Type: Immunogenicity

Abstract published: August 2021

Cardiotoxicity is the most important limitation in the application of trastuzumab, and one of the most important parameters to monitor when assessing the safety of a trastuzumab biosimilar.

Trastuzumab (Herceptin®) is the gold standard of care for people with early and metastatic breast cancers and metastatic gastric cancer overexpressing human epidermal growth factor receptor 2 (HER2). The phase III LILAC trial demonstrated ABP 980 had biosimilarity to trastuzumab reference product (RP) in women with HER2-positive early breast cancer, with no clinically meaningful difference between the two products. Based on the totality of evidence, ABP 980 was approved by the European Medicines Agency (EMA), and subsequently by the FDA, for the same indications as trastuzumab RP.

Cardiac toxicity is a rare but serious concern with trastuzumab; possibly related to HER2 blockade. In the LILAC study, patients were randomized to receive neoadjuvant ABP 980 or trastuzumab RP for 4 cycles prior to surgical resection, and consolidation treatment with either drug given every 3 weeks for up to 1 year thereafter. To monitor cardiac safety, an electrocardiogram and 2-D echocardiogram were performed at all visits.

Overall, no marked decline of left ventricular ejection fraction (LVEF) was observed. In patients who received ABP 980 or trastuzumab RP throughout the study and those who were switched from trastuzumab RP to ABP 980 in the adjuvant (postoperative) phase, LVEF decline (10–50%) was seen in 2.8%, 3.3%, and 3.5% of patients, respectively. There were no meaningful differences between treatment arms. Moreover, incidence of cardiac failure was comparable among the three groups: 2.2%, 0.5%, and 1.2%, respectively. The majority of LVEF decline cases were asymptomatic, and most patients exhibiting LVEF decline during the 1-year study had pre-existing cardiovascular conditions at baseline, including hypertension and arrhythmias. Most cardiac failure reports were grade 1 or 2, although none were classified a serious adverse event.

The LILAC study revealed a low incidence of cardiac toxicity following 1-year treatment with trastuzumab biosimilar ABP 980, with no clinically meaningful difference in the rate of LVEF decline between treatment arms. Cardiotoxicity is the most important limitation in the application of trastuzumab. Hence the acceptable safety and tolerability profile observed in this study suggests ABP 980 may be a useful choice in patients starting treatment or when considering switching from trastuzumab RP.

Key takeaway

Trastuzumab is the gold standard of treatment for HER2-expressing cancers, although it is associated with an increased cardiac toxicity risk. The biosimilar, ABP980, demonstrated biosimilarity to the reference product, suggesting no increased risk from switching to the trastuzumab biosimilar.

Abstract published: August 2021

Biosimilars are approved as highly similar to, but not necessarily interchangeable with, their reference biologic. As markets increasingly move towards accommodating lower-cost biosimilars and best-value biologics, how can clinicians be sure about safe switching?

Biologics are complex molecules manufactured using purified extracts from genetically engineered microorganisms and patented by the innovator company – generally for 10 years. After patent expiration, other manufacturers can market follow-on copies of the originator biologic, called biosimilars. Biosimilars cannot be considered identical to biologics due to differences in manufacturing processes – only “highly similar” – with no clinically meaningful differences.

In the USA,  interchangeability is determined by individual state laws, implying that biologics can be switched for biosimilars at pharmacy level without prescriber intervention. To be considered interchangeable, an applicant drug must demonstrate biosimilarity and evidence that it can be expected to produce the same clinical effects as the originator in any given patient and that switching would have no detectable adverse consequences.

Since biosimilarity does not automatically imply interchangeability, a recent study examined design features intended to support both regulatory designations simultaneously – incorporating elements to establish (1) biosimilarity and (2) interchangeability: (1) study participants are enrolled in a randomized, head-to-head comparator trial investigating safety and efficacy of the biosimilar versus originator; (2) participants are re-randomized in a switching study, receiving the biologic and biosimilar for at least one period of exposure each. Assessment should focus on the drugs’ pharmacokinetics and immunogenicity profiles.

Findings

The researchers concluded that performing switchover studies may not be absolutely necessary to support a designation of interchangeability. Multiple switches between biologics and biosimilars occur in routine daily clinical practice, and accumulating experience of this approach can provide a wealth of “real-world” data. In future, prospective registry studies and clinical trials (with real-world component) may obviate the need for dedicated switchover studies to establish interchangeability status.

Key takeaway

There are multiple instances of ‘real-world’ switches between biologics and biosimilars occurring in daily practice. Collating this data would provide a wealth of information relating to switching to aid in the designation of interchangeability of a given biosimilar.