George Barth Geller Professor of Medicine
Co-Director, Solid Tumor Therapeutics Program
Duke Cancer Institute
Durham, North Carolina
Jeffrey Crawford, MD, has disclosed that he has received consulting fees from Amgen, AstraZeneca, Coherus, Enzychem, Merck, and Pfizer and has served on data and safety monitoring boards for BeyondSpring, G1 Therapeutics, Janssen, Merrimack, Mylan, and Roche.
The use of biosimilars feels relatively unfamiliar for most practicing oncologists, even as there has been a significant increase in the number of FDA approvals. Unlike generics that can be made as exact copies of original small molecules through chemical synthesis, biosimilars are developed through biologic processes where the amino acid sequence and mechanism of action are identical to the reference biologic, but other features, including the host cell line, manufacturing process, and protein structure, may be slightly different.
Through vigorous preclinical testing, molecular characterization, preclinical modeling, pharmacokinetic/pharmacodynamic evaluation, studies of immunogenicity, and limited clinical studies, a biosimilar must be shown to be without any clinically meaningful differences from the reference product. Critical to this process is the concept of extrapolation. If a biosimilar is determined to meet prespecified criteria (ie, sufficient scientific justification), it is not necessary to conduct phase III clinical trials to compare the biosimilar with its reference biologic across different indications. Instead, the approval of the biosimilar agent can be extrapolated from the indications for the reference biologic.
Supportive Care Biosimilars
The FDA approved the first biosimilar in 2015: filgrastim-sndz. PIONEER, a phase III study in patients with breast cancer receiving myelosuppressive chemotherapy, directly compared filgrastim-sndz with filgrastim, finding equivalent outcomes in terms of neutropenia and related clinical endpoints. From those results, through extrapolation, the FDA granted indications for filgrastim-sndz to reduce neutropenia not only in the setting of myelosuppressive chemotherapy but also bone marrow transplantation, treatment of acute myeloid leukemia, and severe chronic neutropenia, and for peripheral blood progenitor cell mobilization.
In 2018, 4 additional supportive care biosimilars gained FDA approval: epoetin alfa-epbx for the treatment of anemia and filgrastim-aafi, pegfilgrastim-jmdb, and pegfilgrastim-cbqv, all for the management of neutropenia with the same indications as their reference products.
Current US guidelines on the use of myeloid growth factors recommend filgrastim-sndz as one option to prevent chemotherapy-related febrile neutropenia but cite a lack of available evidence to support the use of newer biosimilar approvals for this aim. Guidance on managing chemotherapy-related anemia endorses utilization of epoetin alfa-epbx but notes that more data are available in the setting of chronic kidney disease than in patients with cancer.
Biosimilars for the Treatment of Cancer
In 2017, bevacizumab-awwb became the first therapeutic biosimilar approved for patients with cancer. Phase III MAPLE, comparing bevacizumab-awwb with bevacizumab—each with carboplatin and paclitaxel—in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC), showed similar rates of objective response (39% vs 41.7%, respectively) as well as high-grade and treatment-emergent adverse events. Beyond NSCLC, bevacizumab-awwb is indicated in combination with various agents for metastatic renal cell or colorectal cancer and cervical cancer or as a monotherapy for glioblastoma.
Approval of trastuzumab-dkst followed soon after based on data from phase III HERITAGE where, again, objective response rates were equivalent between the biosimilar and its reference product, trastuzumab, (69.6% vs 64.0%, respectively) in patients with HER2-positive metastatic breast cancer receiving concomitant taxane therapy. Trastuzumab-dkst is also indicated for HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. Note that the use of both of these therapeutic biosimilars is still pending patent expiration for their reference products. More recently, after presentation of 2-year follow-up data at SABCS 2018, a second trastuzumab biosimilar—trastuzumab-pkrb—also received FDA approval for patients with HER2-positive breast cancer, setting the stage for future competition.
Finally, rituximab-abbs was approved in 2018 as the first biosimilar for the treatment of adult patients with CD20+ B-cell non-Hodgkin lymphoma following demonstration of tolerability and ORR equivalent to rituximab for patients with advanced (97% vs 92.6%, respectively) or low tumor burden (83% vs 81%, respectively) follicular lymphoma. Ongoing characterization of numerous biosimilar candidates—for reference products with current biosimilar approvals and for those without (eg, cetuximab)—will likely lead to additional approvals in the near future.
How Biosimilars Affect Patient Care and Counseling
For all of the approved agents, comparability in terms of clinical efficacy and safety has been shown. Of importance, in the setting of biosimilars, careful testing for immunogenicity has not demonstrated neutralizing antibodies or other toxicities that are unique from the reference biologics, and ongoing pharmacovigilance studies will be performed to be able to track both the reference biologics as well as the biosimilars in clinical practice over time.
Currently, only supportive care biosimilars are available for patients, but in the next 1-2 years, the therapeutic biosimilars noted above will become available. In all situations, in discussions with patients, it will be important for them to understand the rigorous approval process for these agents and their potential impact on clinical practice and economics. It is estimated that as many as $54 billion will be saved during the next 10 years through the use of biosimilars. These cost savings will occur across health systems, government and private insurance carriers, and for individuals where patient copays will be reduced, thus, hopefully leading to broader access to these important therapies.
Join this conversation on biosimilars in cancer care by leaving a comment or answering our polling question. Then, read earlier installments in this series of certified expert commentaries—one from Gary H. Lyman, MD, MPH, FASCO, FACP, FRCP, on addressing barriers to biosimilar adoption or one from Rowena N. Schwartz, PharmD, BCOP, with more detail on how biosimilars differ from reference biologics.