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.
Findings
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.
Key takeaway
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.
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.
Key takeaway
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.
Findings
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.
Key takeaway
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.
Since the launch of the first biosimilar (Omnitrope®; somatropin) in 2006, 58 biosimilars have been approved in the EU and 26 in the USA. Licensing of biosimilars has several advantages for healthcare systems: increases medication choice, lowers costs, frees up budgets to provide more treatments, supports competition and sustainability in the pharmaceutical industry, and fosters innovation.
There are, however, several potential barriers to broad uptake of biosimilars in clinical practice. Some physicians may lack knowledge of these drugs or confidence in their use and may also have restrictions in choosing or switching between them. In many cases, pharmacopeia stocking of specific biologic agents are decided by administrative bodies and hospital pharmacists without consulting prescribers – often on grounds of cost considerations alone.
Bevacizumab is the first therapeutic agent for which biosimilars are available in mCRC. Like all biosimilars, these were EMA- and FDA-approved based on submitted data confirming structural similarity and functional equivalence as well as confirmatory clinical efficacy and safety studies versus the reference product. The goal of the latter exercise is not to re-establish clinical parameters by unnecessarily repeating the entire clinical development program for the reference product, but to confirm similar benefits in the most sensitive patient population. For bevacizumab biosimilars, sponsors and regulatory bodies agreed overall response rate in patients with NSCLC was a scientifically justified endpoint to confirm similarity. Since bevacizumab exerts its mode of action – the inhibition of tumour angiogenesis – regardless of the type of cancer, based on totality of evidence the licensed indications for bevacizumab biosimilars could be extrapolated to the treatment of mCRC.
Key takeaway
Licensing of biosimilars has a several potential advantages for healthcare systems, although there are several possible barriers to uptake. Bevacizumab biosimilars could serve as an example of extrapolation based on the totality of evidence.