Study of the pharmacokinetics, pharmacodynamics, and safety of the biosimilar pembrolizumab RPH-075 compared to Keytruda® in patients with malignant neoplasms

Introduction: Pembrolizumab is a humanized monoclonal antibody selectively blocking the interaction between the PD-1 receptor and its ligands. The drug RPH-075 is a biosimilar to the original Keytruda®.

Objective: To establish the equivalence of pharmacokinetic (PK) properties, as well as pharmacodynamic (PD) parameters, safety, and immunogenicity of the drug RPH-075 compared to Keytruda® in patients with malignant tumors.

Materials and Methods: This multicenter double-blind randomized study included 90 patients with melanoma and non-small cell lung cancer who were randomized into two treatment groups (RPH-075 and Keytruda ®) in 1:1 ratio. In both groups, pembrolizumab was administered as monotherapy at a dose of 200 mg intravenously every 3 weeks until progression or intolerable toxicity. The primary aim of the study was to assess PK after the first administration. The primary endpoint for PK assessment was AUC(0–504), and for safety, it was the frequency of adverse events (AE). The decision on PK equivalence was planned to be made if the two-sided 90 % confidence interval (CI) for the geometric mean ratio of AUC(0–504) after a single administration of each drug would be within 80.00–125.00 %. Secondary endpoints included Cmax after the first administration, as well as the other PK, safety, and immunogenicity parameters. This study also assessed PK and PD parameters after multiple administrations, and a pilot efficacy assessment was planned.

Results: This article presents the analysis of data from the first stage of the study (after the first drug administration with a 3‑week observation period). The data analysis was blinded, and the treatment groups were coded as A and B. The 90 % CI for the geometric mean ratio of AUC(0–504) after the administration of drug A to AUC(0–504) of drug B was 93.50–121.16 %, and for the ratio of B to A, it was 82.54–106.95 %. The obtained intervals met the specified equivalence limit of 80.00–125.00 %, allowing us to conclude that RPH-075 and original Keytruda® are PK equivalent. Both drugs demonstrated comparably high saturation of PD-1 receptors on CD4+ / CD8+ lymphocytes at the end of the first cycle (day 22). Binding antibodies to pembrolizumab were detected in 2 patients (one in each group) over the analyzed period, indicating comparably low immunogenicity for both drugs. Safety profile analysis during this period revealed 7 AEs in 4 patients in group A and 4 AEs in 3 patients in group B. The frequency of AEs did not significantly differ between the groups.

Conclusions: PK, PD, immunogenicity, and safety parameters of the pembrolizumab biosimilar RPH-075 were equivalent to those of the original Keytruda®.

1. Tsarev I.L., Melerzanov A.V. Review of approaches to immunotherapy in oncology. Res Pract Med J 2017;4(3):51–65. (In Russ.). https://doi.org/10.17709/2409-2231-2017-4-3-5

2. Parry R.V., Chemnitz J.M., Frauwirth K.A., et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25(21):9543–53. https://doi.org/10.1128/MCB.25.21.9543-9553.2005

3. Keir M.E., Butte M.J., Freeman G.J., Sharpe A.H. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331

4. Mellman I., Coukos G., Dranoff G. Cancer immunotherapy comes of age. Nature 2011;480(7378):480–9. https://doi.org/10.1038/nature10673

5. Hamanishi J., Mandai M., Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol 2016;28(7):339–48. https://doi.org/10.1093/intimm/dxw020

6. Zhang H., Wu M., Zhu X., et al. A phase I, randomized, single-dose study to evaluate the biosimilarity of QL1206 to denosumab among Chinese healthy subjects. Front Pharmacol 2020;11:01329. https://doi.org/10.3389/fphar.2020.01329

7. Zhang H., Li C., Liu J., et al. Safety and pharmacokinetics of a biosimilar of denosumab (KN012): Phase 1 and bioequivalence study in healthy Chinese subjects. Expert Opin Investig Drugs 2021;30(2):185–192. https://doi.org/10.1080/13543784.2021.1863371

8. Farahani M.F., Maghzi P., Aryan N.J., et al. A randomized, double-blind, parallel pharmacokinetic study comparing the trastuzumab biosimilar candidate, AryoTrust®, and reference trastuzumab in healthy subjects. Expert Opin Investig Drugs 2020;29(12):1443–1450. https://doi.org/10.1080/13543784.2020.1831470

9. Bushra R., Shoaib M.H., Ali H., Ghayas S. Pharmacokinetics and bioequivalence assessment of optimized directly compressible Aceclofenac (100 mg) tablet formulation in healthy human subjects. PLoS One 2020;15(9):e0238951. https://doi.org/10.1371/journal.pone.0238951

10. Zhu X., Ding Y., Yu Y., et al. A Phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX02 to reference CN- and EU-sourced trastuzumab in healthy subjects. Cancer Chemother Pharmacol 2021;87(3):349–359. https://doi.org/10.1007/s00280-020-04196-9

11. Finck B., Tang H., Civoli F., et al. Pharmacokinetic and pharmacodynamic equivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects. Adv Ther. 2020;37(10):4291–4307. https://doi.org/10.1007/s12325-020-01459-y

12. Shin D., Lee Y.J., Choi J., et al. A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers. Cancer Chemother Pharmacol 2020;86(4):567–575. https://doi.org/10.1007/s00280-020-04144-7

13. Freshwater T., Kondic A., Ahamadi M., et al. Evaluation of dosing strategy for pembrolizumab for oncology indications. J Immunother Cancer 2017;5:43. https://doi.org/10.1186/s40425-017-0242-5