The phase III rituximab study (NCT02787239)  compared the efficacy and safety of HLX01 and the originator biological, Roche’s MabThera/Rituxan (rituximab). It compared the primary efficacy in best overall response rate (ORR) and safety profiles for six 3-week cycle treatments of 375 mg/m2 of either HLX01 with cyclophosphamide, doxorubicin, vincristine and prednisone (H-CHOP) or originator rituximab CHOP (R-CHOP) in previously untreated subjects with CD20+ diffuse large B‑cell lymphoma (DLBCL).
The multicentre,, double-blind, randomized, parallel-controlled, phase III study, which was carried out in China and planned to enrol 400 participants, was completed in May 2018.
Initially, a total of 81 CD20+ BCL patients who had reached complete response (CR) or CR uncertain (CRu) after treatment were randomized to receive a single infusion of 375 mg/m2 of either HLX01 (n = 40) or originator rituximab (n = 41). The geometric means ratio for AUC0-91D and Cmax [90% CIs] were 0.90 [0.81‒1.00] and 1.03 [0.95‒1.11], respectively. The baseline CD19+/CD20(+) B-cell counts were reduced and remained over 95% depletion for up to 91 days; safety profiles were similar in both treatment groups.
Subsequently, a total of 407 CD20+ DLBCL patients were randomized; 402 patients (H-CHOP:199; R-CHOP:203) in the full analysis set (FAS) and 382 patients (H-CHOP:188; R-CHOP:194) in the per-protocol study (PPS) were evaluated. Comparing H-CHOP with R-CHOP, the ORR analysis of the FAS was 92.5% and 92.0% with δ (equivalence margin difference) of 0.3% [95% CI: -4.87% to 5.56%; p = 0.839] and the PPS was 94.1% and 92.8% with δ of 1.4% [95% CI: -3.59% to 6.32%; p = 0.608], respectively. The number of adverse events (AEs), serious AEs (SAEs) and detection of anti-drug antibodies (ADAs) was comparable between the H-CHOP and R-CHOP groups.
The authors concluded that the results ‘successfully demonstrate equivalence in, PK/PD [pharmacokinetic/pharmacodynamic], efficacy and safety between HLX01 and rituximab sourced from China’. Furthermore, they added that ‘HLX01 does not demonstrate new safety signals in comparison with rituximab’.
The phase III trastuzumab study (NCT03084237)  compared the efficacy, safety and immunogenicity of HLX02 and EU-sourced originator trastuzumab, Roche’s Herceptin (trastuzumab), in HER2+, locally recurrent or previously untreated metastatic breast cancer.
The multinational, randomized, double-blind, parallel-controlled, phase III study (HLX02-BC01) planned to enrol 608 patients from approximately 83 centres in China, Poland, Ukraine and Philippines and is expected to be completed in August 2021. The primary efficacy endpoint was best ORR up to Week 24 (ORR24), and safety endpoints included immunogenicity and incidence of adverse events.
After different concentrations of HLX02 demonstrated acute and dose-dependent effect on the serum concentrations of 12 healthy males in a phase I clinical trial, a total of 109 healthy males were randomized to receive 6 mg/kg of HLX02 (n = 37),trastuzumab-EU(n = 37) or trastuzumab-US(n = 35). The geometric mean ratio of the AUC0-∞ [90% confidence intervals] for HLX02 / trastuzumab-EU, HLX02 / trastuzumab-US and trastuzumab-US / trastuzumab-EU were 0.914 [0.858-0.973], 0.950 [0.891‒1.013] and 0.962 [0.902‒1.025], respectively, all within the bioequivalence margin of 0.80‒1.25. No deaths, SAEs or ADA-positive results were observed in any of the treatment groups. Based on these results, 653 previously-untreated females with HER2-overexpressing metastatic breast cancer were randomized in the ongoing phase III pivotal study.
The authors concluded that the ‘three-way PK and safety equivalence of HLX02 and reference trastuzumab were demonstrated’. This they say led to initiation of the pivotal phase III study, which completed enrolment in June 2018. The authors believe the ongoing phase III study to be ‘the first China-manufactured trastuzumab product being investigated in a global setting’.
The results of the studies were presented at the European Society for Medical Oncology (ESMO) 2018 Congress, which took place on 19‒23 October 2018 in Munich, Germany.
Conflict of interest
The authors of the abstracts [1, 2] reported conflicts of interest, including being employed by, or owning stock in, Shanghai Henlius Biotech. For full details of the authors’ conflict of interest, see the abstracts [1, 2].
It should be noted that data of the studies presented in this article were published as abstracts and presented at a conference. These data and conclusions should be considered as preliminary until published in a peer-reviewed journal.
It should be noted that copy biologicals approved in China might not have been authorized following as strict a regulatory process as is required for approval of biosimilars in the European Union. The EMA (European Medicines Agency) regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biologicals, and also include a rigorous comparability exercise with the reference product.
Biosimilars of rituximab
Biosimilars of trastuzumab
1. Shi Y, Zhang Q, Han X, et al. 286P: First China-manufactured proposed rituximab biosimilar met primary efficacy and safety endpoints in CD20-positive diffuse large B-cell lymphoma (generics). Annals Oncol 2018;29(s9):1 November 2018, mdy437.005, https://doi.org/10.1093/annonc/mdy437.005
2. Zhang Q, Xu B, Zhang Q, et al. 44P: Global clinical trials validating bioequivalence with China-manufactured trastuzumab biosimilar, HLX02, and trastuzumab. Annal Oncol 2018;29(s9):1 November 2018, mdy428.005, https://doi.org/10.1093/annonc/mdy428.005
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