Randomised clinical endpoint studies for trastuzumab biosimilars: a systematic review

  • Michael CooryEmail author
  • Kate Thornton



Uptake of biosimilars depends on clinicians and patients having confidence in the evidential basis of marketing approval. The aim of this systematic review was to assess the evidential role of randomised clinical endpoint studies in the marketing approval of trastuzumab biosimilars.


We searched PubMed for any published reports of randomised studies associated with the five trastuzumab biosimilars approved by the EMA, as on 31 January 2019. We also searched for any ongoing studies for other trastuzumab biosimilars.


We identified eight published papers or abstracts for seven randomised clinical endpoint studies for five trastuzumab biosimilars approved by the EMA: four studies in the neoadjuvant setting and three in the first-line metastatic setting. Another six unpublished or ongoing studies for other trastuzumab biosimilars were identified via According to GRADE, and considered in isolation, the randomised studies would be categorised as low-quality evidence because of the use of surrogate endpoints and the small sample size. However, according to GRADE, the totality-of-evidence for each of the five approved trastuzumab biosimilars would be categorised as high quality in that further data would be unlikely to change the conclusion that each biosimilar was not different from Herceptin in any clinically important way.


The pivotal data for each marketing approval was not the randomised clinical endpoint study, but the in vitro analytic characterisation. Regulatory confidence in in vitro analytic characterisation stems from years of experience with manufacturing changes for originator biological medicines. This emphasis on in vitro data, as the most sensitive way to detect clinically important differences, will be a new way of thinking for many oncologists.


Biosimilar Trastuzumab Marketing approval In vitro characterisation Pivotal evidence 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

All the studies included in this systematic review were listed in, which confirmed that written informed consent was obtained from all individual participants included in the studies.


  1. 1.
    WHO Essential Medicines List 20th Edition.
  2. 2.
    Blackwell K, Gligorov J, Jacobs I, Twelves C (2018) The global need for a trastuzumab biosimilar for patients with HER2-positive breast cancer. Clin Breast Cancer 18(2):95–113CrossRefGoogle Scholar
  3. 3.
    Gottlieb S (2018) Capturing the benefits of competition for patients. In: Keynote address by Commissioner Gottlieb to the 2018 FDLI annual conference 2018Google Scholar
  4. 4.
    Camacho LH (2017) Current status of biosimilars in oncology. Drugs 77(9):985–997CrossRefGoogle Scholar
  5. 5.
    Nelson KM, Gallagher PC (2014) Biosimilars lining up to compete with Herceptin–opportunity knocks. Expert Opin Ther Pat 24(11):1149–1153CrossRefGoogle Scholar
  6. 6.
    European Medicines Agency (EMA) (2018) European Public Assessment Report. Ontruzant (trastuzumab) Procedure No. EMEA/H/C/004323/0000Google Scholar
  7. 7.
    European Medicines Agency (EMA) (2018) European Public Assessment Report. Kanjinti (trastuzumab) Procedure No. EMEA/H/C/004361/0000Google Scholar
  8. 8.
    European Medicines Agency (EMA) (2018) European Public Assessment Report. Herzuma (trastuzumab) Procedure No.EMEA/H/C/002575/0000Google Scholar
  9. 9.
    European Medicines Agency (EMA) (2018) European Public Assessment Report. Trazimera (trastuzumab) Procedure No.EMEA/H/C/004463/0000Google Scholar
  10. 10.
    European Medicines Agency (EMA) (2019) European Public Assessment Report. Ogivri (trastuzumab) Procedure No. EMEA/H/C/004916/0000Google Scholar
  11. 11.
    European Medicines Agency (EMA) (2015) Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues: EMEA/CHMP/BMWP/32775/2005_Rev. 1 Committee for Medicinal products for Human Use (CHMP)Google Scholar
  12. 12.
    European Medicines Agency (EMA) (2018) Guideline on similar biological medicinal products 4 containing recombinant granulocyte-colony stimulating 5 factor (rG-CSF) DRAFT: EMEA/CHMP/BMWP/31329/2005 Rev 1.2 Committee for Medicinal Product for Human Use (CHMP)Google Scholar
  13. 13.
    European Medicines Agency (EMA) (2012) Guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues: EMA/CHMP/BMWP/403543/2010 Committee for Medicinal Products for Human Use (CHMP)Google Scholar
  14. 14.
    Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, Gravanis I, Heim HK, Heinonen E, Ho K et al (2012) Biosimilars: what clinicians should know. Blood 120(26):5111–5117CrossRefGoogle Scholar
  15. 15.
    Lemery SJ, Ricci MS, Keegan P, McKee AE, Pazdur R (2017) FDA’s approach to regulating biosimilars. Clin Cancer Res 23(8):1882–1885CrossRefGoogle Scholar
  16. 16.
    Food and Drug Administration (FDA) (2017) Considerations in demonstrating interchangeability with a reference product, Guidance for Industry, Draft. In: U.S. Department of Health and Human Services, Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)Google Scholar
  17. 17.
    Im Y-H, Odarchenko P, Grecea D, Komov D, Anatoliy CV, Gupta S (2013) Double-blind, randomized, parallel group, phase III study to demonstrate equivalent efficacy and comparable safety of CT-P6 and trastuzumab, both in combination with paclitaxel, in patients with metastatic breast cancer (MBC) as first-line treatment. J Clin Oncol 31(5):629Google Scholar
  18. 18.
    Lammers PE, Dank M, Masetti R, Abbas R, Hilton F, Coppola J, Jacobs I (2018) Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer. Br J Cancer 119(3):266–273CrossRefGoogle Scholar
  19. 19.
    Pegram M, Tan-Chiu E, Freyman A, Vana A, Hilton F, Zacharchuk C, Ewesuedo R (2017) A randomized, double-blind study of PF-05280014 (a potential trastuzumab biosimilar) vs trastuzumab, both in combination with paclitaxel, as first-line treatment for HER2-positive metastatic breast cancer (Abstract 238PD). Ann Oncol 28:v74. CrossRefGoogle Scholar
  20. 20.
    Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ et al (2018) A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: final safety, immunogenicity and survival results. Eur J Cancer 93:19–27CrossRefGoogle Scholar
  21. 21.
    Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S et al (2018) Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol 36(10):968–974CrossRefGoogle Scholar
  22. 22.
    Rugo HS, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J, Sharma R, Baczkowski M, Kothekar M, Loganathan S et al (2017) Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial. JAMA 317(1):37–47CrossRefGoogle Scholar
  23. 23.
    Stebbing J, Baranau Y, Baryash V, Manikhas A, Moiseyenko V, Dzagnidze G, Zhavrid E, Boliukh D, Stroyakovskii D, Pikiel J et al (2017) CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial. Lancet Oncol 18(7):917–928CrossRefGoogle Scholar
  24. 24.
    von Minckwitz G, Colleoni M, Kolberg HC, Morales S, Santi P, Tomasevic Z, Zhang N, Hanes V (2018) Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial. Lancet Oncol 19(7):987–998CrossRefGoogle Scholar
  25. 25.
    Rugo HS, Curigliano G, Cardoso F, Gradishar WJ, Pegram M, Barrios CHH, CortesCastan J, Pennella E, Muniz R (2018) 324P settings-based efficacy comparison of trastuzumab biosimilars in breast cancer: a systematic literature review. Ann Oncol 29(suppl_8):mdy272.314–mdy272.314Google Scholar
  26. 26.
    Pivot X, Petit T (2018) Can we establish a hierarchy among trastuzumab biosimilar candidates? Br J Cancer 119(3):263–265CrossRefGoogle Scholar
  27. 27.
  28. 28.
    European Medicines Agency (EMA) (2006) Refusal Assessment Report Alpheon (recombinant human interferon-alfa-2a) Procedure No. EMEA/H/C/000585Google Scholar
  29. 29.
    European Medicines Agency (EMA) (2015) Refusal Assessment Report. Solumarv (human insulin). Procedure No. EMEA/H/C/003858/0000Google Scholar
  30. 30.
    Jackisch C, Scappaticci FA, Heinzmann D, Bisordi F, Schreitmuller T, Minckwitz G, Cortes J (2015) Neoadjuvant breast cancer treatment as a sensitive setting for trastuzumab biosimilar development and extrapolation. Fut Oncol 11(1):61–71CrossRefGoogle Scholar
  31. 31.
    Cortes J, Curigliano G, Dieras V (2014) Expert perspectives on biosimilar monoclonal antibodies in breast cancer. Breast Cancer Res Treat 144(2):233–239CrossRefGoogle Scholar
  32. 32.
    Stebbing J, Baranau Y, Manikhas A, Lee SJ, Thiruchelvam P, Leff D, Esteva FJ (2018) Total pathological complete response versus breast pathological complete response in clinical trials of reference and biosimilar trastuzumab in the neoadjuvant treatment of breast cancer. Expert Rev Anticancer Ther 18(6):531–541CrossRefGoogle Scholar
  33. 33.
    von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804CrossRefGoogle Scholar
  34. 34.
    DeMets DL, Cook T (2018) Challenges of non-intention-to-treat analyses. JAMA 321:145CrossRefGoogle Scholar
  35. 35.
    Wangge G, Klungel OH, Roes KC, de Boer A, Hoes AW, Knol MJ (2010) Room for improvement in conducting and reporting non-inferiority randomized controlled trials on drugs: a systematic review. PLoS ONE 5(10):e13550CrossRefGoogle Scholar
  36. 36.
    Rehal S, Morris TP, Fielding K, Carpenter JR, Phillips PP (2016) Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals. BMJ Open 6(10):e012594CrossRefGoogle Scholar
  37. 37.
    Mauri L, D’Agostino RB Sr (2017) Challenges in the design and interpretation of noninferiority trials. N Engl J Med 377(14):1357–1367CrossRefGoogle Scholar
  38. 38.
    Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B et al (2012) Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13(9):869–878CrossRefGoogle Scholar
  39. 39.
    Kim S, Song J, Park S, Ham S, Paek K, Kang M, Chae Y, Seo H, Kim HC, Flores M (2017) Drifts in ADCC-related quality attributes of Herceptin(R): impact on development of a trastuzumab biosimilar. MAbs 9(4):704–714CrossRefGoogle Scholar
  40. 40.
    Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK (2014) Biosimilars: the science of extrapolation. Blood 124(22):3191–3196CrossRefGoogle Scholar
  41. 41.
    Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N, Schunemann H (2006) An emerging consensus on grading recommendations? ACP J Club 144(1):A8–9Google Scholar
  42. 42.
    Vezer B, Buzas Z, Sebeszta M, Zrubka Z (2016) Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin 32(5):829–834CrossRefGoogle Scholar
  43. 43.
    Hiller L, Dunn JA, Loi S, Vallier AL, Howe DL, Cameron DA, Miles D, Wardley AM, Earl HM (2018) Adjuvant trastuzumab duration trials in HER2 positive breast cancer—what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results. BMC Cancer 18(1):391CrossRefGoogle Scholar
  44. 44.
    Lemery SJ (2017) When one is a hammer, everything looks like a nail. J Oncol Pract 13:10s–11sCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Faculty of Medicine, Dentistry and Health SciencesUniversity of MelbourneMelbourneAustralia

Personalised recommendations