Paper Raises Unanswered Questions About Subcutaneous Trastuzumab

While US patients with HER2-positive cancers do not have an available subcutaneous trastuzumab option, Brazil, Canada, and the European Union have an approved product that has been shown in a phase 3 trial to be noninferior to intravenous trastuzumab. 
The Center for Biosimilars Staff
November 04, 2018
While US patients with HER2-positive cancers do not have an available subcutaneous (SC) trastuzumab option, Brazil, Canada, and the European Union have an approved product that has been shown in a phase 3 trial to be noninferior to intravenous (IV) trastuzumab. 

This product has substantial benefits related to patient comfort and provider time, but it also has benefits for trastuzumab’s sponsor, Roche, as there are no approved biosimilars of the SC formulation to compete with this product.

As explained in a paper recently published in Pharmaceutical Medicine, the SC trastuzumab contains the same monoclonal antibody as the intravenous formulation at a dose of 600 mg per 5-mL vial, plus a recombinant human hyaluronidase, to be used every 3 weeks. The hyaluronidase is used to increase the permeability of the extracellular matrix, allowing for administration of higher volumes and enhanced absorption. 

The SC formulation had a similar safety profile to the IV formulation in the phase 3 HannaH study, but serious adverse events (AEs) were more common with the SC trastuzumab than the IV product (21.0% vs 12.0%; P value not reported). Antidrug antibodies (ADAs) were reported in 7.1% of patients receiving the IV product and 14.6% of those receiving the SC product, but the elicited ADAs were deemed to have no clinical relevance as they were non-neutralizing and did not impact the pharmacokinetic profile of trastuzumab.

However, one of the main concerns with trastuzumab’s biological activity is its interaction with pertuzumab to treat HER2-positive cancer, and interactions among HER2 receptor, pertuzumab, and trastuzumab–ADA complexes have not yet been fully evaluated. The phase 3 SAPPHIRE study did evaluate the safety, tolerability, and efficacy of IV pertuzumab plus SC trastuzumab and a taxane, but the small population enrolled in the study made it difficult to draw conclusions. 

According to the paper’s authors, it also remains unclear whether, in the case of a tumor recurrence, patients who had received the SC product would have more long-lasting memory ADAs, or whether this would impact the safety and efficacy of a subsequent line of treatment using IV trastuzumab and pertuzumab. 

Reference
Pimentel FF, Morgan G, Tiezzi DG, de Andrade JM. Development of new formulations of biologics: expectations, immunogenicity, and safety for subcutaneous trastuzumab. Pharmaceut Med. 2018;32(5):319-325. doi: 10.1007/s40290-018-0247-5.

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