During a symposium held during the 23rd annual conference of the National Comprehensive Cancer Network (NCCN), held last week in Orlando, Florida, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center; Jeffrey Crawford, MD, of Duke University; and Lee Schwartzberg, MD, FACP, of University of Tennessee Health Science Center, presented on the use of biosimilars in oncology.
During a symposium held during the National Comprehensive Cancer Network (NCCN) 23rd Annual Conference, held last week in Orlando, Florida, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center; Jeffrey Crawford, MD, of Duke University; and Lee Schwartzberg, MD, FACP, of University of Tennessee Health Science Center, presented on the use of biosimilars in oncology.
Zelenetz opened the symposium by telling clinicians that, even if they have not yet used 1 of the FDA-approved biosimilars in practice, “Anyone who has used rituximab, I’m going to argue, has used a biosimilar. If you understand that concept, then you’ll understand the concept of biosimilarity.”
The concept, Zelenetz went on to explain, is manufacturing drift: a change in a biologic drug resulting from a change in any step in the manufacturing system. Any alteration in a manufacturing system—even a change in the size of a fermenter—can result in a different product. Rituximab, he argued, has undergone significant antibody-dependent cell-mediated cytotoxicity during changes to its manufacture.
The lot-to-lot variation resulting from product drift renders the rituximab used today, he said, essentially a biosimilar of the originally approved molecule. This fact, however, is not in itself cause for concern; International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use regulations minimize the impact of manufacturing changes on biologics.
Among the more significant problems posed by drift is the fact that it can complicate the development of a biosimilar; “some of the biosimilars that are in development have been in dozens if not a hundred variants before they have a clinical candidate.”
Extrapolation of Indications
Zelenetz also addressed the issue of extrapolation of indications, highlighting the fact that extrapolation is an established principle historically used by regulators and is not new to biosimilars. When there is a major change in manufacturing practice of an existing product, typically, 1 clinical trial is required to confirm equivalence of the original and updated products. The result of that trial may be extrapolated to all indications of the approved drug.
While Zelenetz acknowledged that clinicians might be more comfortable with a biosimilar product subject to trials in all indications, “Without extrapolation, the whole idea of biosimilars goes away…[that attitude] defeats the purpose” of biosimilars. He also underscored the fact that extrapolation only extends to the same mechanism of action; a trial of rituximab in rheumatoid arthritis would not lead to an extrapolated indication for lymphoma, for example, because the drug’s mechanisms of action in these indications are different.
Biosimilars in Supportive Care
Crawford addressed the use of biosimilars in supportive care, explaining that biosimilar filgrastim, Zarxio, was approved on the basis of 5 studies in healthy subjects, as well as on safety data in 204 healthy subjects and 214 patients with breast cancer. Since then, NCCN guidelines recommend the use of biosimilar filgrastim in the management of febrile neutropenia (FN), prophylaxis of FN, and mobilization of stem cells for autologous stem cell transplantation.
He also explained that a biosimilar epoetin alfa is currently under FDA review, and seeks all indications of the original biologic on the basis of preclinical, pharmacokinetic, pharmacodynamic, immunogenicity, and 2 distinct phase 3 trial data in chronic kidney disease; no data are included for chemotherapy-induced anemia.
“We as clinicians would be surprised to see a drug approved without a study in the setting in which we’re using it,” said Crawford.
Biosimilars and Cost
Schwartzberg addressed the growth in the cost of oncology in the United States, saying that nearly half of the $90 billion to $100 billion in annual spending on oncology comprises the cost of drug therapies, driven by “an increase in both usage and potentially the cost of drugs.”
A single year of trastuzumab therapy is, he estimated, $70,000 to $80,000 per patient, and the cost of trastuzumab increased by about 78% over the past decade; biosimilars have a clear potential to drive down spending on cancer treatment.
While Schwartzberg acknowledged that “there is perhaps a higher standard [of evidence] in the therapeutic setting” in cancer care when physician acceptance of biosimilars is concerned, and “clearly we have to look at long term outcomes, so pharmacovigilance for biosimilars will be important,” biosimilars’ effect on cost will be key. “[Biosimilars are] bending the cost curve, and reducing the cost of care.”