A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer
S. M. Tolaney
J. Najita
1
J. Sperinde
0
W. Huang
4
W. Y. Chen
3
J. Savoie
M. Fornier
2
E. P. Winer
C. Bunnell
I. E. Krop
0
Research and Development
1
Biostatistics and Computational Biology, Dana-Farber Cancer Institute
,
Boston
;
Departments of
2
Department of Medicine, Memorial Sloan-Kettering Cancer Center
,
New York, USA
3
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital
,
Boston
4
Clinical Research, Monogram Biosciences
, Inc., South San Francisco
Background: A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Patients and methods: Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1-2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m2 as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored. Results: Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatmentrelated toxic effects included neuropathy (grade 2, 56%), leukopenia (grade 2, 26%), myalgias (grade 2, 21%), neutropenia (grade 2, 23%), and anemia (grade 2, 18%). Conclusions: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.
-
introduction
Trastuzumab, a humanized monoclonal antibody directed
against the extracellular domain of HER2, is a critical
component of treatment of HER2-positive breast cancer. Its
use in combination with chemotherapy, particularly with
taxanes, is well established and results in an improvement in
progression-free survival (PFS) and overall survival [1, 2].
However, many patients have tumors that fail to respond to
these agents, and nearly all patients with metastatic breast
cancer will eventually progress [3]. Novel therapies for
metastatic breast cancer are therefore needed.
The epothilones are a new class of antineoplastic agents that
act by disrupting microtubule function [4, 5]. These agents
bind to -tubulin subunits and inhibit microtubule
depolymerization, leading to mitotic arrest and apoptosis [6, 7].
Ixabepilone (BMS-247550, aza-epothilone B), a semi-synthetic
analog of epothilone B, has demonstrated efficacy as
These authors contributed equally to this work.
monotherapy or in combination with capecitabine in
anthracycline- and taxane-pretreated metastatic breast cancers
and has recently been approved for use in refractory breast
cancer [8].
Several clinical trials have explored the efficacy of
ixabepilone. Ixabepilone as a single agent was investigated in a
phase II study in 126 patients with metastatic breast cancer
resistant to an anthracycline, taxane, and capecitabine [9].
Patients received ixabepilone 40 mg/m2 every 3 weeks and the
objective response rate (ORR) was 11.5%, with an additional
50% of patients with stable disease. In a phase III study, 1221
women with anthracycline-pretreated or resistant and
taxaneresistant locally advanced or metastatic breast cancer were
randomized to ixabepilone (40 mg/m2 every 3 weeks) in
combination with capecitabine (2000 mg/m2 daily for 2 weeks,
followed by 1 week off ) or to capecitabine (2500 mg/m2 given
in the same schedule) alone [10]. In this study, ixabepilone
capecitabine was found to prolong PFS compared with
capecitabine alone (5.8 versus 4.2 months, P = 0.003). These
studies led to the FDA approval of ixabepilone, in combination
with capecitabine, for the treatment of patients with metastatic
or locally advanced breast cancer after failure of an
anthracycline and a taxane and as monotherapy for the
treatment of patients with metastatic or locally advanced breast
cancer after failure of an anthracycline, taxane, and
capecitabine.
Because trastuzumab has demonstrated synergistic activity in
combination with several microtubule-stabilizing agents, we
designed this trial to explore the safety and efficacy of
ixabepilone in combination with trastuzumab. A preliminary
analysis to identify tumor biomarkers that may predict
sensitivity to trastuzumab was also performed.
patients and methods
Patients 18 years of age with measurable metastatic HER2-positive breast
cancer were eligible. HER2 positivity was defined as 3+ positive for HER2
overexpression by immunohistochemistry (IHC) or amplified by
fluorescence in situ hybridization (FISH) (FISH/CEP17 2.0) by local
review. Two cohorts of patients were eligible. Patients in cohort 1 could not
have received prior chemoth (...truncated)