Biosimilar monoclonal antibodies in lymphoma: a critical appraisal

Abstract

Rituximab, an anti-CD20 monoclonal antibody, revolutionized the treatment of lymphoma. Although newer generation anti-CD20 monoclonal antibodies are being examined, patent expiries and patient demand have fueled the development of rituximab biosimilars. The development of such agents is both an important and difficult undertaking. By definition, although they aim to have safety and efficacy comparable with their reference agents, biosimilars are not exact replicas of those agents, and small changes in nonclinical and preclinical properties may ultimately affect in vivo activity. Consideration must be given to the complex mechanisms of action, sensitive patient populations that may be treated, and appropriate clinical trial endpoints. Furthermore, extrapolation of indications is multifaceted, deserving close examination. This review represents a critical look at biosimilars in lymphoma and their safety, efficacy and long-term effects on patient outcomes.

Keywords:

• Biosimilar
• biosimilar monoclonal antibody
• lymphoma
• MabThera^®
• non-Hodgkin lymphoma
• Rituxan^®
• rituximab

Financial & competing interests disclosure

G Salles has received research grants, speakers fees and honorarium from Roche Genentech, Amgen, Celgene, Gilead, Janssen, Mundipharma and Roche. C Rioufol has received research funding from Roche. J Solis, C Goins and H Tomlinson from prIME Oncology provided medical writing assistance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The majority of lymphomas originate from B lymphocytes. The first B-cell antigen, B-1 (CD20), was identified in 1981.

• Rituximab, an anti-CD20 biologic was approved for the treatment of cancer in the late 1990s and revolutionized the treatment of non-Hodgkin lymphoma.

• Pending patent expiries and patient demand have driven the development of biosimilar anti-CD20 monoclonal antibodies.

• By definition, while aiming to be comparable in terms of quality, safety and efficacy, biosimilars are not exact replicas of their reference agent, and small changes in nonclinical and preclinical properties may ultimately affect in vivo activity.

• The EMA requires that comparability between a biosimilar and its originator should be demonstrated in a scientifically and appropriately sensitive clinical model and study conditions; however, identifying a sensitive and homogenous study population in lymphoma may not be simple because the disease state itself is not homogenous. More discussion is required around the definition of homogenous and sensitive populations and definitive guidelines should be drafted, examined and released.

• Multiple clinical trial endpoints have been used to demonstrate the benefit of agents, such as rituximab in lymphoma, including response rate, progression-free survival, event-free survival and overall survival. Although the EMA suggests that overall response rate may be a sufficient primary endpoint for some biosimilar monoclonal antibody trials, examination of clinical data in indolent lymphoma suggests otherwise.

• Extrapolation of indications is complex and must take into account the multiple indications of an agent, its multiple modes of action, and its variable dosing and routes of administration. Extrapolation of indications should only be accepted on a case-by-case basis with rigorous scientific justification.

• A critical examination of the safety, efficacy and long-term effects of biosimilars in lymphoma is recommended as additional approvals move forward.