Expert perspectives on biosimilar monoclonal antibodies in breast cancer

J. Cortes 0 1 2 G. Curigliano 0 1 2 V. Dieras 0 1 2 0 V. Dieras Department of Clinical Research, Curie Institute , 26 rue d'Ulm, 75248 Paris, France 1 G. Curigliano Division of Early Drug Development for Innovative Therapies, European Institute of Oncology , via Ripamonti 435, Milan, Italy 2 J. Cortes (&) Department of Oncology, Vall D'Hebron University Hospital , Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain While biosimilars of low molecular-weight biologics such as G-CSF have been available in Europe since 2006, biosimilars of monoclonal antibodies (mAbs) have only become available in the last year. Unlike G-CSF, mAbs are large and complex and often play a direct role in the survival of patients with life-threatening illnesses such as breast cancer. Several biosimilars are currently under development for the treatment of breast cancer, and the use of biosimilars in a setting that directly impacts patient survival raises a number of questions. In this review, we discuss the biosimilar mAbs currently in development for the treatment of breast cancer. We provide an overview of the European Medicine Agency guidelines and historic data on the development of biosimilars in order to discuss the development of biosimilar mAbs for breast cancer. Biosimilars offer a highly attractive path toward reducing the cost of medical care and should be pursued with great interest. However, for agents used to treat life-threatening diseases such as cancer, a cautious approach must be taken to ensure that there is no negative impact on patient care. Clinical trials for biosimilar mAbs must be carried out in an appropriately sensitive patient population using endpoints that can accurately demonstrate both the similarity of the biosimilar and its efficacy in the indication. Due to the abbreviated approval pathway, rigorous pharmacovigilance must be in place once a biosimilar mAb is approved in order to ensure its long-term safety and efficacy. - The discovery of the HER2 proto-oncogene and the development of the HER2-targeted antibody trastuzumab (Herceptin , Genentech) more than two decades ago represent landmark achievements in the treatment of breast cancer. Prior to trastuzumab, women with HER2-positive breast cancer had few treatment options and progressed rapidly. The introduction of trastuzumab in previously untreated patients with metastatic disease resulted in a 4.8 month increase in median overall survival (OS) [1]. Women with HER2-positive metastatic breast cancer now have survival rates similar to patients with hormone receptorpositive breast cancer, a disease that historically had a more favorable prognosis. Trastuzumab has since been approved for use in many indications, including neoadjuvant and adjuvant breast cancer. In early breast cancer, one year of treatment with adjuvant trastuzumab with chemotherapy results in a statistically significant reduction in the risk of disease recurrence by as much as 48 % in some trials [2, 3]. Since its approval, trastuzumab has become the standard of care for patients with HER2-positive breast cancer. In 2014, the patent exclusivity rights for trastuzumab will expire in Europe, opening the door for the creation of copy versions. Unlike small-molecule drugs such as aspirin and tyrosine kinase inhibitors, which are produced via chemical synthesis, trastuzumab belongs to a unique class of agents known as biologics. Biologics are complex drugs that are derived from living organisms such as bacterial and eukaryotic cells [4]. Because of the size and complexity of biologics and the variability introduced during production, it is impossible to make an identical copy, or generic version, of a biologic. Instead, copies of biological medicines are known as biosimilars, a term that highlights the fact that they are similar to the reference products but not entirely identical. Importantly, only copies of biologics that have undergone a comparability exercise and have been approved by a regulatory body can be called biosimilar [5]. The first biosimilars introduced in Europe were biosimilar somatropins in 2006. These were followed by biosimilar erythropoietins in 2007 and biosimilar filgrastims starting in 2008 [6]. Until recently, only biosimilars of these lower molecular-weight biologics were available in Europe. This changed in September 2013 when the European Commission granted marketing authorization for two biosimilars of the anti-tumor necrosis factor alpha (TNF-a) antibody infliximab [7]. This represents the first time a biosimilar of a monoclonal antibody (mAb) has been approved by a regulatory body. Currently, several biosimilar versions of trastuzumab are under development. It is expected that approval of a biosimilar trastuzumab may come as early as 2014. If so, biosimilar trastuzumab will be the first biosimilar mAb available for the treatment of cancer. The development of biosimilar trastuzumab represents a unique and exciting opportunity in the field of breast cancer. In this review, we will explore the development and approval of biosimilar trastuzumab and discuss in detail a number of issues relevant to breast oncologists when considering biosimilar trastuzumab for their patients. Pathway to biosimilar trastuzumab approval Guidelines for biosimilar mAb development Biosimilars are approved on the basis of a regulatory pathway different from both generics and originators. Because biosimilars are the copies of molecules that have already been approved through a rigorous clinical trial program, the dossiers for their approval are reduced compared to those of the originators. However, because they are not identical to the reference products, biosimilars require more thorough testing than generics. The European Medicines Agency (EMA) has issued several guidelines regulating the development of biosimilars, including guidelines for the development and testing of biosimilar mAbs [8, 9]. Prior to being approved, a biosimilar must demonstrate comparability to a reference product in terms of quality characteristics, biological activity, safety, and efficacy. This is achieved through a stepwise comparability exercise that includes in vitro analytical testing, non-clinical comparative testing, and one or more clinical trials [8]. A key component of the biosimilarity exercise is an accelerated clinical trial program in which the pharmacokinetics, clinical efficacy, clinical safety, and immunogenicity of the biosimilar are compared to that of the originator. According to the EMA, the goal of the clinical trial program is to demonstrate similar efficacy and safety compared to the reference medicinal product, not patient benefit per se, which has already been established by the reference medicinal product [8]. Throughout the clinical trial program, all testing must be done in a sensitive and homogenous patient population so that any differences between the biosimilar and the originator can be easily detected. Likewise, the clinical endpoi (...truncated)