Expert Point of View: Joshua Brody, MD

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Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at the Icahn School of Medicine at Mount Sinai, New York, commented on where zanubrutinib might fit in once the drug is approved. “The two abstracts presented at ASH 2019 …demonstrated remarkably high response rates, durations of response, and excellent tolerability for this newer Bruton’s tyrosine kinase (BTK) inhibitor.”

Dr. Brody continued: “Zanubrutinib is an exciting molecule in that it is somewhat ‘cleaner’ than ibrutinib, specifically, its selectivity for BTK over ITK [interleukin-2 inducible T-cell kinase] is around seven times more selective. As ITK is critical for aspects of T-cell function, it is suspected that some of the [moderately] increased infection risk associated with ibrutinib might be due to off-target ITK inhibition. If so, then a cleaner BTK inhibitor might have less associated risk of infections. This may already be panning out with the other clean BTK inhibitor, acalabrutinib, which also reported in phase III trial results at ASH, suggestive of improved safety profile compared with prior ibrutinib trials,” Dr. Brody wrote in an e-mail.

Comparable Efficacy, Different Side-Effect Profiles

According to Dr. Brody, the three BTK inhibitors appear to be comparably effective, so the side-effect profiles may distinguish them. The availability of three different agents of the same class should broaden access.

“Just as we have multiple inhibitors of BCR-ABL for chronic myeloid leukemia and aromatase inhibitors for estrogen receptor–positive breast cancer, it will likely improve access for patients to have multiple approved BTK inhibitors for chronic lymphocytic leukemia, marginal zone lymphoma, Waldenstrom’s macroglobulinemia, and mantle cell lymphoma,” he continued.

“Zanubrutinib has been distinguishing itself to a degree by undertaking a large randomized trial in Waldenström’s, which might give it a high-level National Comprehensive Cancer Network [NCCN] recommendation for that disease. Beyond that, these ‘cleaner’ BTK inhibitors might have an opportunity to succeed in a setting where ibrutinib has failed—in combination with chemotherapy for front-line treatment of nongerminal cell diffuse large B-cell lymphoma. Whereas ibrutinib showed some improved efficacy in this setting, the increased toxicity, particularly in older patients, resulted in R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone] plus ibrutinib failing to show superiority over R-CHOP in the Phoenix trial. These newer BTK inhibitors might be just safe enough to show efficacy in that combination setting,” Dr. Brody suggested.

DISCLOSURE: Dr. Brody reported financial relationships with Merck, Genentech, Seattle Genetics, BMS, Acerta, Celldex, and Kite.


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