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Review

Biosimilar monoclonal antibodies in lymphoma: a critical appraisal Expert Rev. Anticancer Ther. 15(5), 569–578 (2015)

Catherine Rioufol1 and Gilles Salles*2 Hospices Civils de Lyon, Unite de Pharmacie Clinique Oncologique, Universite de Lyon – EMR 3738, Pierre-Benite, France 2 Hospices Civils de Lyon, Service d’Hematologie, Universite de Lyon – UMR-CNRS 5239, Pierre-Benite, France *Author for correspondence: Tel.: +33 478 864 302 Fax: +33 478 864 348 [email protected] 1

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

Biologics have revolutionized the treatment of hematologic malignancies, including lymphoma. However, access to agents, such as the chimeric monoclonal CD20 antibody rituximab, can be challenging, particularly in countries with limited resources [1]. In light of marketplace demands and pending patent expirations, a number of pharmaceutical companies have pursued the development of biosimilar monoclonal antibodies (mAbs). Biosimilars are copies, but not exact replicas, of individual branded reference biologics that aim to have comparable quality, security and efficacy. Although these new agents may improve access to treatment for some patients, it is imperative to move forward with great caution, critically examining in vivo safety, efficacy and long-term effects on patient outcomes. Role of mAbs in lymphoma

Lymphoma is a malignancy of mature lymphocytes and includes more than 50 distinct clinical entities of Hodgkin lymphoma and non-Hodgkin lymphoma (NHL) [2,3]. The most common NHL subtypes diagnosed in adults are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) [3].

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10.1586/14737140.2015.1028919

Worldwide, more than 415,000 new cases of NHL are expected to be diagnosed in 2015, with more than 215,000 people dying from their disease [4]. The majority of lymphomas originate from B lymphocytes. The first B-cell antigen, B-1 (CD20), was identified in 1981 [5]. CD20 is a nonglycosylated transmembrane surface antigen expressed on normal B cells and malignant B cells. CD20 regulates B-cell proliferation and differentiation, but is not critical to B-lymphocyte development [6,7]. CD20 is an ideal target in the treatment of B-cell lymphoma given its pattern of expression on >95% of these B-cell-derived lymphomas, its general lack of rapid internalization or shedding from the plasma membrane following mAb treatment, and its lack of expression on hematopoietic stem cells or terminally differentiated plasma cells [7,8]. A number of mAbs have been engineered in an effort to achieve targeted therapy in B-cell lymphoma, transforming treatment and prognosis. Rituximab, a mouse/human chimeric mAb, was the first mAb and the first antiCD20 biologic approved for the treatment of cancer in the USA (in 1997 as Rituxan
) and

 2015 Informa UK Ltd

ISSN 1473-7140

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Table 1. Steps required for biosimilar product development and marketing approval [36]. Stand-alone data packages

Quality

Comparative exercises with reference product

. .

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. . .

Target/quality by design Physicochemical and biological comparability Nonclinical studies Clinical studies Risk-management plan

the EU (in 1998 as MabThera
) [9–11]. Although many patients benefit from rituximab, especially when used in combination with chemotherapy, a substantial proportion ultimately relapse or fail to respond [12–17]. Thus, multiple second- and thirdgeneration anti-CD20 antibodies have been developed, including fully humanized agents and engineered Fc regions [18]. Ofatumumab was the first human anti-CD20 mAb approved in the USA (2009) and the EU (2010). The original approval, based on interim results from a pivotal Phase II trial, was for chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab [19,20]. Ofatumumab has since been approved in the EU in combination with chlorambucil or bendamustine in patients who have not received prior therapy and who are not eligible for fludarabine-based therapy [21]. Obinutuzumab (GA101) is an anti-CD20 mAb glycoengineered for enhanced Fc-mediated effector mechanisms and induction of direct cell death [22,23]. Obinutuzumab was approved in the EU in combination with chlorambucil for the treatment of previously untreated CLL with comorbidities contraindicating full-dose fludarabine-based therapy, after a study demonstrating its benefit against rituximab in this context [24]. Rituximab is approved for the treatment of B-cell NHL and CLL and is a frequent component in the treatment of multiple hematologic malignancies [9]. In FL, studies with rituximab have demonstrated the first survival advantage in decades [16,24–26]. Other studies have demonstrated that the addition of rituximab to standard therapy in DLBCL results in decreased disease progression and significantly improved overall survival (OS) rates [12,17,27]. Although rituximab is not indicated for the treatment of Hodgkin lymphoma, Burkitt’s lymphoma or Waldenstro¨m macroglobulinemia, positive clinical outcomes have also been observed [9,10,28–34]. Biologics are vital to oncology care and have transformed the treatment of B-cell lymphomas. However, the development and manufacturing of biologics are complex and expensive, which may lead to diminished patient access [35]. Such challenges, along with recent and pending patent expiries, have driven the development of biosimilar agents.

biopharmaceuticals made using, or derived from, living organisms using biotechnology and exhibiting comparable quality, efficacy and safety with originator reference medicinal products [36]. Although biosimilars aim to have no clinically meaningful difference, they are not exact replicas of their reference biologics, which may lead to a number of clinical issues that healthcare professionals must consider [37]. The first biosimilar mABs approved in the EU were Inflectra (infliximab) and Remsima (infliximab), which were approved in 2013 for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriasis and psoriatic arthritis [38]. The MabThera (rituximab) patent expired in November 2013 in the EU and is expected to expire in the USA in September 2016 [39]. On the basis of market opportunities presented by these expirations, we found that a number of rituximab biosimilars are in development. As patents expire, the number of biosimilars approved and in development is expected to increase substantially. Overview of EMA guidelines for biosimilar mAbs

The first EMA guideline related to the development of biosimilars went into effect in 2003 [36]. In 2012, the EMA issued the first guidelines specific to similar biologic medicinal products containing mAbs [37]. The EMA requires that biosimilars undergo rigorous preclinical, clinical and postapproval evaluation, including postapproval studies evaluating safety, as part of an ongoing risk-management plan using the collection of realworld clinical evidence. This is a fundamentally comparative process (TABLE 1) [36]. Requirements for biosimilar antibody clinical trials

Beyond preclinical data, there are three overarching requirements for the development and approval of biosimilar antibodies: Phase I pharmacokinetics/pharmacodynamics studies; Phase III studies in a sensitive, representative population and indication and a risk-management plan [37]. The EMA suggests that clinical testing of mAb biosimilars should build upon the principles used for testing simpler proteins. That is, an identical amino acid sequence with high similarity in chemical, physical and biological characteristics should first be demonstrated in a nonclinical setting. Clinical similarity should then be tested in a head-to-head setting [37,40,41]. Comparative clinical studies should be designed to demonstrate similar efficacy and safety to the reference product. Ultimately, for any biosimilar, it is important to demonstrate no clinically meaningful difference between the new agent and the originator with regard to pharmacokinetics, efficacy, safety and immunogenicity [37]. To meet these goals for pending agents in lymphoma, the appropriate patient types for anti-CD20 antibody trials and appropriate clinical trial endpoints must be considered. Sensitive patient population(s) for anti-CD20 antibodies

Emergence of biosimilar antibodies in lymphoma

Biosimilars are approximate copies of branded biologic therapies. The EU defines biosimilars as a subclass of 570

According to the EMA, comparability should be demonstrated in a scientifically and appropriately sensitive clinical model and study conditions. This method aids in detecting product-related Expert Rev. Anticancer Ther. 15(5), (2015)

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Biosimilar mAbs in lymphoma

differences, thereby reducing patient- and disease-related factors, increasing precision and simplifying interpretation [37]. Identifying a sensitive and homogenous study population in lymphoma may not be simple because the disease state itself is not homogenous [2]. Patient populations and rituximab regimens that have been included in pivotal originator trials and considered for biosimilar development include rituximab alone in relapsed low-grade or FL, rituximab combined with chemotherapy in FL and rituximab as maintenance therapy after induction with rituximab combined with chemotherapy in relapsed/resistant FL or newly diagnosed FL with a high tumor burden. Even if the focus is narrowed to include only the disease states included in the pivotal trials that precipitated approval of the reference product, one must then consider patient disease characteristics and overall treatment regimen. In 2011, the European Centre of Regulatory Affairs, Freiburg, convened a workshop of over 100 attendees from 15 countries, including regulators from 11 agencies to discuss regulatory acceptance of biosimilar antibodies in Europe. The definition of a ‘sensitive and homogeneous study population’ was a topic of open discussion. Attendees agreed that the word homogenous indicates that all patients enrolled in a study should have the same tumor stage. For example, patients with large tumor masses are expected to have different clinical outcomes and varying levels of antigen compared with patients having undergone resection. However, the meaning of ‘sensitive’ remains less precise. A sensitive population is one that allows detection of even small differences in the clinically relevant functions of the molecule. The attendees suggested that one way to identify a sensitive population is to select a subgroup from the pivotal study of the reference product [42]. It also seems logical that sensitivity will be better assessed using single-agent treatment rather than combinations, for which the intrinsic efficacy of biologics as a part of the overall therapeutic effect is more difficult to evaluate. However, more discussion is required around the definitions of homogenous and sensitive populations. Selecting an appropriate clinical trial endpoint

For anti-CD20 agents, such as rituximab, a number of clinical trial endpoints have been used to demonstrate benefit in lymphoma, including response rate, progression-free survival (PFS) [43], event-free survival (EFS) [44] and OS [45,46]. This range of clinical endpoints may be driven by the varying treatment goals across lymphoma subtypes. For example, treatment with curative intent is a possibility in DLBCL, whereas in CLL or FL, treatment goals may focus on prolonged PFS, improved response rate or minimal residual disease negativity [12,15,47–51]. OS, defined as the time from randomization to death, has been accepted as the gold standard for demonstrating direct clinical benefit to patients. However, OS is a more difficult endpoint to achieve than others, requiring larger patient numbers, as well as considerable time and cost for patient follow-up. This ultimately may delay introduction of a potentially beneficial agent. Thus, a number of surrogate endpoints, including PFS and tumor response rate, have been explored to predict clinical efficacy [52,53]. informahealthcare.com

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In the 2012 guidelines on similar biological medicinal products containing mAbs, the EMA states that overall response rate may be a sufficient primary endpoint for some biosimilar mAb trials [37]. Response rate is an attractive endpoint because outcomes are rapidly and easily measured. However, while response rate has been widely used as an endpoint in Phase II oncology trials, researchers have argued that it is not an appropriate endpoint for agents that impact tumor growth by nonconventional mechanisms [53]. Furthermore, in patients with lymphoma, response rate differences are not always observed with PFS or OS, especially when indolent lymphomas are considered [54]. Conversely, differences in PFS and OS may not always result from differences observed in response rate, even in patients with DLBCL [55]. Oncology studies have yet to definitively establish a correlation between response, progression, disease control and survival. Thus, even if a study demonstrates that response rates are statistically equivalent between a biosimilar and a reference agent, this may not translate into a clinically meaningful difference in survival [56,57]. Of note, the Cheson criteria for standardized response rates in NHL were established in 1999 and updated in 2007 and 2014. Thus, definitions of standards have varied over time [58–60]. This is further complicated by the introduction of new response assessment methods, especially PET-computed tomography [61,62]. A review of efficacy endpoints in 38 randomized controlled trials for systemic therapy in aggressive NHL identified a correlation between 3-year PFS/EFS and 5-year OS. Linear regression determined that a 10% improvement in 3-year PFS or EFS predicted a 7% improvement in 5-year OS. Of the 38 trials examined, 26 had paired results, where differences in 3-year PFS and EFS and 5-year OS between treatment arms were assessed for statistical significance. Concordance was identified in 23 trials. Of the three discordant trials, all demonstrated a significant difference in 3-year time-to-event endpoint, but no difference in 5-year OS was observed [54]. Similar results were seen in an analysis of 20 randomized controlled trials for indolent NHL [54]. Hence, findings demonstrating a robust correlation between overall response rate and survival endpoints are still missing, especially in indolent NHL. Given this, it is surprising that overall response rate has been chosen as the primary endpoint for the ongoing Phase III trial with GP2013, a rituximab biosimilar in development by Sandoz [63]. Challenges for extrapolation of biosimilar anti-CD20 antibodies

Extrapolation of indications occurs when a successful comparability exercise demonstrates clinical similarity between a biosimilar and an originator for one indication, but the biosimilar obtains regulatory approval for multiple or all of the originator’s approved indications. The EMA has provided an approval pathway for extrapolation of indications for biosimilar mAbs, stating that adequate justification must be demonstrated and that the evidence of the comparability exercise must be compelling [64]. Supporters of extrapolation claim that this process is a logical extension of the comparability exercise principle, which is 571

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Fc: FcyR-dependent mechanisms

C1q Complement-dependent cytotoxicity

Effector cell

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Malignant B-cell Homotypic adhesion nonapoptotic cell death CD 20 modulation shaving

Activated T-cells

Dendritic cell Adaptive cellular immunity

Figure 1. Mechanisms of action of rituximab [77].

patients with stage III–IV FL that is chemoresistant or who are in their second or subsequent relapse after chemotherapy, and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) for patients with CD20-positive DLBCL [10]. Extrapolating across lines of therapy may put patients at risk as both the number and function of immune cells, which account for rituximab efficacy, vary across disease stage. For example, natural killer cells, which are necessary for antibody-dependent cell-mediated toxicity (ADCC), are frequently reduced in patients with compromised immune systems. Furthermore, extrapolation from monotherapy to combination therapy is not recommended due to probability of net contributions of the modes of action and the potential for drug–drug interactions [73,74]. Multiple modes of action

founded in physiochemical and biological characterization and equivalency. The biosimilar developer is not ‘awarded’ extrapolation, but rather is burdened to collect and demonstrate compelling and stringent scientific evidence [65]. Inflectra, an infliximab biosimilar, is an example of a mAb biosimilar approved for multiple indications by the EMA via extrapolation. The Inflectra Phase I program included patients with active ankylosing spondylitis [66], and the Phase III program enrolled patients with active rheumatoid arthritis with an inadequate response to methotrexate [67]. Upon EMA approval, Inflectra was indicated for rheumatoid arthritis, Crohn’s disease (adult and pediatric), ulcerative colitis (adult and pediatric), ankylosing spondylitis, psoriatic arthritis and psoriasis [68]. However, in the 2013 Assessment Report, the EMA stated that Hospira, the manufacturer of Inflectra, must conduct a randomized, double-blind, parallel group comparative study with Inflectra and Remicade
in patients with active Crohn’s disease [69]. While this experience may not prove typical, the EMA has opened the door to extrapolation and related concerns within the lymphoma space, which must be critically examined. Multiple indications

The multiple mechanisms of action of rituximab have likely contributed to its efficacy and approval across multiple disease states, including NHL, CLL and rheumatoid arthritis [10]. However, the same characteristics that allow rituximab to benefit patients across multiple indications may cause concern when considering extrapolation. Rituximab has demonstrated varying dose dependency based on disease state. In NHL, there is no established dose–response relationship [70]; in rheumatoid arthritis, there is a weak dose– response relationship with saturation [71]; and in CLL there is a clear dose–response relationship [72]. Not only is rituximab approved across multiple disease states but is approved for multiple lines of therapy within one indication. Within NHL, rituximab is approved in combination with chemotherapy for the treatment of patients with previously untreated stage III–IV FL, as maintenance therapy for patients with FL responding to induction therapy, as monotherapy for 572

mAbs are known to have multifaceted, and often not fully characterized, mechanisms of action. They are composed of multiple domains contributing to complex mechanisms of action. mAbs may perform several functional activities, with an individual molecule interacting with a number of receptors [75,76]. Rituximab is associated with a number of mechanisms of action, including effector mechanisms of ADCC, complementdependent cytotoxicity, antibody-dependent cellular-phagocytosis and programmed cell death (FIGURE 1) [77]. Antibody-dependent cellular toxicity involves rituximab binding the Fcg receptors on effector cells, triggering the release of preforming proteins and proteases, thereby leading to targeted cell death. During complement-dependent cytotoxicity, rituximab activates the complement cascade and generates membrane attack complexes, resulting in cell death. In antibody-dependent cellular phagocytosis, rituximab binds the Fcg receptors of monocytes/macrophages, which results in their engulfment of antibody-coated tumor cells. In programmed cell death, antigen–antibody complex formation and Fc-Fcg receptor complex binding to CD20 triggers membrane-bound and intracytoplasmic proteins, activating the intrinsic apoptotic caspase pathway and mitochondrial outer membrane permeabilization [75]. Some data have suggested that anti-CD20 mAbs also may potentially induce an adaptive antitumor response, which may support durable remissions in some patients [78]. The net contribution of each of these mechanisms of action remains unknown, and may change based on patient and disease factors, including tumor load and expression levels of the target antigen [79]. However, despite being commercially available for 17 years, the full mechanism of action of rituximab remains to be elucidated [8,80]. Not only is the full in vivo mechanism of action of rituximab poorly understood but also the contribution of different mechanisms of action in different indications is not clear either [77]. For mAbs, mechanism of action relates not only to binding of the fragment antigen-binding region to its epitope and the resulting signaling events but also to the complex interaction between Fc domain and Fc receptor [76]. Two anti-CD20 mAbs, such as rituximab and tositumomab, might bind the Expert Rev. Anticancer Ther. 15(5), (2015)

Biosimilar mAbs in lymphoma

Review

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Table 2. Current trials with rituximab biosimilars in non-Hodgkin lymphoma. Agent (company)

Phase

Trial design

Disease state

Comparator

n

Primary Endpoint

Status

GP2013 (Sandoz)

III

Randomized, double blind

FL

MabThera

618

ORR

Recruiting

I

Open label

Indolent B-cell NHL

NA

6

Safety

Recruiting

III

Randomized, double blind

FL

Rituxan

250

PK, ORR

Recruiting

I

Open label

DLBCL

NA

1

Safety

Terminated

MK8808 (Merck)

I

Open label

FL

NA

22

Safety

Ongoing, not recruiting

[95]

TL011 (TEVA)

I

Randomized, double blind

DLBCL

Rituximab

186

PK

Completed

[96]

PF-05280586 (Pfizer)

III

Randomized, double blind

FL

MabThera

394

ORR

Not yet open for recruitment

[97]

BI-695500 (Boehringer Ingelheim)

I

Randomized, double blind

FL

MabThera

90

PK

Recruiting

[98]

CT-P10 (Celltrion)

Ref. [63,93]

[94]

DLBCL: Diffuse large B-cell lymphoma; FL: Follicular lymphoma; NHL: Non-Hodgkin lymphoma; ORR: Overall response rate; PK: Pharmacokinetics.

same epitope, but cause varying downstream signals. When Type I anti-CD20 antibodies bind (e.g., rituximab), there is a translocation of CD20 into the lipid raft and resulting apoptosis [81]. When type II anti-CD20 antibodies bind (e.g., tositumomab), it is a downstream signal, rather than translocation, that causes a direct nonapoptotic cell death [82–84]. Furthermore, even small changes in glycosylation on the Fc region can have a profound effect on how an antibody works. The Fc region has been shown to play a critical role in ADCC and antibody-dependent cellular phagocytosis [85]. In vitro, a low-fucose content is associated with dramatically enhanced ADCC [86]. Obinutuzumab (GA101), a humanized, glycolengineered, type II anti-CD20 antibody, was designed with enriched bisected nonfucosylated glycosylation variants, to enhance ADCC and nonapoptotic programmed cell death [87,88]. In fact, the 2012 EMA guidelines required that biosimilar developers assess any differences in biological activity with the reference product by conducting in vitro studies that demonstrate comparability in binding the target antigen, binding representative isoforms of the relevant three Fcg receptors, fragment antigen binding-associated functions and Fc-associated functions [37]. It has already been shown that the glycosylation of the rituximab commercialized molecule has evolved over time, and that even subtle modifications in the glycosylation pattern have resulted in differences in ADCC in vitro. Furthermore, even small changes in the manufacturing process, such as process improvements, scale changes and site transfers, may ultimately affect product quality, efficacy and safety [89]. Variable dosing & routes of administration

The dose and schedule of rituximab therapy changes by disease state and line of therapy. Rituximab was originally approved informahealthcare.com

based on a Phase II study in the USA in relapsed NHL, dosed at 4 weekly infusions at 375 mg/m2 [9]. When approved in combination with chemotherapy in first-line NHL, the approved regimen was 8 infusions every 3 weeks at 375 mg/m2 [10]. Lower efficacy was observed in CLL and a high-dose regimen of 6 infusions every 4 weeks at 500 mg/m2 with chemotherapy was approved. In rheumatoid arthritis, the approved regimen is 2 infusions of 1000 mg every 15 days [9]. Overall, exposure may range from 2 weeks to 2 years, depending on the indication [10]. Although rituximab is approved as an intravenous infusion, studies have evaluated other routes of administration. In 2014, the first subcutaneous formulation of MabThera was approved by the European Commission for the treatment of FL and DLBCL [90]. Although the biosimilarity concept is dependent upon extrapolation, strong caution is necessary when proceeding. A number of physician groups have spoken out against extrapolation, including the European Crohn’s and Colitis Organisation and the Association of the British Pharmaceutical Industry [91,92]. In general, extrapolation should only be accepted with rigorous scientific justification and allowed on a case-by-case basis. The use of randomized trials to demonstrate equivalent clinical outcomes is necessary to ensure patients are not at risk for inferior outcomes [92]. Biosimilar antibodies currently in development for lymphoma

A number of strategies are being adopted by companies seeking approval of biosimilar mAbs. Ongoing trials in FL and DLBCL vary by endpoint, treatment regimen, trial design and study location (TABLE 2) [63,93–98]. The pathway to approval has not been easy, and a number of rituximab biosimilar trials have 573

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been halted (temporarily or permanently), including Samsung’s SAIT101 [99], Celltrion’s CT-P10 Phase I [100], and Teva’s TL011 (in rheumatology) [101].

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Expert commentary

Rituximab revolutionized the treatment of lymphoma, yet a number of patients still fail to respond or suffer from relapse [102]. Newer generation anti-CD20 mAbs have been engineered to enhance and refine the targeted effects of these agents [18]. In addition, in response to pending patent expiries and patient demand, a number of companies are pursuing the development of biosimilar anti-CD20 mAbs. The development of biosimilars for the treatment of lymphoma is both an important and difficult undertaking. By definition, biosimilars are not exact replicas of their reference agents, and while aiming to have similar quality, safety and efficacy, small changes in nonclinical and preclinical properties may ultimately affect in vivo activity. Consideration must be given to the complex mechanism of action of anti-CD20 mAbs, which is yet to be fully understood even for rituximab, which has been in use for almost two decades. In addition, sensitive patient populations and appropriate clinical trial endpoints must be established within each disease state. Extrapolation of indications is complex and should only be accepted on a case-by-case basis with rigorous scientific justification. A number of rituximab biosimilars are already in development. While these new agents may improve access to treatment for some patients, a critical examination of safety, efficacy and long-term effects on patient outcomes is recommended as additional approvals move forward.

Five-year view

The standard of care in lymphoma is evolving. The advent of glycoengineered mAbs has led to the development and approval of third-generation Type II anti-CD20 agents, such as obinutuzumab, and the first evidence of superior outcomes compared with rituximab. New agents targeting intracellular signaling pathways or attempting to modify the tumor microenvironment are being rapidly developed. Interestingly, some of them seem to be clinically more active when combined with rituximab, suggesting the mobilization of complex cellular and molecular interactions between the tumor cells themselves and tumor-infiltrating immune cells with this combination [103]. In this context, the next 5 years are also likely to see the approval of biosimilar rituximab in the EU. The speed of approval and uptake of such new biosimilars will depend on how well the clinical trials are designed, particularly in terms of which endpoints are used and what the reported outcomes will be. Both physicians and regulators should look for evidence to confirm or deny suspicions and assumptions about biosimilar antibodies and keep a critical eye on the experience with infliximab biosimilars over the next 2–3 years. 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.

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with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005;105:1417-23

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