize this doublet for a future randomized phase III comparison in the metastatic setting and possibly the adjuvant setting,” he said.
Study Details
The study randomly assigned 212 patients with previously untreated metastatic breast cancer to receive nab-paclitaxel at 260 mg/m2 every 3 weeks plus bevacizumab at 15 mg/kg every 3 weeks (arm A), nab-paclitaxel at 260 mg/m2 every 2 weeks plus bevacizumab at 10 mg/kg every 2 weeks with prophylactic filgrastim (Neupogen) or pegfilgrastim (Neulasta) (arm B), or nab-paclitaxel at 130 mg/m2 weekly uninterrupted plus bevacizumab at 10 mg/kg every 2 weeks (arm C). Both drugs were continued until disease progression or limiting toxicity. The primary endpoints were overall response rate and toxicity. Time to tumor progression and overall survival were secondary endpoints.
Arm B was closed early due to toxicity, primarily fatigue and bone pain. Neurotoxicity grade ≥ 2 was equivalent across the arms (> 50%) and reversible for most patients. Peripheral neuropathy was common and treatment-limiting, which resulted in protocol withdrawal in 19%, 43%, and 27% of patients in arms A, B, and C, respectively, though neuropathy was reversible in the vast majority of the patients. Febrile neutropenia occurred in ≤ 3% of patients in all arms.
All Regimens Active, but Toxicity Not Equal
Significant antitumor activity was observed in all study arms. The response rate was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median time to progression was slightly longer in arm C (9.0 months) vs arms A (8.0 months) and B (5.8 months) (overall, P = .105). Median progression-free survival for arms A, B, and C was 7.7, 5.8, and 8.8 months, respectively (P = .537 for arm A vs arm C). Median overall survival for arms A, B, and C was 21.3, 19, and 23.7 months (P = .650 for arm A vs arm C).
Weekly nab-paclitaxel with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment-limiting, which suggests that a schedule of 3 weeks on and 1 week off should be explored, the investigators concluded.
“Regardless of administration schedule, nab-paclitaxel with bevacizumab is an active regimen as first-line therapy in HER2-negative metastatic breast cancer. Although there were no statistically significant differences in response rates (the primary endpoint) or time to progression between arm A and arm C, statistically nonsignificant trends in these endpoints appear to favor weekly dosing, a finding consistent with prior published experience with nab-paclitaxel and solvent-based paclitaxel,” the authors noted in the study.
“Taken together with prior published clinical experience for weekly nab-paclitaxel, the use of a qw 3/4 schedule [the first 3 of 4 weeks], with or without bevacizumab, may be preferable to uninterrupted weekly dosing to mitigate treatment-limiting neuropathy. Furthermore, weekly nab-paclitaxel has served as a feasible foundation on which gemcitabine or capecitabine [Xeloda] could be added for patients deemed appropriate for combination chemotherapy for metastatic breast cancer,” the authors concluded.
Expert Perspective
“This study was initiated at a moment where a strong signal for benefit was observed when bevacizumab was added to weekly Cremophor-EL–based paclitaxel in ECOG 2100. Our study demonstrated similar efficacy for weekly nab-paclitaxel as first-line chemotherapy for metastatic breast cancer, without the need for prophylactic antiallergy premedication,” Dr. Seidman said in an interview with The ASCO Post.
“The every-3-week arm was less promising, and the every-2-week regimen using the conventional every-3-weekly dose (with pegfilgrastim) was prohibitively toxic,” he added. “Our results suggest that a weekly 3-on/1-off nab-paclitaxel schedule may be preferable, due to limiting peripheral neuropathy.”
Results of the ongoing Meridian trial, which recapitulates E2100 with a focus on defining a biomarker-enriched subset who might benefit most from bevacizumab, should inform the potential future application of weekly paclitaxel and bevacizumab for metastatic breast cancer, he added.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
