As biosimilars become more widely available in oncology, it is important that clinicians appreciate the distinct confirmatory role of comparative clinical studies in the biosimilar paradigm.
Biologics have a significant role in the clinical management of a range of medical conditions, including cancer and have the potential to provide cost savings and widen patient access to biologics. Despite the introduction of several therapeutic biosimilars, including monoclonal antibodies (mAbs), many oncologists in Europe and the USA remain uncomfortable or unfamiliar with their regulatory approval framework and use.
The FDA defines a biosimilar as “highly similar to the reference biologic with no clinically meaningful differences in terms of safety, purity, and potency”. Biosimilar development requires a stepwise hierarchical characterisation exercise to demonstrate structural and functional comparability to the originator and a comparative clinical trial to rule out any differences. This exercise may differ in study design and choice of endpoints to those of traditional phase III trials because the aim is to ascertain clinical equivalence, or biosimilarity between the products. As an example, cancer studies may include progression-free survival and overall survival as efficacy endpoints, whereas biosimilars may have short-term endpoints, such as overall response rate, which would be considered appropriate to expose any product-related differences. Determination of biosimilarity is based on the totality of evidence from all stages of development.
From scientific, cost, and ethical perspectives, biosimilars should not aim to replicate data acquired for the originator product in all its indications, but approval may be ‘extrapolated’ to these based on successfully demonstrating biosimilarity in one clinical scenario, if adequately justified. As an example, five trastuzumab biosimilars have been approved in Europe and the USA. During development, these five biosimilars each underwent comparative pharmacokinetic assessment in healthy volunteers and were then clinically compared to trastuzumab originator in patients with HER2-positive breast cancer. However, the five comparative clinical studies were conducted in different patient populations – three trials included patients with early breast cancer in neoadjuvant and adjuvant settings, whereas two of the studies assessed first-line treatment against metastatic breast cancer. These trial designs were all accepted by FDA and EMA as sufficiently sensitive to assess similarity, confirming there were no clinically meaningful differences between the proposed biosimilars and trastuzumab.
Thus, comparative clinical trials remain a central component of biosimilars development.
Key takeaway
Clinical trials for biosimilars do not need to show clinical benefit against a disease but, instead, need to show clinical equivalence (biosimilarity) to the originator. Determination of biosimilarity is based on the totality of evidence from all stages of development and extrapolation of indications may be justified from results demonstrating clinical equivalence in one clinical scenario.
The anti-ERBB2 humanised monoclonal antibody trastuzumab (Herceptin®) is well known to improve of progression-free survival and overall survival in patients with ERBB2-positive breast cancer. However, trastuzumab is not widely available around the world, and a biosimilar treatment option may increase global access. This confirmatory efficacy and safety study was performed as the final step in assessing bioequivalence of a proposed trastuzumab biosimilar, Mylan®.
Development of biosimilars is a high priority for drug developers and health authorities throughout the world to provide access to high-quality alternatives to approved biologics including monoclonal antibodies. Trastuzumab (Herceptin®) is a monoclonal antibody that, in combination with chemotherapy, markedly improves survival in metastatic and early-stage HER2-positive breast cancer compared with chemotherapy alone. The Heritage Study was designed to compare efficacy, safety, and immunogenicity of a proposed biosimilar, Mylan®, versus reference trastuzumab, each combined with a taxane, in patients with HER2-positive metastatic breast cancer.
Findings
After 24 weeks’ treatment, overall response rate was 69.9% for the biosimilar and 64% for trastuzumab. This result was within the predefined equivalence boundaries for efficacy of the proposed biosimilar versus trastuzumab. There were no statistically significant differences between the two treatment groups for any of the secondary endpoints (time to tumour progression, progression-free survival, and overall survival at 48 weeks). Population pharmacokinetics parameters were comparable for the proposed biosimilar and trastuzumab, as were the respective safety profiles. There were no changes of left ventricular ejection fraction in any patients at week 24, and low immunogenicity was confirmed for both drugs.
This confirmatory safety and efficacy study demonstrated that 24-week treatment with proposed biosimilar, Mylan®, results in equivalent objective response rate compared with trastuzumab in women with HER2-positive metastatic breast cancer receiving taxanes. This clinically effective biosimilar may help increase access to trastuzumab therapy.
Key takeaway
The trastuzumab biosimilar Mylan® had similar efficacy, pharmacokinetic parameters, and safety profiles as the reference product. This may help increase access to trastuzumab therapy for patients with HER2-positive metastatic breast cancer.
Pegfilgrastim (EU-approved Neulasta®) is widely used for prevention of chemotherapy-induced neutropenia in patients with cancer. This study investigated PK/PD comparability of a new pegfilgrastim biosimilar (Pelmeg®) versus Neulasta® in healthy subjects.
Neutropenia, defined as an absolute neutrophil count (ANC) <0.5 x 109 cells/L, is an important limiting factor in the application of myelosuppressive chemotherapy in cancer patients. Duration of neutropenia and the ANC nadir are correlated with the development of infectious complications, which can necessitate chemotherapy dose reductions, compromise tumour control, and adversely affect patient survival.
Pegfilgrastim is a long-acting granulocyte colony-stimulating factor (G-CSF) analogue indicated for the prevention of neutropenia in this setting. This first-in-human study looked at the pharmacokinetics (PK) and pharmacodynamics (PD) of Pelmeg® (development code B12019), a novel biosimilar version of pegfilgrastim, with the aim of confirming comparability to the reference product (EU-approved pegfilgrastim; Neulasta®). Safety and immunogenicity, as detected by anti-drug antibody (ADA) assay, were also analysed. The study featured a two-way cross-over design whereby patients were randomised to receive Pelmeg followed by Neulasta or vice versa.
Findings
Analysis of PK endpoints showed no relevant difference in exposure of pegfilgrastim after administration of Pelmeg® or Neulasta®. Hence, PK comparability between test and reference products was shown. ANC profiles were very similar after administration of Pelmeg® or Neulasta®. Following administration of either drug, mean ANC increased and reached a peak 3.5 days post-dose, decreasing thereafter and reaching pre-dose level at around day 18. No difference in ANC was seen between either drug. The percentage of subjects with adverse events was comparable for both Pelmeg® and Neulasta®, and no clinically relevant ADA signals were detected. Pelmeg® was found to be highly similar to the reference product.
Key takeaway
Pelmeg®, a pelgrastim biosimilar, was found to have comparable absolute neutrophil PK and PD properties to its reference product.
Although screening programs exist, most patients with colorectal cancer (CRC) are diagnosed after onset of symptoms and have advanced disease. Biologic medicines are vital for the treatment of serious conditions such as CRC – but at a high financial burden. BE1040V is a bevacizumab biosimilar developed with the aim of increasing access to treatment and reducing mortality due to CRC.
Metastatic colorectal cancer (mCRC) is the second-highest cause of cancer death worldwide with a 5-year survival rate around 14%. In unresectable cases, first-line systemic therapy may be an option – which includes combination chemotherapy plus biologics targeted against vascular endothelial growth factor (VEGF) (e.g., bevacizumab). This phase III randomised study conducted in 22 centres in Iran aimed to evaluate the efficacy, safety, and immunogenicity of BE1040V, a bevacizumab biosimilar, versus its reference product in patients with mCRC.
Findings
Following treatment with BE1040V or bevacizumab, the primary endpoint of progression-free survival (PFS) was 7.7 months and 7 months, respectively, suggesting noninferiority between BE1040V and bevacizumab. No significant intergroup differences were detected for adverse events nor for any secondary endpoints including overall survival (OS), objective response rate (ORR), and time to treatment failure (TTF). Anti-drug antibodies developed in only two patients (one per treatment group).
No statistically meaningful differences were found between BE1040V and reference bevacizumab in terms of PFS, OS, ORR, TTF, safety, and immunogenicity. The trialists concluded BE1040V has noninferior efficacy and comparable tolerability to reference bevacizumab in patients with mCRC.
Key takeaway
The bevacizumab biosimilar BE1040V was found to have no meaningful differences in safety and efficacy to the originator in a multi-centre, randomised, study conducted in metastatic colorectal cancer patients.