What is biosimilarity

Biosimilars in Oncology (Part 2): How to scientifically confirm biosimilarity

For the three biologics effective in oncology, rituximab, trastuzumab and bevacizumab, it is shown by way of example that the clinical results of the biosimilars can be confirmed with different approaches.

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Rituximab is a genetically engineered monoclonal, chimeric antibody (mouse / human) and approved in adults for the following areas of application:

  • Non-Hodgkin lymphoma (NHL),
  • chronic lymphocytic leukemia (CLL),
  • rheumatoid arthritis (RA),
  • Granulomatosis with polyangiitis and
  • microscopic polyangiitis.

Rituximab is an interesting case insofar as this active substance is used in different therapeutic areas (autoimmune disease, oncology). Rituximab binds to the CD20 receptor, which is B-cell specific and found on the membranes of pre-B and mature B lymphocytes. The cells are eliminated by 4 known mechanisms of action:

  • complement-dependent toxicity (CDC),
  • antibody-dependent cellular cytotoxicity (ADCC) by binding to the Fc-gamma receptor,
  • antibody dependent cellular phagocytosis (ADCP),
  • direct signal induction and apoptosis.

There are indications in the literature that the contribution of the known mechanisms of action could be different in the various indications (1).

The direct induction of apoptosis in vitro is seen primarily in rapidly dividing Burkitt lymphoma cells, but is difficult to detect in other lymphoma cell types. FcR polymorphism (s) influence effectiveness in follicular lymphoma (FL), suggesting that ADCC is more important in FL than in CLL. Finally, it is observed that the expression of CD20 receptors on the surface of B cells and also the number of B cells vary greatly between NHL patients and patients with rheumatoid arthritis (RA).

A good understanding of the mechanisms of action and the use of suitable test methods are therefore essential to ensure that data obtained in one clinical indication (e.g. rheumatoid arthritis) can also be transferred to another indication in which the mode of action, the dosage and / or pharmacokinetics may be different (e.g. oncology).

6 Rituximab biosimilar products are currently approved, whereby these products are based on only 2 different active substances: Celltrion is the manufacturer for Truxima, Ritemvia, Rituzena, Blitzima (duplicates or bioidenticals) and Sandoz is the manufacturer for Riximyo and Rixathon. The market approval of Rituzena was withdrawn by the manufacturer in summer 2019.

While Truxima and Rixathon have all the indications of the reference drug MabThera, Ritemvia is not approved for CLL and Tuxella is not approved for follicular lymphoma. The reason for the different indications is that the applicants applied for it that way. It is not the result of a regulatory restriction of indications.

The two manufacturers developed their biosimilars differently, but in both cases this led to a positive approval decision.

A pivotal comparative pharmacokinetic study in patients with active rheumatoid arthritis was conducted for both Rituximab-Celltrion and Rituximab-Sandoz. In both cases, the comparison was made between the biosimilar and the MabThera approved in the EU.

A comparative pivotal phase III study in patients with rheumatoid arthritis then followed for the development of Rituximab-Celltrion. In addition, the company carried out a supportive study in patients with advanced follicular lymphoma, which was not necessary from an EU perspective. This additional study had a follow-up period of 3 years, but too few patients to formally prove equivalence.

In the case of Rituximab-Sandoz, the developer carried out the pivotal phase III study in patients with advanced follicular lymphoma and was able to demonstrate comparability in terms of efficacy and safety.

Trastuzumab is a genetically engineered, humanized monoclonal IgG1 antibody. Trastuzumab is approved for the treatment of breast cancer in the early stage, i.e. in the (neo) adjuvant phase, and in the metastatic stage, as well as for the treatment of metastatic gastric cancer.

The mechanism of action of trastuzumab has been well studied for many years and involves both the Fab binding part and the Fc domain with its effector functions. Therefore, various comparative in vitro studies to characterize the biological properties of this antibody were also carried out here in the development of biosimilars: Binding to HER2 and inhibition of cell proliferation were investigated with multiple assays. A comparable binding to the HER2 target antigen on the tumor cell surface could be confirmed and comparable HER2 signal chains were detected. The comparable ADCC activity was shown in different, orthogonal ADCC assays as well as the binding to the important Fcgamma receptors. Binding to FcγRIIa has been accepted as a surrogate for antibody-dependent cellular phagocytosis (ADCP) function.

No differences were found between the biosimilar and the EU or US reference drug in terms of binding to FcγRI, FcγRIIb, FcγRIIIb, the neonatal Fc receptor (FcRn) and the C1q complement protein.

An expected lack of CDC activity has also been scientifically proven.

The results of the biological comparability are shown as an example for trastuzumab-Celltrion (2):

There are now 5 approved biosimilars for trastuzumab (no duplicates) and all 5 products went through their own development program.

In all cases, a comparative pharmacokinetic study was carried out in healthy volunteers and all cases showed similar pharmacokinetic properties.

Two manufacturers selected patients with metastatic breast cancer as a patient collective for carrying out the comparative clinical study (Trazimera, Ogivri). Overall response rate (ORR) was the primary endpoint in these studies. Three manufacturers chose the neoadjuvant therapy phase for early breast cancer with pathological response rate (pCR) as the primary endpoint to demonstrate efficacy and safety (Kanjinti, Ontruzant, Herzuma). The equivalence limits were selected on the basis of existing efficacy studies with the originator according to statistical and clinical aspects.

In 2 cases (Kanjinti, Ontruzant) the 95% confidence interval (95% CI) for the comparison of the pCR exceeded the pre-specified upper equivalence limit. Formally, this did not rule out the possibility that the biosimilars in question could be more effective. However, when looking at all of the evidence from all comparability data, this was considered very unlikely.

Trastuzumab is a good example that authorization holders of originators anticipate the end of patent protection at an early stage and that this represents an incentive for further developments:

1. First, trastuzumab emtansine (Kadcyla) was approved in 2013. Kadcyla is an antibody-drug conjugate that contains trastuzumab and is covalently linked to DM1, a microtubulin inhibitor, through a thioether linker. Kadcyla is approved for the treatment of adult patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, individually or in combination.

Second, pertuzumab, a recombinant humanized monoclonal antibody that specifically binds to the extracellular dimerization domain of HER2 and thereby inhibits the ligand-dependent heterodimerization of HER2 with other receptors of the HER receptor family.

Pertuzumab is approved in all indication areas, i.e. for the (neo) adjuvant treatment of adult patients with HER2-positive early breast cancer and for the treatment of metastatic breast cancer, always indicated in combination with trastuzumab and chemotherapy.

This leads to the question of whether a doctor can also use the trastuzumab biosimilar instead of the trastuzumab originator, which is harmless from a scientific and regulatory point of view, since there are 2 versions of the same substance. The international non-proprietary name (INN), in this case trastuzumab, is deliberately listed in the product information and is not a trade name.

3. A third further development of the trastuzumab originator is an extension of the application options to include subcutaneous administration.

Pertuzumab plus trastuzumab

In Perjeta’s product information, use in the 3 stages of breast cancer ([neo] adjuvant and metastatic) is indicated, together with trastzumuab. Doctors are free to decide whether they want to use or prescribe the Originator Herceptin (in intravenous or subcutaneous administration) or one of the 5 available biosimilars. From a regulatory point of view, the trastuzumab products are comparable and interchangeable in their clinical behavior.

Bevacizumab is a recombinantly produced humanized monoclonal IgG1 antibody that is approved for the treatment of various advanced, metastatic, or recurrent cancers.

The mechanism of action has been well studied. Bevacizumab binds to the vascular growth factor VEGF ("vascular endothelial growth factor"), which is a key factor in vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) the surface of endothelial cells. Neutralizing the biological activity of VEGF reduces the vascularization of tumors, normalizes the existing tumor vasculature, and inhibits the formation of new tumor vasculature, thereby inhibiting tumor growth.

The characterization of the biological properties in the context of a biosimilar development follows the same principles as described above: the use of several test systems for the known biologically important properties in comparison with the reference drug.

There are currently 2 biosimilar bevacizumab products on the market in Germany: Bevacizumab Amgen (Mvasi) and Bevacizumab Pfizer (Zirabev). Both manufacturers each carried out a comparability study on pharmacokinetics in healthy volunteers in a 3-arm study (EU Avastin vs. US Avastin vs. biosimilar). It was the characterization after a single dose over a longer period of time. The pharmacokinetic properties were similar for the originator and biosimilars.

The determination of the comparable efficacy and safety was carried out in each case in a 2-arm randomized clinical study with over 600 patients with non-quamous non-small cell lung cancer. It showed a comparable effectiveness with regard to the objective response rate (ORR): The difference in the total population (“intent-to-treat”; ITT) for Mvasi was -2.90 (95% CI of the difference [-10.48 ; 4.67]) and for Zirabev 0.65 (95% CI of the difference [–6.61; 7.91]), and the secondary endpoints were similar in both cases.

The evaluation of the safety data did not reveal any differences in the type and frequency of the observed adverse drug reactions. ▄

DOI: 10.3238 / PersOnko.2019.11.15.03

Dr. med. Elena Wolff-Holz

Dr. med. Jan Müller-Berghaus
Paul Ehrlich Institute, Langen (PEI),

Dr. med. Martina way
Federal Institute for Drugs and Medical Devices, Bonn (BfArM)

Conflict of Interest: The authors declare that there is no conflict of interest

Part 1 was published on September 2, 2019 in "Perspektiven der Onkologie 2/2019".
Part 3 follows in "Perspektiven der Onkologie 1/2020", which will appear on March 13, 2020.

Literature on the Internet:

Jaglowski S, Alinari L, Lapalombella R, et al .: The clinical application of monoclonal antibodies in chronic lymphocytic leukemia. Blood 2010; 116: 3705-14 CrossRefMEDLINE PubMed Central
European Medicines Agency: Assessment report. Trazimera. International non-proprietary name: trastuzumab. Procedure No. EMEA / H / C / 004463/0000 https://www.ema.europa.eu/en/documents/assessment-report/trazimera-epar-public-assessment-report_en.pdf (last accessed on 21 October 2019).