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Molecular targets for therapy

Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in mature B-cell malignancies

Leukemia volume 35, pages 3201–3211 (2021)Cite this article

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Abstract

Bruton tyrosine kinase (BTK) inhibition is an effective therapy for many B-cell malignancies. Acalabrutinib is a next-generation, potent, highly selective, covalent BTK inhibitor. To characterize acalabrutinib tolerability, we pooled safety data from 1040 patients with mature B-cell malignancies treated with acalabrutinib monotherapy in nine clinical studies (treatment-naïve: n = 366 [35%], relapsed/refractory: n = 674 [65%]; median [range] age: 67 [32–90] years; median [range] prior treatments: 1 [0–13]; median [range] duration of exposure: 24.6 [0.0–58.5] months). The most common adverse events (AEs) were headache (38%), diarrhea (37%), upper respiratory tract infection (22%), contusion (22%), nausea (22%), fatigue (21%), and cough (21%). Serious AEs (SAEs) occurred in 39% of patients; pneumonia (6%) was the only SAE that occurred in ≥2%. Deaths due to AEs occurred in 52 patients (5%); pneumonia (n = 8) was the only fatal AE to occur in ≥3 patients. AEs led to treatment discontinuation in 9%. Rates for the AEs of interest (all grades) included infections (67%), hemorrhages (46%), neutropenia (16%), anemia (14%), second primary malignancies (12%), thrombocytopenia (9%), hypertension (8%), and atrial fibrillation (4%). This pooled analysis confirmed acalabrutinib’s tolerability and identified no newly emerging late toxicities, supporting acalabrutinib as a long-term treatment for patients with mature B-cell malignancies.

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Fig. 1: Cumulative incidence of selected non-hematologic events of clinical interest.

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Acknowledgements

This pooled analysis was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The first draft of this article was co-written by RRF, NC, PP, and Allison Green (Peloton Advantage LLC). All authors contributed to the design of the pooled analysis and/or interpretation of data for this article, contributed to drafts of the article, and approved the final version to be published. The authors thank the investigators and coordinators at each of the clinical sites; the patients who participated in the trials included in this pooled analysis and their families; Rakesh Raman for valuable discussion; and Peloton Advantage, LLC, an OPEN Health company, for medical writing assistance, which was funded by Acerta Pharma, South San Francisco, CA, a member of the AstraZeneca Group. JCB was supported by the National Cancer Institute R35 CA198183. The authors are grateful for the contributions of our co-author NC, who sadly has recently passed away.

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Authors and Affiliations

  1. Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA

    Richard R. Furman

  2. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    John C. Byrd & Beth Christian

  3. St. James’s University Hospital, Leeds, UK

    Roger G. Owen & Peter Hillmen

  4. Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA

    Susan M. O’Brien

  5. Dana-Farber Cancer Institute, Boston, MA, USA

    Jennifer R. Brown

  6. University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA

    Deborah M. Stephens

  7. AstraZeneca, South San Francisco, CA, USA

    Nataliya Chernyukhin, Tamara Lezhava, Ahmed M. Hamdy, Raquel Izumi, Priti Patel & Marshall Baek

  8. The Ernest and Helen Scott Haematological Research Institute, University Hospitals of Leicester NHS Trust, Leicester, UK

    Martin J. S. Dyer

  9. Guy’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

    Matthew J. Streetly

  10. National Heart, Lung, and Blood Institute, Bethesda, MD, USA

    Clare Sun

  11. Plymouth University Medical School, Plymouth, UK

    Simon Rule

  12. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael Wang

  13. Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy

    Paolo Ghia

  14. Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland

    Wojciech Jurczak

  15. Swedish Cancer Institute, Seattle, WA, USA

    John M. Pagel

  16. Willamette Valley Cancer Institute/US Oncology, Eugene, OR, USA

    Jeff P. Sharman

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  1. Richard R. Furman
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Correspondence to Richard R. Furman.

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Conflict of interest

RRF has been a consultant for Pharmacyclics, Janssen Biotech, Genentech/Roche, Sunesis Pharmaceuticals, Loxo, TG Therapeutics, Verastem, Acerta Pharma, AstraZeneca, BeiGene, Incyte, OncoTracker, and AbbVie; has received reimbursement for travel, accommodations, and expenses from TG Therapeutics and Janssen Oncology; has provided expert testimony for AbbVie and Janssen Oncology; has received honoraria from Janssen and Genentech/Roche; has received research funding from Acerta Pharma and TG Therapeutics; and reports “other relationship” for Incyte, Janssen Biotech, and AbbVie. JCB has received research funding from Acerta Pharma, Genentech, Janssen, and Pharmacyclics. RGO has been a consultant for Acerta Pharma, BeiGene, Janssen, and Celgene, and has received honoraria from AstraZeneca, Janssen, BeiGene, Celgene, and Takeda. SMO is employed by the University of California, Irvine; has been a consultant for Amgen, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie/Genentech, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences, Pharmacyclics, TG Therapeutics, Pfizer, Verastem, Eisai, Juno Therapeutics, and Vida Ventures; has received reimbursement for travel, accommodations, and expenses from Celgene, Janssen, Gilead Sciences, Regeneron, and Janssen Oncology; has received honoraria from Celgene, Janssen, Pharmacyclics, Gilead Sciences, Pfizer, Amgen, Astellas Pharma, GlaxoSmithKline, Aptose Biosciences, Vaniam Group, AbbVie, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Loxo, Eisai, and TG Therapeutics; and has received research funding (to institution) from Acerta Pharma, Regeneron, Gilead Sciences, Pfizer, TG Therapeutics, Pharmacyclics, Kite Pharma, and Sunesis Pharmaceuticals. JRB has been a consultant for AbbVie, Acerta, AstraZeneca, BeiGene, Catapult, Dynamo, Eli Lilly, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, MEI Pharma, Nextcea, Novartis, Octapharma, Rigel, Pfizer, Pharmacyclics, Redx, Sun, Sunesis, TG Therapeutics, and Verastem; has received honoraria from Janssen and Teva; has received research funding from Gilead, Loxo, Sun, and Verastem; and is on Data Safety Monitoring Committees for Morphosys and Invectys. PH has been a consultant for AbbVie, Acerta Pharma, Alexion Pharmaceuticals, Gilead, and Janssen; has received honoraria from AbbVie, Acerta Pharma, Alexion Pharmaceuticals, Gilead, and Janssen; and has received research funding from AbbVie, Gilead, Janssen, GlaxoSmithKline, Pharmacyclics, and Roche. DMS has been a consultant for Pharmacyclics/Janssen, Karyopharm, BeiGene, and Innate; has received honoraria from Genentech; and has received research funding from Acerta Pharma, Gilead Sciences, Karyopharm Therapeutics, Verastem, and Juno Therapeutics. TL, PP, and MB are employees of Acerta Pharma (a member of the AstraZeneca Group) and may or may not have equity ownership in Acerta Pharma and/or AstraZeneca. AMH and RI were employees of Acerta Pharma (a member of the AstraZeneca Group) at the time of this study, are patent holders, and have equity ownership in Acerta Pharma and/or AstraZeneca. NC was an employee of Acerta Pharma (a member of the AstraZeneca Group) at the time of this study. BC has received research funding from Acerta, Celgene, Genentech, Merck, Millennium, MorphoSys, F Hoffman-La Roche, Triphase, and Seattle Genetics, and has been a consultant on advisory boards for Verastem, Seattle Genetics, and AstraZeneca. MJSD has been a consultant for Sandoz, has participated in speakers bureaus for Teva, and has received research funding (Institution) from Gilead Sci, AstraZeneca, Astex Pharma, Bioinvent, and Roche. CS has received research funding from Genmab. SR is an employee and stockholder of VelosBio; has received research funding from Janssen, and has served on advisory boards for Janssen Kite. MW has been a consultant for Pharmacyclics, Celgene, Janssen, AstraZeneca, MoreHealth, Pulse Biosciences, Nobel Insights, Guidepoint Global, Kite Pharma, Juno, Loxo Oncology, InnoCare, and Oncternal; has received research funding from Janssen, AstraZeneca, Acerta Pharma, Pharmacyclics, Juno Therapeutics, Celgene, Kite Pharma, Loxo Oncology, VelosBio, Verastem, Molecular Templates, BioInvent, and Oncternal; has received honoraria from Pharmacyclics, Janssen, AstraZeneca, OMI, Targeted Oncology, OncLive, Dava Oncology, Beijing Medical Award Foundation, and Lu Daopei Medical Group; and has received reimbursement for travel, accommodations, and expenses from Janssen, Pharmacyclics, Celgene, OMI, Kite Pharma, and AstraZeneca. PG has received consulting/advisory fees/honoraria from Acerta Pharma/AstraZeneca, AbbVie, BeiGene, Janssen, Gilead Sci, Sunesis Pharma, Juno Therapeutics, ArQule, Adaptive Bio, Dynamo Therapeutics, and MEI Pharma; and has received research funding from AbbVie, Janssen Oncology, Gilead Sci, Sunesis Pharma, and Novartis. WJ is employed by the Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland; and has received research funding from Acerta, Bayer, BeiGene, Janssen, MeiPharma, Merck, Pharmacyclics, Roche, Takeda, and TG Therapeutics. JMP has been a consultant for Pharmacyclics, Gilead Sciences, AstraZeneca, and Actinium Pharmaceuticals. JPS has been a consultant for and has received research funding from AstraZeneca, AbbVie, Pharmacyclics, Genentech, TG Therapeutics, BeiGene, and Pfizer. The other author declares no competing interests.

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Furman, R.R., Byrd, J.C., Owen, R.G. et al. Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in mature B-cell malignancies. Leukemia 35, 3201–3211 (2021). https://doi.org/10.1038/s41375-021-01252-y

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