Zanubrutinib for treatment-naïve and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study

Abstract

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

Keywords: Bruton tyrosine kinase; chromosome 17p deletion; chronic lymphocytic leukaemia; small lymphocytic lymphoma; zanubrutinib.

Conflict of interest statement

Gavin Cull has received research funding from BeiGene, Acerta, and Glycomimetics; travel, accommodations, and expenses from Glycomimetics. Jan A. Burger has received research funding from Pharmacyclics, Gilead, and BeiGene; and received honoraria from Janssen and AstraZeneca. Stephen Opat has received honoraria from AbbVie, Roche, AstraZeneca, Merck, Gilead, Janssen, and Novartis; has a consulting or advisory role for AbbVie, Roche, AstraZeneca, and Merck; received research funding from BeiGene, Roche, AstraZeneca, Janssen, Merck, Amgen, and Epizyme; and received travel, accommodations, and expenses from Roche. David Gottlieb has equity in Indee; has received honoraria from AbbVie, Link Health Care, Gilead, Merck, Novartis, and Pfizer; and received research funding from Haemaologix. Emma Verner has received research funding from Janssen‐Cilag Pty Ltd. Judith Trotman has received research funding from BeiGene, Roche, Pharmacyclics, Celgene, a Bristol‐Myers Squibb Company, and Takeda. Paula Marlton has had an advisory role for BeiGene, Janssen, AstraZeneca, AbbVie, Roche, Astellas, Novartis, and Gilead. Javier Munoz has received honoraria from Kyowa and Seattle Genetics; has a consulting or advisory role with Pharmacyclics, Bayer, Gilead, Kite Pharma, Pfizer, Janssen, Juno, Celgene, a Bristol‐Myers Squibb Company; Kyowa, Alexion, BeiGene, Fosunkite, Innovent, and Seattle Genetics; has participated in speakers’ bureaus for Gilead, Kite Pharma Kyowa, Bayer, Pharmacyclics, Janssen, Seattle Genetics, Acrotech, BeiGene, Verastem, AstraZeneca, Celgene, a Bristol‐Myers Squibb Company, Genentech, and AbbVie; received research funding from Kite Pharma, Celgene, a Bristol‐Myers Squibb Company, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium. Patrick Johnston has nothing to disclose. David Simpson has employment and equity at BeiGene; received honoraria from AbbVie, Janssen, and Roche; received research funding from AbbVie, Amgen, BeiGene, Celgene, a Bristol‐Myers Squibb Company, MSD, Acerta, Pharmacyclics, Sanofi, and GSK; and received funding for travel, accommodations, and expenses from AbbVie. Jennifer C. Stern, Radha Prathikanti, Kenneth Wu and William Novotny have employment and equity at BeiGene. Jane Huang has employment, equity, and leadership at BeiGene. Constantine S. Tam has received research funding from Janssen, AbbVie, BeiGene, Pharmacyclics, and TG Therapeutics.

© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1

Forest plot of ORR. CLL, chronic lymphocytic leukaemia; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; LDi, longest transverse diameter; ORR, overall response rate; SLL, small lymphocytic leukaemia. *Stage at study entry: high risk includes (Rai) high risk of CLL, and (Ann Arbor) Stage III–IV for SLL; intermediate risk includes intermediate risk of CLL and Stage I–II for SLL; low risk includes low risk of CLL only. †Includes patients without baseline target lesion. ‡Cytopenia is defined as haemoglobin ≤110 g/l or platelet count ≤100 × 109/l or absolute neutrophil count ≤1·5 × 109/l.

Fig 2

Kaplan–Meier estimates of DOR (A), PFS (B), PFS by prior lines of therapy (C), and OS (D) in TN or R/R patients. Number of events: (A) five TN, 20 RR; (B) five TN, 24 R/R; (C) five, six, four, six, eight events for zero, one, two, three and >3 lines respectively; (D) two TN, 14 R/R. DOR, duration of response; PFS, progression‐free survival; OS, overall survival; RR, relapsed/refractory; TN, treatment‐naïve. [Colour figure can be viewed at wileyonlinelibrary.com]