Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study

Wei Xu, Shenmiao Yang, Keshu Zhou, Ling Pan, Zengjun Li, Jianfeng Zhou, Sujun Gao, Daobin Zhou, Jianda Hu, Ru Feng, Haiwen Huang, Meng Ji, Haiyi Guo, Jane Huang, William Novotny, Shibao Feng, Jianyong Li, Wei Xu, Shenmiao Yang, Keshu Zhou, Ling Pan, Zengjun Li, Jianfeng Zhou, Sujun Gao, Daobin Zhou, Jianda Hu, Ru Feng, Haiwen Huang, Meng Ji, Haiyi Guo, Jane Huang, William Novotny, Shibao Feng, Jianyong Li

Abstract

Background: Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Methods: The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee.

Results: Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction.

Conclusion: Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile.

Trial registration: Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/. Retrospectively registered in ClinicalTrials.gov (NCT03206918) on July 2, 2017.

Keywords: Bruton’s tyrosine kinase; Chronic lymphocytic leukemia; Clinical trial; Relapsed/refractory; Zanubrutinib.

Conflict of interest statement

Meng Ji, Haiyi Guo, Jane Huang, William Novotny, and Shibao Feng are employees of and own stock in BeiGene. All other authors declare no potential competing interests.

Figures

Fig. 1
Fig. 1
Maximal Percent Change in the Sum of the Products of Perpendicular Diameters of Target Lesions (SPD) and Corresponding Best Responses
Fig. 2
Fig. 2
Subgroup analysis of ORR
Fig. 3
Fig. 3
a Independent review committee-assessed progression-free survival. b Independent review committee-assessed duration of response

References

    1. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007. doi: 10.1056/NEJMoa1315226.
    1. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–322. doi: 10.1056/NEJMoa1513257.
    1. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42. doi: 10.1056/NEJMoa1215637.
    1. Petlickovski A, Laurenti L, Li X, Marietti S, Chiusolo P, Sica S, et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood. 2005;105:4820–4827. doi: 10.1182/blood-2004-07-2669.
    1. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118:4313–4320. doi: 10.1182/blood-2011-06-338855.
    1. Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood. 2009;114:1029–1037. doi: 10.1182/blood-2009-03-212837.
    1. Ponader S, Chen S-S, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182–1189. doi: 10.1182/blood-2011-10-386417.
    1. de Rooij MFM, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119:2590–2594. doi: 10.1182/blood-2011-11-390989.
    1. Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223. doi: 10.1056/NEJMoa1400376.
    1. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437. doi: 10.1056/NEJMoa1509388.
    1. Imbruvica (ibrutinib) [prescribing information]. Pharmacyclics LLC, Sunnyvale, CA, and Janssen Biotech, Inc, Horsham, PA: 2016.
    1. O’Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131:1910–1919. doi: 10.1182/blood-2017-10-810044.
    1. Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103:874–879. doi: 10.3324/haematol.2017.182907.
    1. de Weerdt I, Koopmans SM, Kater AP, van Gelder M. Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach. Haematologica. 2017;102:1629–1639. doi: 10.3324/haematol.2017.164103.
    1. Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134:851–859. doi: 10.1182/blood.2019001160.
    1. Kamel S, Horton L, Ysebaert L, Levade M, Burbury K, Tan S, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29:783–787. doi: 10.1038/leu.2014.247.
    1. Levade M, David E, Garcia C, Laurent P-A, Cadot S, Michallet A-S, et al. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014;124:3991–3995. doi: 10.1182/blood-2014-06-583294.
    1. McMullen JR, Boey EJH, Ooi JYY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829–3830. doi: 10.1182/blood-2014-10-604272.
    1. Thompson PA, Lévy V, Tam CS, Al Nawakil C, Goudot F-X, Quinquenel A, et al. Atrial fibrillation in CLL patients treated with ibrutinib. An international retrospective study. Br J Haematol. 2016;175:462–466. doi: 10.1111/bjh.14324.
    1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111:5446–5456. doi: 10.1182/blood-2007-06-093906.
    1. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4. Lyon: IARC Publications; 2008.
    1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–3067. doi: 10.1200/JCO.2013.54.8800.
    1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use . Introductory guide: MedDRA version 20.0. Geneva: ICH; 2017.
    1. NCI-CTEP . Common terminology criteria for adverse events (CTCAE) Bethesda, MD: National Cancer Institute; 2010.
    1. Sorensen JM, Vena DA, Fallavollita A, Chun HG, Cheson BD. Treatment of refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C protocol mechanism of the National Cancer Institute: five-year follow-up report. J Clin Oncol. 1997;15:458–465. doi: 10.1200/JCO.1997.15.2.458.
    1. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26:404–413. doi: 10.1093/biomet/26.4.404.
    1. Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982;38:29–41. doi: 10.2307/2530286.
    1. Greenwood M. A report on the natural duration of cancer. London: HMSO; 1926.
    1. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–332. doi: 10.1056/NEJMoa1509981.
    1. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94. doi: 10.1200/JCO.2012.42.7906.
    1. European Medicines Agency. IMBRUVICA: Summary of product characteristics. 2019. . Accessed 21 March 2020.
    1. Mu S, Tang Z, Novotny W, Tawashi M, Li T-K, Ou Y, et al. Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton’s tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. Cancer Chemother Pharmacol. 2020;85:391–399. doi: 10.1007/s00280-019-04015-w.
    1. de Jong J, Hellemans P, De Wilde S, Patricia D, Masterson T, Manikhas G, et al. A drug-drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies. Leuk Lymphoma. 2018;59:2888–2895. doi: 10.1080/10428194.2018.1460474.
    1. de Jong J, Skee D, Murphy J, Sukbuntherng J, Hellemans P, Smit J, et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect. 2015;3:e00156. doi: 10.1002/prp2.156.
    1. Brukinsa (zanubrutinib) [prescribing information]. San Mateo, CA: BeiGene USA, Inc; 2019.
    1. Brown JR, Hillmen P, O’Brien S, Barrientos JC, Reddy NM, Coutre SE, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32:83–91. doi: 10.1038/leu.2017.175.
    1. Ghia P, Pluta A, Wach M. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: Annual Meeting of the European Hematology Association; 2019 Jun 16; Abstract LBA2606.
    1. O’Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17:1409–1418. doi: 10.1016/S1470-2045(16)30212-1.
    1. Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, et al. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018;7:1043–1055. doi: 10.1002/cam4.1337.
    1. Hilal T, Gea-Banacloche JC, Leis JF. Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: linking mechanisms with infections. Blood Rev. 2018;32:387–399. doi: 10.1016/j.blre.2018.03.004.
    1. Wadhwa PD, Morrison VA. Infectious complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33:240–249. doi: 10.1053/j.seminoncol.2005.12.013.
    1. Chei C-L, Raman P, Ching CK, Yin Z-X, Shi X-M, Zeng Y, et al. Prevalence and risk factors of atrial fibrillation in Chinese elderly: results from the Chinese Longitudinal Healthy Longevity Survey. Chin Med J. 2015;128:2426–2432. doi: 10.4103/0366-6999.164918.
    1. Tam CS, Robak T, Ghia P, Kahl BS, Walker P, Janowski W, et al. Efficacy and safety of zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): initial results from arm C of the Sequoia (BGB-3111-304) trial. Blood. 2019;134(Suppl 1):499. doi: 10.1182/blood-2019-125394.
    1. Tam C, Opat S, Zhu J. Pooled analysis of safety data from monotherapy studies of the Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib (BGB-3111), in B-cell malignancies. Presented at: Annual Meeting of the European Hematology Association. 2019 Jun 15; Abstract PS1159.
    1. Tam C, Seymour J, Cull G, Trotman J, Gottlieb D, Simpson D, et al. High overall response rate with the BTK inhibitor BGB-3111 in patients with chronic lymphocytic leukemia/small lympocytic lymphoma: an update on safety and activity. Presented at: International Conference on Malignant Lymphoma; Abstract 237.

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