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The Evolution of Biosimilars in Oncology, with a Focus on Trastuzumab

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The Evolution of Biosimilars in Oncology, with a Focus on Trastuzumab EVOLUTIONPERSPECTIVES OF BIOSIMILARS IN INONCOLOGY, ONCOLOGY Nixon et al. The evolution of biosimilars in oncology, with a focus on trastuzumab †‡ N.A. Nixon MD,* M.B. Hannouf PhD, and S. Verma MD* ABSTRACT Cancer therapy has evolved significantly with increased adoption of biologic agents (“biologics”). That evolution is especially true for her2 (human epidermal growth factor receptor-2)–positive breast cancer with the introduction of trastuzumab, a monoclonal antibody against the her2 receptor, which, in combination with chemotherapy, significantly improves survival in both metastatic and early disease. Although the efficacy of biologics is undeniable, their expense is a significant contributor to the increasing cost of cancer care. Across disease sites and indications, biosimilar agents are rapidly being developed with the goal of offering cost-effective alternatives to biologics. Biosimilars are pharmaceuticals whose molecular shape, efficacy, and safety are similar, but not identical, to those of the original product. Although these agents hold the potential to improve patient access, complexities in their production, evaluation, cost, and clinical application have raised questions among experts. Here, we review the landscape of biosimilar agents in oncology, with a focus on trastu- zumab biosimilars. We discuss important considerations that must be made as these agents are introduced into routine cancer care. Key Words Biosimilars, trastuzumab, Herceptin, value Curr Oncol. 2018 Jun;25(S1):S171-S179 www.current-oncology.com INTRODUCTION alternatives to biologics. Although these agents have the potential to improve patient access, complexities in their In recent years, cancer treatment has been revolutionized production, evaluation, and clinical application have raised by the introduction of biologic agents (“biologics”). That questions among experts. revolution is especially evident for her2 (human epider- mal growth factor receptor 2)–positive breast cancer with HISTORY OF BIOSIMILAR AGENTS the introduction of trastuzumab, a monoclonal antibody against her2 that significantly improves survival in both Compared with small-molecule drugs, biologics are larger metastatic and early disease. and more complex—and therefore more susceptible to Although their efficacy is undeniable, expensive bio- production differences. Unlike traditional small-molecule logics, including trastuzumab, are a significant contrib- drugs for which generic versions can be produced, bio- utor to the increasing cost of cancer care. In developing logics cannot be identically copied. Biologic agents are countries, fewer than 10% of patients have access to her2- manufactured using cell lines and processes exclusive to targeted therapies, largely because of the cost1. In 2012, the manufacturer. They require multiple steps for cloning, the World Health Organization released a proposal for the selecting, and expanding the cell line, and then isolating inclusion of trastuzumab in its list of essential medicines. and purifying the product2. At multiple points during that Trastuzumab was subsequently added to the list in 2015, process, clinically significant alterations can potentially with the caveat that the petition for inclusion was based on occur. A different cell line, for example, might result in a the possibility of obtaining a lower-cost biosimilar product. difference in post-translational protein modification that Biosimilars are pharmaceuticals whose molecular can affect immunogenicity and alter a drug’s pharmaco- shape, efficacy, and safety are similar, but not identical, to kinetics and dynamics. the original product. Across disease sites and indications, The European Medicines Agency (ema) was the first biosimilar agents are rapidly being developed with the goal regulatory body to develop, in 2003, guidelines for bio- to create price competition and to provide cost-effective similars. In 2010, Canada adopted the guidance document Correspondence to: Sunil Verma, Department of Oncology, Tom Baker Cancer Centre, Faculty of Medicine, University of Calgary, 1331 29th Street NW, Calgary, Alberta T2N 4N2. E-mail: [email protected] n DOI: https://doi.org/10.3747/co.25.3942 Current Oncology, Vol. 25, Supp. 1, June 2018 © 2018 Multimed Inc. S171 EVOLUTION OF BIOSIMILARS IN ONCOLOGY, Nixon et al. Information and Submission Requirements for Biosimilar stages i–iiia her2+ breast cancer evaluated CT-P6, the Biologic Drugs3, which was updated in 2016. Also in 2010, Celltrion Healthcare version of an anti-her2 monoclonal then U.S. president Barack Obama signed into law the antibody. The CT-P6 product was found to be noninferior Affordable Care Act, which amended the Public Health in the rate of pathologic complete response (pcr), defined Service Act to create an abbreviated pathway to licensure as the absence of invasive disease in the breast, and in for biosimilar agents. For biosimilars to be approved, the absence of invasive and in situ disease in the breast Health Canada, the ema, and the U.S. Food and Drug and axilla (ypT0/isypN0), with a risk ratio of 0.9212. Those Administration (fda), require that the quality, activity, findings met the predefined margin for risk. A second safety and efficacy of the new agent be comparable to those randomized phase iii study with SB3, a trastuzumab bio- of the original agent (Table i). similar from Samsung Bioepis, demonstrated equivalence Since 2006, 25 biosimilar agents have been approved in neoadjuvant treatment, with a primary endpoint of pcr by regulatory agencies in Europe and North America (Ta- in the breast. The rate was 51.7% for SB3 compared with ble ii). The first biosimilars were the somatropin analogs, 42.0% for trastuzumab, for an adjusted ratio of 1.259 (95% introduced in Europe. Erythropoietin biosimilars followed confidence interval: 1.112 to 1.426)15. in 2007, and agents similar to filgrastim, in 2008. It was not At the 2017 meeting of the European Society for Med- until more recently that agents similar to the monoclonal ical Oncology, studies on two additional agents in the antibodies, which are larger and more complex biologics, neoadjuvant setting were presented. Pfizer’s PF-05280014 were introduced. The first biosimilar was the anti–tumour was examined in the neoadjuvant setting in combination necrosis factor α antibody infliximab, introduced in Europe with docetaxel; pharmacokinetics was the primary end- in 2013. With the patents on several monoclonal antibodies point, and pcr was a secondary endpoint. In this case, now approaching or past expiry (including trastuzumab, the biosimilar agent was noninferior, with a pcr of 47% bevacizumab, cetuximab, and rituximab), development compared with 50% for trastuzumab (see NCT02187744 at programs for similar therapeutics are under way. http://ClinicalTrials.gov). Amgen’s ABP 980 also resulted in a noninferior pcr when combined with docetaxel in the CURRENT LANDSCAPE AND CONSIDERATIONS neoadjuvant setting14. FOR TRASTUZUMAB BIOSIMILARS Metastatic Disease Trastuzumab (Herceptin) is a fully humanized monoclonal An evaluation of CT-P6 was also conducted in metastatic antibody to the extracellular domain iv of her2, developed her2+ breast cancer (Table iii). In a pooled analysis of data by Genentech (San Francisco, CA, U.S.A.). In the landmark from phase i/iib and iii studies comparing CT-P6–paclitaxel trial by Slamon and colleagues4, trastuzumab added to with trastuzumab–paclitaxel for metastatic disease, the standard chemotherapy for metastatic disease signifi- overall response rates (orrs) during the first 8 cycles of cantly improved overall survival (os) by approximately 5 treatment were 57% and 62% respectively (5% difference; months. Trastuzumab has since been shown to confer a 95% confidence interval: –0.14 to 0.04). That finding met the survival benefit in multiple settings, including adjuvant criteria for equivalence. Median time to progression was and neoadjuvant treatment of her2-positive (her2+) breast 11.07 months with CT-P6 and 12.52 months with trastu- cancer, and her2+ metastatic gastric cancer5–8. Herceptin zumab, with serious adverse event rates of 13.5% and 12.1% is now well-established in guidelines as a standard of care, respectively11. The full trial has yet to be published; how- but it remains costly: estimates place the cost at more than ever, in January 2014, CT-P6 was granted approval in South CA$4,500 per month or CA$54,000 for a full 1-year course Korea for metastatic breast cancer (mbca), early breast of treatment9,10. cancer (ebc), and gastric cancer. In the population with The patent on Herceptin expired in 2014 in Europe, metastatic disease, Biocad’s BCD-022 also demonstrated opening the door for biosimilar agents to enter the market a noninferior orr (primary endpoint) of 53.6% compared and to lower the price by creating competition. In July with 53.70% in the group receiving Herceptin–paclitaxel. 2017, a trastuzumab biosimilar agent, MYL-1410 (Mylan, Complete responses, partial responses, stable disease, and Canonsburg, PA, U.S.A.), received unanimous recom- progression rates were also similar (Table iii). mendation for approval from the fda’s Oncologic Drugs The Heritage study, a phase iii study evaluating the Advisory Committee, and on 1 December 2017, it was ap- biosimilar MYL-1401O combined with docetaxel in her2+ proved. Despite that rapid progress, important regulatory mbca, showed a noninferior orr of 69.6% compared with and clinical factors have to be considered. Those factors 64% with Herceptin–docetaxel, meeting
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