Effect of a Proposed Trastuzumab Biosimilar Compared
With Trastuzumab on Overall Response Rate in Patients
With ERBB2 (HER2)–Positive Metastatic Breast Cancer.
A Randomized Clinical Trial
IMPORTANCE Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab
and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)–positive
metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy.
OBJECTIVE To compare the overall response rate and assess the safety of a proposed
trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior
treatment for ERBB2-positive metastatic breast cancer.
DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized, parallel-group,
phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to
August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or
trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed
by antibody alone until unacceptable toxic effects or disease progression occurred.
INTERVENTIONS Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane.
MAIN OUTCOMES AND MEASURES The primary outcome was week 24 overall response rate
(ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24
with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15% with a 95%
CI for ORR difference. Secondary outcome measures included time to tumor progression,
progression-free and overall survival at week 48, and adverse events.
RESULTS Among 500 women randomized, the intention-to-treat population included 458
women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women.
The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI,
57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference
(5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no
statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor
progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3%
vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI,
−2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233
(94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%),
peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).
CONCLUSIONS AND RELEVANCE Among women with ERBB2-positive metastatic breast cancer
receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab
resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess
safety and long-term clinical outcome.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier:
2011-001965-4