The potential of pirtobrutinib in multiple B-cell malignancies Review
| Authors: | Jensen, J. L.; Mato, A. R.; Pena, C.; Roeker, L. E.; Coombs, C. C. |
| Review Title: | The potential of pirtobrutinib in multiple B-cell malignancies |
| Abstract: | Bruton’s tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies. © The Author(s), 2022. |
| Keywords: | signal transduction; cancer survival; treatment response; overall survival; clinical trial; drug tolerability; review; cancer recurrence; rituximab; follow up; progression free survival; mantle cell lymphoma; plasmacytoma; waldenstroem macroglobulinemia; b cell lymphoma; drug combination; chimeric antigen receptor; cll; clinical outcome; covalent bond; ibrutinib; human; btk; acalabrutinib; bruton tyrosine kinase inhibitor; zanubrutinib; pirtobrutinib; non-covalent; loxo-305 |
| Journal Title: | Therapeutic Advances in Hematology |
| Volume: | 13 |
| ISSN: | 2040-6207 |
| Publisher: | Sage Publications |
| Date Published: | 2022-01-01 |
| Start Page: | 1 |
| End Page: | 10 |
| Language: | English |
| DOI: | 10.1177/20406207221101697 |
| PROVIDER: | scopus |
| PMCID: | PMC9210100 |
| PUBMED: | 35747462 |
| DOI/URL: | |
| Notes: | Review -- The publisher incorrectly assigned Catherine C. Coombs' ORCiD profile to Anthony R. Mato -- Export Date: 1 August 2022 -- Source: Scopus |
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