Anaemia is a common complication of chemotherapy treatment. The advent of ESAs has led to a reduction in transfusion requirements, improved QoL and reduced fatigue for patients with CIA . An important limitation of ESAs and biological medicines in general remains the high cost, which may limit access in some countries . EU-approved biosimilar medicines can offer physicians the reassurance of rigorous comparability studies and extensive clinical and post-marketing surveillance programmes, in addition to cost savings due to lower development costs. Post-approval studies are an important aspect of post-approval efficacy and safety assessment of biosimilar medicines. This study forms part of an ongoing surveillance programme for epoetin zeta, a biosimilar of epoetin alfa.
The primary objective of this observational study was to record the rate of response to treatment of CIA with biosimilar epoetins in the oncology and onco-haematology settings. The definitions of Hb response utilised herein reflect the nature of this study, as it not only includes achieving target Hb but also clinically significant increases in Hb (achievement of 10 g/dL, or an increase in 1 g/dL from inclusion). The results of this study contribute to the growing body of evidence regarding the efficacy and safety of epoetin biosimilars in oncology.
The efficacy results reported herein correlate closely with previous research on epoetin zeta. A phase III non-controlled study of epoetin zeta in CIA over a 12-week period reported a mean Hb increase of 1.8 g/dL in the intention-to-treat (ITT) population, with 81.5% of patients achieving ≥1 g/dL Hb increase , both outcomes being similar to the findings here. This was the first open-label study on biosimilars conducted in Europe, and while more are currently planned or underway, ORHEO remains the largest with regard to patient numbers. Mean Hb response reported in the current study is similar to that reported for epoetin alfa in CIA associated with multiple myeloma .
The rate of Hb response showed a reduction at M6 for patients with myeloma compared to M3. Myeloma therapy is associated with a relatively high risk of deep vein thrombosis, particularly in the case of thalidomide-anthracycline regimens . A possible reason for the reduction in Hb response noted here could be the setting of more conservative treatment targets due to thromboembolic risk associated with myeloma chemotherapy and the disease itself.
No unexpected adverse events (AEs) were seen during the course of this study. The overall rate of treatment-related AEs was similar to that reported previously for epoetin zeta (10.4%). The rate of thromboembolic events (3.55%) was lower than reported previously for epoetin zeta (4.2%)  and epoetin alfa (4.0%). Patient death was the main reason for discontinuing this study. No deaths were considered related to treatment, and the death rate in the current study can be attributed to the characteristics of the population, particularly the high rate of metastatic cancer at baseline.
As part of this study, WHO performance scale data and disease progression were collected to give context to Hb response rates reported. At baseline, 73.0% of patients were characterised by a WHO performance status of 0 or 1, compared to 68.3% at M3 and 69.7% at M6. Evidence suggests Hb levels correlate with WHO performance status , and while it is hard to distinguish changes due to disease progression and changes due to improvement in Hb, the number of patients with a WHO performance status of 0 increased at both M3 and M6, indicating that some patients felt more physically able upon completion of the study. In terms of disease progression, an improvement in disease state was considerably more common in patients with a lymphoma, at M6 (60.9%). This could be a result of the efficacy/safety profiles of treatments in this group. Any improvement or exacerbation in disease outcomes should not be considered related to epoetin treatment. Such outcomes are confounded by patient characteristics such as age and disease status, as well as the nature of chemotherapy regimens, which vary considerably, particularly in the case of the solid tumour category.
This manuscript reports the results of an observational study. It is therefore difficult to address potential confounding factors surrounding treatment. However, it is anticipated that the ORHEO study can complement the findings of controlled clinical trials through offering real-life treatment observation. There was a significant disparity between the numbers of patients with solid tumours compared to those with myeloma or lymphoma, which corresponds well with the relative epidemiology of these cancer types in Europe [24, 25]. The definition of response in this study relates to clinically meaningful change in Hb, as befits the real-life setting and observational nature. As such, the rate of response should not be compared with that reported in randomised controlled clinical trials. One important limitation in this study was the lack of representation from biosimilar epoetins other than Retacrit. This reflects availability at the centres involved during the course of the study, and is not through deliberate omission or inherent study design.
Given the negative impact anaemia has on the QoL and overall survival in most cancer types [2, 3], it is not surprising that European guidelines recommend ESA treatment to correct CIA and reduce the need for transfusion . Guidance from the EMA states that in patients with non-myeloid malignancies treated with chemotherapy and an Hb level of <10 g/dL, treatment with ESAs might be considered to increase Hb to ≤12 g/dL or to prevent further decline in Hb. In patients treated with curative intent, ESAs should be used with caution. Furthermore, the use of ESAs should be carefully reconsidered in patients with a high risk of thromboembolic events. ESAs have been of great use to vast numbers of cancer patients receiving chemotherapy and are associated with patient benefits such as freedom from RBC transfusion and improvements in QoL. However, biological medicines such as recombinant ESAs are costly. The introduction of biosimilar medicines has the potential to provide cost competition and reduce cost to the payer due to their lower development costs . Indeed, a recent cost-efficiency study conducted in France, Germany, Italy, Spain, and the UK compared various regimens of biosimilar and originator ESAs in the management of CIA . Biosimilar ESA therapy was consistently cost-efficient over treatment with originator products under both fixed and weight-based dosing scenarios. The cost benefits of biosimilar ESAs may therefore increase patient access to this important form of treatment. However, physicians should not be obliged to prescribe biosimilars for purely cost reasons; only on proof of quality, efficacy and safety should biosimilars be considered a viable option. This study adds to the body of evidence supporting the efficacy and safety of the biosimilar ESA epoetin zeta in patients with CIA.