Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase III equivalence trial

Background and purpose: For patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients. However, the reference original research trastuzumab (Herceptin^®) is more expensive. Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment. This clinical trial aimed to evaluate the efficacy, pharmacokinetics, safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab (Herceptin^®) in patients with HER2-positive metastatic breast cancer. Methods: This multi-center, randomised, double-blind phase III clinical trial was conducted in 43 subcenters in China. This study complied with the research protocol, the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials. It was approved by the hospital's medical ethics committee. The clinical trial registration agency is the State Food and Drug Administration (clinical trial approval number: 2015L04224; clinical trial registration number: CTR20170516). Written informed consent was obtained from subjects before enrollment. Enrolled patients were randomly assigned to the AK-HER2 group and the control group, respectively receiving AK-HER2 or trastuzumab (initial loading dose 8 mg/kg, maintenance dose 6 mg/kg, every 3 weeks as a treatment cycle, total treatment time is 16 cycles) in combination with docetaxel (75 mg/m2, treatment duration is at least 9 cycles). The primary endpoint of this clinical trial was the objective response rate (ORR9) between the AK-HER2 group and the control group in the 9th cycle. Secondary efficacy endpoints included ORR16, disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS) and 1-year survival rate. In this study, 100 subjects (AK-HER2 group to control group=1:1) were randomly selected for blood sample collection after the 6th cycle of medication, The collection time points were 45 minutes after infusion (the end of administration), 4, 8, 24, 72, 120, 168, 336, and 504 hours after the end of administration. After collection, blood samples were analyzed by PK parameter set (PKPS). Other evaluation parameters included safety and immunogenicity assessment. Results: A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep. 2017 and Mar. 2021. In the AK-HER2 group (n=237), 129 subjects in the experimental group achieved complete response (CR) or partial response (PR), and the ORR9 was 54.4%. There were 134 subjects in the control group (n=241) who achieved CR or PR, and the ORR9 was 55.6%. The ORR9 ratio between the AK-HER2 group and the control group was 97.9% [90% confidence interval (CI): 85.4%-112.2%, P=0.784], which was not statistically significant. In all secondary efficacy endpoints, no statistically significant differences were observed between the two groups. We conducted a mean ratio analysis of pharmacokinetics (PK) parameters between the AK-HER2 group and the control group, and the results suggested that the pharmacokinetic characteristics of the two drugs are similar. The incidence of treatment emergent adverse event (TEAE) leading to drug reduction or suspension during trastuzumab treatment was 3.6% (10 cases) in the AK-HER2 group and 8.1% (22 cases) in the control group. There was statistically significant difference between the two groups (P=0.027). The incidence rate was significantly lower in the AK-HER2 group than in the control group, and there was no statistically significant difference among the other groups. The differences in the positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAB) between groups were of no statistical significance (P=0.385 and P=0.752). Conclusion: In patients with HER2-positive metastatic breast cancer, AK-HER2 was comparable to the trastuzumab (Herceptin^®) in terms of drug efficacy, pharmacokinetics, safety and immunogenicity.