Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer

Abstract

Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2-positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.

Can we establish a hierarchy among trastuzumab biosimilar candidates?

“…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 .…”

“…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.…”

“…Notably, several previous studies have validated the absence of observable discrepancies in PK profiles for trastuzumab between healthy volunteers and patients. 2,4,11,12 Iterative drug administration causes an accumulation of plasma drug levels, thus resulting in an increase of the average AUC (0-t) . For trastuzumab exposure, large variability in the AUC (0-t) is observed up to cycle 5, beyond which the values become stable and homogeneous over time.…”

“…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.…”