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Clinical equivalence in oncology biosimilar trials Posted 19/06/2020

Researchers from the US propose using restricted mean survival time (RMST) rather than the overall response rate (ORR) and progression-free survival (PFS) or overall survival (OS) in clinical trials evaluating the equivalence of biosimilars [1].

Biosimilar studies in oncology typically use the ORR evaluated at a specific time point as the primary endpoint. This is generally accepted by regulatory bodies, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, PFS would be a secondary endpoint in a biosimilar trial. However, authors, Hajime Uno and colleagues argue that ‘with a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study’.

As an example, the authors point to the HERiTAge trial, which evaluated the efficacy and safety of the trastuzumab biosimilar, Ogivri (trastuzumab‑dkst) vs originator trastuzumab (Herceptin), in combination with taxane as first-line therapy for patients with human epidermal growth factor receptor 2+(HER2+) metastatic breast cancer [2]. The primary endpoint was ORR on combination therapy at 24 weeks and was 69.6% for Ogivri (MYL-1401O) compared to 64% for Herceptin [3]. Biosimilar vs trastuzumab: ORR = 1.09, 90% confidence interval (CI) = 0.974 to 1.211), which supported the equivalence claim as it fell within the prespecified boundary of the CI of 0.81 to 1.24. However, the authors point out that the CIs of secondary endpoints, which included PFS and OS times during a 48-week follow-up, were rather large.

The authors believe that these wide confidence intervals may be interpreted as insufficient information regarding PFS and OS. They add that ‘it seems difficult to claim these two groups were similar with such a large range of possible hazard ratio values for the PFS or OS endpoint. For PFS, the hazard from the biosimilar group might be 28% higher than that from the reference product. Consequently, even if the biosimilar product is approved by the regulatory agencies, clinicians and patients may not be convinced to adopt the biosimilar as an alternative to the reference product’.

The authors therefore outline an alternative procedure based on the RMST, which has been discussed extensively for design and analysis of a general equivalence study, and which they say is ‘readily applicable to a biosimilar trial’. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence.

Using data from the HERiTAge trial the researchers calculated the RMST difference for PFS (38.8 weeks vs 37.5 weeks) as 1.3 weeks (95% CI = −1.3 weeks to 3.8 weeks). The largest plausible difference of 3.8 weeks was only 10.1% of 37.5 weeks from the reference group. Unlike the results from the hazard ratio, these time-scaled small differences in OS and PFS, coupled with the reference RMST values from the trastuzumab group, according to the authors, ‘provide a clinically meaningful way to evaluate whether the biosimilar is clinically equivalent to trastuzumab over a 48-week time window’.

Using the RMST as a summary measure of the survival curve, according to Uno et al., ‘will enhance better treatment decision making in adopting a biosimilar product over the reference product’.

Conflict of interest
Authors of the research paper [1] reported conflict of interest, including being an employee of Novartis. For full details of the authors’ conflict of interest, see the research paper [1].

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References
1. Uno H, Schrag D, Kim DH, et al. Assessing clinical equivalence in oncology biosimilar trials with time-to-event outcomes. JNCI Cancer Spectr. 2019;3(4):pkz058.
2. GaBI Online - Generics and Biosimilars Initiative. Safety and immunogenicity of originator and biosimilar trastuzumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Jun 19]. Available from: www.gabionline.net/Biosimilars/Research/Safety-and-immunogenicity-of-originator-and-biosimilar-trastuzumab
3. GaBI Online - Generics and Biosimilars Initiative. Candidate trastuzumab biosimilar meets equivalence requirements [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Jun 19]. Available from: www.gabionline.net/Biosimilars/Research/Candidate-trastuzumab-biosimilar-meets-equivalence-requirements

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