A prospective review of the future of oncology and haematology therapeutics concludes emphatically that biosimilars have arrived in this space. The impact of these agents on cancer care will be great – as long as challenges to their uptake can be overcome.
Biological drugs (biologics) are a cornerstone of treatment for advanced solid tumours and haematological malignancies. However, they are structurally complex and expensive to develop and manufacture, and biologic treatment costs remain high. Patent expiration for various anti-cancer biologics has enabled the development of biosimilars – highly similar biologic products that have gained regulatory approval. Biosimilars are subject to abbreviated approval pathways and their lower development cost usually translates to discounted prices once marketed.
The EMA and FDA’s stepwise approach to establish comparability between a candidate biosimilar and its reference product involves a range of analytical, pre-clinical, and clinical studies. These trials determine that the biosimilar pharmacokinetics and efficacy are statistically equivalent (or non-inferior) to the reference product and that there are no differences in safety, pharmacodynamics, and immunogenicity. Regulatory approval of a biosimilar may be granted if the totality of evidence from all these investigations shows no clinically meaningful difference between the biosimilar and the originator. Extrapolation, licensing permission for the additional indications held by the originator biologic, may be considered by regulatory authorities if evidence shows it is scientifically justified. As an example, the anti-CD20 antibody rituximab’s mechanism of action is lysis of B cells expressing this surface protein, therefore the rituximab biosimilar CT-P10 was considered by EMA likely to exert therapeutic effects against other CD20+ cancers and extrapolated approval for these indications accordingly.
To date, biosimilars approved for cancer treatment are generally licensed for all indications held by their originator product. Parallel considerations have also led to broader acceptance that chronic patients may be switched from biologics to biosimilars without affecting treatment outcomes – subject to national and regional regulations on interchangeability. Nonetheless, decisions regarding switching should be led by treating physicians. Further data collection in this area is strongly encouraged.
The availability of new biosimilars offers the potential for direct cost savings as well as stimulating competition among alternative biologic/biosimilar options, pushing down prices and enabling better patient access to these vital treatments. Barriers to the marketing and uptake of biosimilars must be addressed to attain the full benefits of these drugs.
Biosimilars have abbreviated approval pathways leading to lower market costs. Biosimilars approved for cancer treatment are generally licensed for all indications held by their originator product offering the potential for direct cost savings as well as stimulating competition among alternative biologic/biosimilar options. Current barriers to uptake need to be addressed to increase biosimilar market share.
Biosimilars are ‘similar’ but not ‘identical’ to the originator. This distinction has caused considerable anxiety for cancer clinicians and patients alike. Better understanding of the rigorous process of developing and approving biosimilars, and increasing experience of their use, should eliminate this anxiety.
Biosimilars are an increasingly central element of the cancer treatment armamentarium; the three biggest-selling cancer drugs are the monoclonal antibodies rituximab, bevacizumab, and trastuzumab. Since biosimilar versions of all these drugs are now available, it is important to understand what biosimilars are, and what they are not.
The FDA and EMA have defined biosimilars as highly similar biologic products to approved originator products with no clinically meaningful differences. However, biosimilars and originator biologics have very different approval pathways. Originator biologics require extensive basic research, establishment of a production and purification plant, and a comprehensive program of clinical trials, separately performed for each indication. By contrast, biosimilars require a production facility and mostly physicochemical and functional comparisons with the originator. Clinical trials are then performed to compare the biosimilar’s pharmacokinetic attributes, efficacy, and safety in a highly sensitive population versus the originator drug. Clinical evaluation for biosimilars is less extensive because evidence for safety and efficacy in one indication may be extrapolated across all other indications for the originator.
Extensive analytical similarity testing to establish biosimilarity relative to the originator effectively justifies abridged clinical development programs for regulatory approval of biosimilars. Although clinicians may be understandably cautious about making substitutions of biosimilars for their familiar branded products, they should be reassured that the rigorous regulatory pathway for biosimilars ensures they are appropriate options for their approved indications.
Biosimilars and originator biologics have different approval pathways: originators require extensive basic research, whereas biosimilars require physicochemical and functional comparisons with the originator. Extensive analytical similarity testing establishes biosimilarity, justifying an abbreviated development and approval process.
ABP 215 is a novel biosimilar for bevacizumab. In this phase III randomised study its clinical efficacy and safety were compared versus reference product in patients with non-small cell lung cancer (NSCLC).
Bevacizumab is approved in the USA and EU for the treatment of several malignancies including NSCLC. ABP 215 is the first approved biosimilar for bevacizumab. Similarity between ABP 215 and bevacizumab reference product (RP) has been demonstrated in multiple, rigorous non-clinical and pre-clinical evaluations. To add further evidence in support of the clinical value of ABP 215, the phase III, randomised MAPLE study was conducted to compare its efficacy, safety, immunogenicity, and pharmacokinetic profiles versus bevacizumab RP in patients with NSCLC.
Eligible patients starting first-line chemotherapy for NSCLC were randomly assigned to receive add-on ABP 215 or bevacizumab for up to six 3-weekly cycles. In ABP 215 and bevacizumab RP groups, objective responses (defined as complete or partial response) were recorded in 39% and 42% of patients, respectively. Since this result was within the prespecified equivalence margin, clinical efficacy of the two treatments was concluded similar. Secondary endpoints such as progression-free survival and overall survival were also comparable in both treatment groups. Adverse events, pharmacokinetic values (i.e., trough serum concentrations), and immunogenicity assessments (i.e., anti-drug antibodies) were also similar between the two groups.
This phase III equivalence study comparing ABP 215 and bevacizumab RP completes the totality of evidence recommended by regulatory agencies for biosimilars development. Together with the results of previous studies, this study confirms biosimilarity between ABP 215 and bevacizumab RP.
The biosimilarity between the bevacizumab RP and the biosimilar ABP 215 was confirmed by the totality of evidence from previous studies and a phase III equivalence study in patients with NSCLC.
In the last few years, five new biosimilar versions of trastuzumab (Herceptin®) have been rigorously tested and approved by the FDA, although patent issues with the originator initially halted their market launch. With so many options becoming available, widespread adoption of trastuzumab biosimilars may depend on healthcare providers’ degree of comfort with evidence for their safety and efficacy.
Trastuzumab (Herceptin®) is approved in the USA for the treatment of early-stage and metastatic breast cancer overexpressing HER2. However, its high cost – at least $70,000 per year – can be a barrier to patient access. Due to their abbreviated approval processes, biosimilars including trastuzumab can potentially enter healthcare markets at lower cost than the original drug; hence biosimilar trastuzumab may provide patients an opportunity for expanded utilisation of this therapy.
Based on supporting evidence for their structural and functional similarity, equivalent pharmacological properties and efficacy versus originator product, the US FDA has approved five trastuzumab biosimilars for use in multiple indications to-date. The first of these biosimilars, named trastuzumab-tkst (Ogivri®), was evaluated clinically in a phase 3 trial in HER2+ metastatic breast cancer. This biosimilar, in combination with chemotherapy, was associated with a 69.9% overall response rate (ORR) compared with 64% for trastuzumab. Trastuzumab-tkst was FDA approved in 2017. Subsequently, four more trastuzumab biosimilars – namely trastuzumab-pkrb (Herzuma®; approved 2018), trastuzumab-dttb (Ontruzant®; 2019), trastuzumab-qyyp (Trazimera®; 2019), and trastuzumab-anns (Kanjinti®; 2019) – were assessed in phase III trials, all in the setting of HER2+ breast cancer, and demonstrated equivalent response rates and survival endpoints to those elicited by originator trastuzumab. Moreover, similar rates of adverse events were seen for biosimilar and trastuzumab groups in all studies.
Misconceptions on the level of evidence for biosimilars may pose a barrier to the utilisation of these drugs. Probably the most unfamiliar concept in the approval process for biosimilars is extrapolation of indications for which the originator biologic, but not the biosimilar, has been studied. However, scientific evidence to justify extrapolation based on biosimilarity is available for all approved products. Trastuzumab’s safety and efficacy are established for early-stage and metastatic breast cancer and metastatic gastric cancer. Based on the overall totality of evidence for trastuzumab biosimilars, they were also approved for the same indications. Uptake of these biosimilars will likely be proportionate with the level of confidence they inspire.
Trastuzumab biosimilars have been approved based on the totality of evidence demonstrating biosimilarity to the reference product. Biosimilar uptake will be proportionate with the level of confidence inspired depending upon education of biosimilar efficacy and safety.