Can we establish a hierarchy among trastuzumab biosimilar candidates?

Abstract

The European patent for intravenous trastuzumab lapsed in 2017, and this stimulated research into a number of trastuzumab biosimilars. Quality assessment of their development and clinical results might enable establishment of a clinical hierarchy of these agents. This editorial will underline the key points for consideration when determining such an evaluation.British Journal of Cancer (2018) 119:263-265; https://doi.org/10.1038/s41416-018-0171-1 MAINThe extraordinary clinical achievements of trastuzumab have made history in the systemic management of breast cancer. Unfortunately, it is not uniformly available for routine use owing to its prohibitively high cost. With financial contingencies following the economic crisis together with rapidly increasing healthcare costs, even the richest countries are exploring ways to reduce their healthcare expenditures. 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.The development of a biosimilar drug requires the collation of extensive pre-clinical comparability studies to demonstrate similar structural, physicochemical, and functional biological characteristics with the referent medical product. 9,10 . PK comparability in animal models is required prior to the first in-human study, and this is usually aimed at demonstrating PK equivalence between the biosimilar candidate and the referent. These steps have already been successfully achieved for PF-05280014.6,7 Treatment with trastuzumab can result in the production of anti-trastuzumab antibodies; therefore, initial phase I trials for PK assessment include healthy male subjects, because they are less likely to require treatment with trastuzumab for breast cancer in the future. 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. 13,14 Therefore, a large randomised study aimed at comparing the activities should also perform a PK assessment in patients receiving iterative administration.A randomised clinical study represents the ultimate step in the path towards drug registration, with the intention of providing evidence for similar efficacy between the biosimilar candidate and the reference medical product in a...

Biologic Drug Quality Assurance to Optimize HER2 + Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3

“…In general, a phase III equivalence design with a pre-specified equivalence margin is recommended to rule out inferiority or superiority of the biosimilar candidate to its reference product in the most sensitive and homogenous patient population possible using practical and sensitive endpoints [ 23 , 25 , 49 ]. A recommended approach for deriving equivalence margins relies on preserving 50‒60% of the reference treatment effect based on major historic studies [ 50 , 51 ].…”

“…Pathological complete response may be assessed as bpCR or tpCR. Although tpCR has a stronger correlation with long-term survival, bpCR avoids confounding factors related to axillary lymph node status and assessment [ 41 , 50 ]. Initial use of a surrogate endpoint like pCR does not obviate the need to assess survival during a longer term follow-up [ 13 , 22 ].…”

Screening and selection strategy for the establishment of biosimilar to trastuzumab-expressing CHO-K1 cell lines

“…The extraordinary achievements of trastuzumab in clinical setting have made history in the systematic treatment of breast cancer. Unfortunately, it is not uniformly available for routine use owing to its prohibitively high cost (Pivot and Petit, 2018). The expiration of the European Union (EU) patent of trastuzumab in 2014, and the last version of US patent in 2019 (Nelson, 2014), has encouraged the development of biosimilars to this antibody (Curigliano et al, 2016).…”

Screening and selection strategy for the establishment of biosimilar to trastuzumab-expressing CHO-K1 cell lines

“…The extraordinary achievements of trastuzumab in clinical setting have made history in the systematic treatment of breast cancer. Unfortunately, it is not uniformly available for routine use owing to its prohibitively high cost (Pivot and Petit 2018). The expiration of the European Union (EU) patent of trastuzumab in 2014, and the last version of US patent in 2019 (Nelson 2014) encouraged the development of biosimilars to this antibody (Curigliano et al 2016).…”