The arrival of biosimilar monoclonal antibodies in oncology: clinical studies for trastuzumab biosimilars

www.nature.com/bjc REVIEW ARTICLE The arrival of biosimilar monoclonal antibodies in oncology: clinical studies for trastuzumab biosimilars Liese Barbier 1 , Paul Declerck1, Steven Simoens 1 , Patrick Neven2, Arnold G. Vulto3 and Isabelle Huys1 The monoclonal antibody trastuzumab (Herceptin®), which targets the human epidermal growth factor receptor 2 (HER2), is approved for the treatment of early breast and advanced breast and gastric cancer in which HER2 is overexpressed. Several biosimilar versions of trastuzumab are expected to enter the European market over the course of 2018 and 2019. The biosimilar development pathway consists of a comprehensive comparability exercise between the biosimilar candidate and the reference product, primarily focussing on data from analytical studies. Clinical studies for biosimilar candidates follow a different design to those for a new biological, as the aim is not to independently establish clinical benefit, but to confirm biosimilarity between the two agents. The different trastuzumab biosimilar candidates have followed diverse pathways in their clinical development, with differences in clinical trial design (equivalence or non-inferiority design), patient population (those with metastatic or early breast cancer) and endpoint (overall response rate or pathological complete response). These differences in approach in phase 3 testing must be viewed in the totality of evidence demonstrating biosimilarity. Adequate information on the biosimilar approval pathway, the nature of the biosimilarity exercise and how the clinical development of a biosimilar is tailored to meet the licensing requirements can help informed decision making in clinical practice. British Journal of Cancer (2019) 121:199–210; https://doi.org/10.1038/s41416-019-0480-z BACKGROUND Biological medicines, and anticancer biological medicines in particular,1 represent a growing financial burden on healthcare budgets. The loss of exclusivity rights on original biological medicines has allowed biosimilar medicines to enter the market. Biosimilars offer cost-effective treatment options that can help contain the rising healthcare expenditure. The European Medicines Agency (EMA) defines a biosimilar as ‘a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product in the European Economic Area’.2 Owing to the intrinsic variability that is inherent to all biological medicines, and the complex manufacturing process of these products, a biosimilar cannot be considered an identical copy of the originally approved biological product (the reference product or originator).3,4 Minor differences can exist between the biosimilar and the reference product, but it needs to be demonstrated that these differences are not clinically meaningful.2,3 ‘Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established’.2 Table 1 provides an overview of the difference between biosimilars and copies of originally approved smallmolecule medicines, called generics. Regulatory authorities such as the EMA and the United States Food and Drug Administration (FDA) have developed a regulatory approval pathway for biosimilars.2,3 Since the authorisation of the first biosimilar in 2006 in Europe, >40 biosimilars have received a positive opinion from the EMA and been subsequently authorised by the European Commission (EC).5 Since 2015, the FDA has approved over 10 biosimilars.6 The number of approved biosimilars will grow substantially in future years, accompanied by an increasing loss of exclusivity of biological reference products, especially in oncology.7,8 By providing more-affordable treatment options and introducing price competition to the market, biosimilar medicines can generate significant savings. The cumulative savings between 2016 and 2020 in the EU5 and the USA are estimated to range between 49 and 98 billion Euros.7 Savings derived from biosimilar market entry can relieve burdened healthcare budgets and open up budgetary room for new treatment options. Furthermore, biosimilar entry can increase patient access to biological therapies.7,9 Biosimilars have been integrated in cancer care for over a decade, as the first biosimilars of epoetin and filgrastim were authorised by the EMA in 2007 and 2008, respectively.5 The number of biosimilars available in oncology is likely to increase rapidly, with the therapeutic focus shifting from supportive care for chemotherapy to targeted, potentially life-prolonging or curative monoclonal antibodies (mAbs). The first mAb biosimilar versions in oncology, of rituximab, were approved by the EMA in 2017 (Blitzima®, Ritemvia®, Rituzena®, Truxima® by Celltrion Healthcare Hungary Kft and Rixathon®, Riximyo® by Sandoz GmbH).5 The mAb trastuzumab (developed by Genentech, marketed by Roche as Herceptin®) targets the human epidermal growth factor receptor 2 (HER2), and is approved for the treatment of early breast and advanced breast and gastric cancer in which HER2 is overexpressed (HER2+).10 HER2+ breast cancer accounts for 1 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Department of Oncology, UZ Leuven, Leuven, Belgium and 3Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands Correspondence: Liese Barbier () These authors contributed equally: Arnold G. Vulto, Isabelle Huys Received: 13 May 2018 Revised: 11 April 2019 Accepted: 24 April 2019 Published online: 1 July 2019 © The Author(s) 2019 Published by Springer Nature on behalf of Cancer Research UK The arrival of biosimilar monoclonal antibodies in oncology L Barbier et al. 200 Table 1. The difference between biosimilars and generics A generic is a copy of a an existing small-molecule-based therapeutic and its approval is based on the demonstration of bioequivalence with its reference product by appropriate pharmacokinetic studies.2,27 A biosimilar is a biological medicinal product that is highly similar to an already licensed biological medicine, the reference product.2 Owing to the intrinsic variability that is inherent to all biological medicines and the complex manufacturing of these medicines, it is impossible to produce identical products. Minor differences can thus exist between the biosimilar and the reference product, however it needs to be demonstrated that these differences are not clinically meaningful.3 The development of a biosimilar is based on the demonstration of biosimilarity via extensive head-to-head comparability studies to the reference product.2 1234567890();,: Generics and biosimilars both follow an abbreviated development pathway for regulatory approval compared with that of an original medicine, however, the requirements are different. As a biosimilar cannot be an exact copy of the reference product, owi (...truncated)