Pegfilgrastim is indicated for reducing duration of neutropenia and incidence of febrile neutropenia associated with chemotherapy regimens in cancer patients. This study compared the prophylactic efficacy of MYL-1401 biosimilar versus reference pegfilgrastim in a guideline-recommended sensitive population of breast cancer patients receiving high-risk chemotherapy.
Biologics have great therapeutic potential but are associated with a high cost, which consequently affects their availability – the two principal limitations that biosimilars are designed to address. Among the first biosimilars to receive EMA/FDA approval was filgrastim, indicated for the prophylaxis of chemotherapy-induced neutropenia (CIN), infections, and dose reductions in cancer patients. Whereas filgrastim is administered daily, its long-acting form, pegfilgrastim, can be given once per chemotherapy cycle. MYL-1401H is a pegfilgrastim biosimilar with preclinical and pharmacokinetic/pharmacodynamic data that supports equivalence to the originator drug. This phase III safety and efficacy trial was designed to confirm equivalence between MYL-1401H and pegfilgrastim for CIN prophylaxis.
The study included patients with breast cancer eligible to receive adjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy every 3 weeks for six cycles. CIN prophylaxis was administered 24 hours after day 1 of each chemotherapy cycle.
Mean duration of severe neutropenia in both the MYL-1401H and pegfilgrastim groups was 1.2 days, demonstrating equivalent efficacy between the two groups. Secondary endpoints including absolute neutrophil count (ANC) nadir and time to ANC nadir were also similar. Across all cycles, febrile neutropenia (FN) occurred in 6% patients receiving MYL-1401H and 2% pegfilgrastim, suggesting noninferiority of this parameter. All cases of FN were of short duration and no infections required treatment. Similar rates of treatment-emergent adverse events (TEAEs) were observed between groups. One patient in the pegfilgrastim group and no patients in MYL-1401H group had treatment-induced antidrug antibodies.
In this study MYL-1401H demonstrated equivalent efficacy to pegfilgrastim for prophylaxis of CIN in patients with breast cancer undergoing TAC chemotherapy. Both products were generally well tolerated, with no clinically meaningful differences of TEAEs.
Long-acting pegfilgrastim is indicated for the prophylaxis of CIN, infections, and dose reductions in cancer patients. This phase III trial demonstrated equivalent efficacy of the biosimilar MYL-1401H to the originator product.
Trastuzumab is a humanised monoclonal antibody that binds to HER2 and effectively fights breast cancer cells overexpressing this oncoprotein. This study looked at the pharmacokinetics of a novel biosimilar version of trastuzumab and aimed to confirm its bioequivalence with both EU- and US-sourced originator biologics.
Monoclonal antibody (mAb) biologics that target the host immune response or modify specific intracellular pathways have been successfully established for the treatment or palliation of many different cancers. Trastuzumab is a mAb directed against HER2, an oncoprotein overexpressed in some patients with breast and gastric cancers. MYL-0140 is the first FDA-approved trastuzumab biosimilar. In this phase I bioequivalence study, its pharmacokinetics profile was compared with those of both EU- and US-sourced trastuzumab (i.e., EU-trastuzumab and US-trastuzumab).
Healthy male subjects were randomized to take a single infusion of MYL-0140, EU-trastuzumab, or US-trastuzumab. Blood samples were collected regularly over the first 48 hours post-infusion and at approximately 1–2-week intervals thereafter for up to 10 weeks. Treatment-emergent adverse events (TEAEs) were monitored throughout the study.
Serum trastuzumab concentration–time curve was similar across all three treatment groups. All pharmacokinetic parameters (peak serum concentrations and the area under the curve values) across the groups were within the pre-defined bioequivalence interval. All TEAEs were mild or moderate in severity, and the number of subjects with antidrug antibodies (ADAs) was comparable among the groups.
This study demonstrates bioequivalence between single-dose MYL-0140, EU-trastuzumab, and US-trastuzumab administered to healthy subjects. All three drugs had similar safety profiles and there was no evidence of immunogenicity.
Trastuzumab is a monoclonal antibody directed against HER2-overexpressing cancers. This phase I bioequivalence study demonstrated bioequivalence between single-dose MYL-0140, EU-trastuzumab, and US-trastuzumab administered to healthy subjects.
A large body of experience shows trastuzumab is safe and effective for neoadjuvant treatment of HER2-positive early breast cancer. This study assessed the biosimilarity of ABP 980 and reference trastuzumab in terms of efficacy, safety, and immunogenicity and thereby sought to add to the existing totality of evidence from analytical, functional, and pharmacokinetic studies for ABP 980.
Trastuzumab is the gold standard of care in many countries for patients with HER2-overexpressing breast cancers. The biosimilar ABP 980 has demonstrated analytical similarity to trastuzumab with respect to structure, function, and pharmacokinetic profile; this randomised study was performed to assess the two drugs’ clinical similarity, as well as the safety and efficacy of switching between originator and biosimilar, in women with operable HER2-positive early breast cancer.
Enrolled patients were divided into three groups: a loading dose and three cycles of 3-weekly neoadjuvant ABP 980 or trastuzumab (in combination with chemotherapy) prior to surgery and, thereafter, continued to receive adjuvant ABP 980 (group 1) or trastuzumab (group 2) or were switched from trastuzumab to ABP 980 every 3 weeks (group 3) for a total treatment period of 1 year.
The rate of patients achieving the primary endpoint (a pathological complete response based on laboratory tests of tumour tissue at time of surgery) in ABP 980 and trastuzumab groups was 48% and 41%, respectively. According to the sensitivity analysis, the risk difference and the relative risk of achieving the primary endpoint were within the predefined equivalence margins. The overall incidence of adverse events in the two treatment groups during both the neoadjuvant and adjuvant phases was similar. Moreover, switching patients from ABP 980 to trastuzumab did not affect safety – incidence of adverse events in the switching group was similar to that in patients who continued to receive trastuzumab in adjuvant phase. No patients in all groups tested positive for neutralizing antibodies.
Safety, efficacy, and clinical outcomes did not differ for ABP 980 and trastuzumab reference product in women with HER2-positive early breast cancer. Similarities continued during the neoadjuvant and adjuvant phases and switching from trastuzumab to ABP 980 did not lead to any new or unexpected safety signals.
Trastuzumab is the gold standard of care in many countries for patients with HER2-overexpressing breast cancers. The biosimilar ABP 980 has demonstrated analytical similarity to trastuzumab with respect to structure, function, and pharmacokinetic profile; switching from trastuzumab to ABP 980 does not lead to any new or unexpected safety signals.
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.
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.