Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)–Positive Metastatic Breast Cancer

Abstract

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.

Can we establish a hierarchy among trastuzumab biosimilar candidates?

“…In 2017, the patent for intravenous trastuzumab (Herceptin) expired across Europe, which stimulated the development of numerous trastuzumab biosimilar agents (Table 1). [1][2][3][4][5] In this issue of the British Journal of Cancer, Lammers et al report evidence establishing another step towards the registration of PF-05280014, a trastuzumab biosimilar candidate developed by Pfizer. 1,[6][7][8] This significant trial has provided clinical efficacy results of this candidate in patients with early breast cancer, and insight into its pharmacokinetic (PK) non-inferiority.…”

“…Variable margins of equivalence using different ranges of confidence were prespecified to define equivalence (Table 1). [1][2][3][4][5] This variability reflects the difficulty in reaching a consensus on the acceptable and/or reasonable difference in efficacy of a biosimilar compound.…”

“…Variable margins of equivalence using different ranges of confidence were prespecified to define equivalence (Table 1). [1][2][3][4][5] This variability reflects the difficulty in reaching a consensus on the acceptable and/or reasonable difference in efficacy of a biosimilar compound.The second parameter of interest to consider is the population studied and the endpoint criterion used to claim equivalence. According to guidelines, clinical trials should be carried out on a sensitive and homogenous patient population, using endpoints that will; most easily detect differences between the biosimilar and the reference product.…”

“…20 If a hierarchy based on clinical assessment could be developed for trastuzumab biosimilar candidates, then the agents with a favourable clinical assessment using pCR after neoadjuvant therapy might appear at the top of such classification (Table 1). [1][2][3][4][5] A single clinical study, in either the metastatic or the neoadjuvant setting, is usually sufficient to prove the equivalent efficacy of a biosimilar drug. CPT-6 was previously assessed in studies using both settings, but this was due to small changes in the production process that required duplication of all the comparability exercises .…”

Biosimilars in oncology and inflammatory diseases: current and future considerations for clinicians in Latin America

“…106 In December 2017, MYL-1401O became the first trastuzumab biosimilar to be licensed by the US FDA, as trastuzumab-dkst 107 ; the evidence supporting biosimilarity included a comparative study carried out in the metastatic breast cancer setting. 108 Later that month, MYL-1401O was approved in Brazil, where it will be commercialized by local pharmaceutical company Libbs Farmaceutica. 109 Although the product will initially be supplied to Libbs by the manufacturer Biocon, over time the technology will be transferred to Libbs and public partner Butantan, enabling domestic production.…”