THE ADVENT OF RITUXIMAB BIOSIMILARS: WHERE ARE WE NOW?
A biosimilar version of rituximab (TruximaTM) has recently been granted approval for the treatment of NHL, CLL, and rheumatoid arthritis (RA) in South Korea.44 Several potential rituximab biosimilars are currently in development, each in comparison with the originator (reference) rituximab (Table 3). A study in patients with newly diagnosed advanced FL showed pharmacokinetic similarity between a potential biosimilar to rituximab, CT-P10, and rituximab (each administered with CVP), with similar B-cell kinetics and immunogenicity.45 In another study, CT-P10 and rituximab showed equivalent pharmacokinetics, and comparable efficacy, pharmacodynamics, immunogenicity, and safety in patients with RA.46 A clinical study in patients with previously untreated FL showed therapeutic equivalence in overall response rate between another proposed biosimilar to rituximab, GP-2013, and rituximab sourced from the EU. In this trial, similarity was demonstrated for efficacy, pharmacokinetic, and pharmacodynamic parameters, with similar safety findings.47 In addition, the efficacy and safety of another potential biosimilar, BI-695500, in patients with low-tumor-burden lymphoma is under clinical investigation (ClinicalTrials.gov, NCT01950273). ABP 798, a potential biosimilar to rituximab, is in clinical development in patients with CD20-positive B-cell NHL (ClinicalTrials.gov, NCT02747043). Another potential biosimilar to rituximab, MabionCD20, is in development in patients with CD20-positive DLBCL (ClinicalTrials.gov, NCT02617485).
(To view a larger version of Table 3, click here.)
In nonclinical studies, PF-05280586, a proposed biosimilar to rituximab, showed the same primary amino acid sequence and similar physicochemical and in vitro functional properties as the licensed originator biologic.48 A study in patients with active RA demonstrated pharmacokinetic similarity of PF-05280586 to rituximab sourced from the EU (rituximab-EU) and the US (rituximab-US) and that of rituximab-EU to rituximab-US.49 In this trial, all 3 treatments were generally well tolerated, and the incidence of treatment-related adverse events was low. These encouraging findings support the ongoing development of PF-05280586 as a potential biosimilar to rituximab. A trial is ongoing to compare the efficacy, safety, pharmacokinetics, and immunogenicity of PF-05280586 to rituximab in patients with low-tumor-burden FL (ClinicalTrials.gov, NCT02213263).
FL accounts for up to 20% of all lymphomas. Debate continues over the optimal treatment strategy for untreated FL: the watch-and-wait approach vs therapeutic intervention. However, for patients who are candidates for systemic therapy, an anti-CD20 monoclonal antibody alone or in combination with chemotherapy remains at the forefront of the therapeutic landscape.
It is well recognized that rituximab will remain as the cornerstone of therapy in the treatment of patients with FL. The loss of exclusivity of composition-of-matter patents of biologics in recent and coming years, and the lack of access to rituximab in some countries are of particular concern for patients and physicians. Thus, it is relevant, appropriate, and necessary to develop a biosimilar to rituximab with the potential to generate cost savings and efficiencies for health care systems and to increase access to patients worldwide, which can help augment resources for other important aspects of health care.
It will be crucial to engage clinicians on the importance of biosimilars, and moreover, to increase understanding of data that underpin the development of biosimilars and how these data may translate into clinical practice. At present, several potential rituximab biosimilars are in development. As a result of extensive studies, the availability of safe and effective rituximab biosimilars is eagerly anticipated, potentially offering a greater range of therapeutic options and improved clinical benefits to patients with FL.
Medical writing support was provided by Neel Misra, MSc, of Engage Scientific Solutions, and funded by Pfizer Inc.
All the authors made substantial contributions to conception and design, execution, or analysis and interpretation of data; drafted the article or revised it critically; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
This review was supported by Pfizer Inc. JS has served on advisory boards for Pfizer, Boehringer Ingelheim, and Bristol-Myers Squibb, and on speakers bureaus for Celgene, Boehringer Ingelheim, and Eli Lilly. BD was a full-time employee of Pfizer at the time this manuscript was initiated. IJ is a full-time employee of Pfizer. JC has no conflicts of interests to declare in this work.
1. Cancer Research UK. Non-Hodgkin lymphoma incidence statistics. London: Cancer Research UK; 2011. Available from: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/nhl/incidence/uk-nonhodgkin-lymphoma-incidence-statistics#world. Accessed August 5, 2016.
2. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11. Lyon: International Agency for Research on Cancer; 2013 [updated October 9, 2014]. Available from: http://globocan.iarc.fr. Accessed August 5, 2016.
3. Union for International Cancer Control. Follicular lymphoma. Union for International Cancer Control, 2014 review of cancer medicines on the WHO list of essential medicines. Executive summary. Geneva: World Health Organization; 2014. Available from: http://www.who.int/selection_medicines/committees/expert/20/applications/FollicularLymphoma.pdf. Accessed August 5, 2016.
4. Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104(5):1258–1265.
5. Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980;125(4):1678–1685.
6. Genentech Inc. Rituxan (rituximab) injection prescribing information. South San Francisco, CA: Genentech Inc.; 1997 [updated April 2016]. Available from: http://www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed August 5, 2016.
7. Roche. MabThera 100 mg and 500 mg concentrate for solution for infusion. eMC+; 2014 [updated May 26, 2016]. Available from: http://www.medicines.org.uk/emc/medicine/2570/SPC/Mabthera+100mg+and+500mg+concentrate+for+solution+for+infusion. Accessed August 5, 2016.
8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. B-cell Lymphomas. Version 1. 2017. Fort Washington, PA: NCCN ; 2017 [updated 2017]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed February 9, 2017.
9. Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U, Ladetto M; ESMO Guidelines Working Group. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii76–iii82.
10. Czuczman MS, Gregory SA. The future of CD20 monoclonal antibody therapy in B-cell malignancies. Leuk Lymphoma. 2010;51(6):983–994.
11. Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol. 1996;14(4):1282–1290.
12. Wilder RB, Jones D, Tucker SL, et al. Long-term results with radiotherapy for Stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys. 2001;51(5):1219–1227.
13. Pugh TJ, Ballonoff A, Newman F, Rabinovitch R. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer. 2010;116(16):3843–3851.
14. Ardeshna KM, Smith P, Norton A, et al; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362(9383):516–522.
15. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014;15(4):424–435.
16. Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15(3):1110–1117.
17. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944–2952.
18. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203–1210.
19. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42–51.
20. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group Protocol e4402. J Clin Oncol. 2014;32(28):3096–3102.
21. Janssen Biotech, Inc. Imbruvica prescribing information. Horsham, PA: Janssen Biotech, Inc; 2016 [updated June 2016]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205552Orig1s012lbl.pdf. Accessed December 5, 2016.
22. National Cancer Institute. FDA approval for ibrutinib (Imbruvica): approved for chronic lymphocytic leukemia after previous treatment. Bethesda, MD: US Department of Health and Human Services; 2013 [updated April 8, 2015]. Available from: http://www.cancer.gov/about-cancer/treatment/drugs/fda-ibrutinib. Accessed August 5, 2016.
23. Janssen-Cilag International NV. IMBRUVICA 140 mg hard capsules. eMC+; 2014 [updated October 21, 2014]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003791/WC500177775.pdf. Accessed December 5, 2016.
24. US Food and Drug Administration. FDA approves Zydelig for three types of blood cancers [FDA news release]. Silver Spring, MD: US Department of Health and Human Services; 2014 [updated July 23, 2014]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm. Accessed August 5, 2016.
25. Genentech Inc. Gazyva prescribing information. South San Francisco, CA: Genentech Inc.; 2016 [updated February 2016]. Available from: https://www.gene.com/download/pdf/gazyva_prescribing.pdf. Accessed December 5, 2016.
26. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081–1093.
27. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013;122(7):1137–1143.
28. Marcus RE, Davies AJ, Ando K, et al. Obinutuzumab-based induction and maintenance prolongs progression-free survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study. Poster presented at: American Society of Hematology (ASH); December 3–6, 2016; Washington, DC.
29. Sehn LH, Assouline SE, Stewart DA, et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood. 2012;119(22):5118–5125.
30. Salles G, Morschhauser F, Lamy T, et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012;119(22):5126–5132.
31. Celgene. Revlimid prescribing information. Summit, NJ: Celgene; 2015 [updated February 2015]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021880s041lbl.pdf. Accessed December 5, 2016.
32. Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15(12):1311–1318.
33. Vital EM, Kay J, Emery P. Rituximab biosimilars. Expert Opin Biol Ther. 2013;13(7):1049–1062.
34. Baer WH, Maini A, Jacobs I. Barriers to the access and use of rituximab in patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: a physician survey. Pharmaceuticals (Basel). 2014;7(5):530–544.
35. Li E, Subramanian J, Anderson S, Thomas D, McKinley J, Jacobs IA. Development of biosimilars in an era of oncologic drug shortages. Drug Des Devel Ther. 2015;9:3247–3255.
36. Gogineni K, Shuman KL, Emanuel EJ. Survey of oncologists about shortages of cancer drugs. N Engl J Med. 2013;369(25):2463–2464.
37. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111–5117.
38. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. Silver Spring, MD: U.S. Department of Health and Human Services, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER); 2015 [updated April 2015]. Available from: http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed August 5, 2016.
39. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: European Medicines Agency; 2015 [updated December 18, 2014]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf. Accessed August 5, 2016.
40. European Medicines Agency. European public assessment reports (EPAR) for human medicines: biosimilars. London: European Medicines Agency; 2016. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125. Accessed June 21, 2016.
41. Sandoz, Inc. Zarxio (filgrastim-sndz) injection prescribing information. Princeton, NJ: Sandoz, Inc.; 2015 [updated March 20, 2015]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125553lbl.pdf. Accessed August 5, 2016.
42. US Food and Drug Administration. Filgrastim-sndz. Silver Spring, MD: US Department of Health and Human Services, US Food and Drug Administration; 2015 [updated March 6, 2015]. Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm436953.htm. Accessed August 5, 2016.
43. Expert Committee on Biological Standardization. Guidelines on evaluation of similar biotherapeutic products (SBPs). Geneva: World Health Organization; 2009 [updated October 19–21, 2009]. Available from: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. Accessed August 5, 2016.
44. Generics and Biosimilars Initiative (GaBI). Biosimilar rituximab approved in South Korea. GaBI online; 2016 [updated December 2, 2016]. Available from: http://gabionline.net/Biosimilars/News/Biosimilar-rituximab-approved-in-South-Korea. Accessed December 5, 2016.
45. Coiffier B, Sancho JM, Jurczak W, et al. Pharmacokinetic and safety of CT-P10, a biosimilar candidate to the rituximab reference product, in patients with newly diagnosed advanced stage follicular lymphoma (AFL). Poster presented at: American Society of Hematology (ASH); December 3–6, 2016; Washington, DC.
46. Yoo DH, Suh CH, Shim SC, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(3):566–570.
47. Jurczak W, Ilidia M, Govindbabu KS, et al. A phase III efficacy and safety study of the proposed rituximab biosimilar GP2013 versus rituximab in patients with previously untreated advanced follicular lymphoma. Poster presented at: American Society of Hematology (ASH); December 3–6, 2016; Washington, DC.
48. Karnik S, Thompson MS, DeGruttola H, et al. Characterization and comparison of PF-05280586—a proposed rituximab biosimilar to the licensed product. Poster presented at: American Association of Pharmaceutical Scientists-National Biotechnology Conference (AAPS-NBC 2013); May 20–22, 2013; San Diego, CA.
49. Becker JC, Melia LA, Gumbiner B, Thomas D, Spencer-Green G, Meng X. A phase I trial comparing PF-05280586 (a potential biosimilar) and rituximab in subjects with active rheumatoid arthritis. Poster presented at: 2014 American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Annual Scientific Meeting; November 15–19, 2014; Boston, MA.
50. Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly × 4 schedule. Blood. 2004;103(12):4416–4423.
51. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010;28(17):2853–2858.
52. Forstpointner R, Unterhalt M, Dreyling M, et al; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006;108(13):4003–4008.
53. Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004;22(23):4711–4716.
54. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106(12):3725–3732.
55. McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16(8):2825–2833.
56. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26(28):4579–4586.
57. Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156–5164.
58. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-Line Indolent trial. J Clin Oncol. 2013;31(16):1977–1983.
59. Hagenbeck A, Radford J, Van Hoof A, et al. 90Y-Ibritumomab tiuxetan (Zevalin®) consolidation of first remission in advanced-stage follicular non-Hodgkin’s lymphoma: updated results after a median follow-up of 66.2 months from the International, Randomized, Phase III First-Line Indolent Trial (FIT) in 414 patients. Blood. 2010;116 Suppl:abstr 594.
60. Leonard J, Jung SH, Johnson JL, et al. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. J Clin Oncol. 2012;30 Suppl:abstr 8000.
61. Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20(15):3262–3269.
62. Hainsworth JD, Litchy S, Burris HA 3rd, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20(20):4261–4267.
63. Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001;97(1):101–106.
64. Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28(29):4480–4484.
65. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–1018.
66. Martin P, Jung SH, Johnson JL, et al. CALGB 50803 (Alliance): a phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. J Clin Oncol. 2014;32 Suppl 5:abstr 8521.
67. Czuczman MS, Koryzna A, Mohr A, et al. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005;23(4):694–704.
68. McLaughlin P, Hagemeister FB, Rodriguez MA, et al. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol. 2000;27(6 Suppl 12):37–41.
69. Feuerlein K, Zucca E, Ghielmini M. First-line treatment of follicular lymphoma: a patient-oriented algorithm. Leuk Lymphoma. 2009;50(3):325–334.
Source: Cancer Management and Research.
Originally published april 24, 2017.