Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results

Abstract

Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Conflict of interest statement

Conflict-of-interest disclosure: J.C.B. has received research funding from Acerta Pharma, Genentech, Janssen, and Pharmacyclics, and is a consultant (<$5000) for Acerta Pharma, Pharmacyclics, and Jazz Pharmaceuticals. W.G.W. has been a consultant for, and has received honoraria from, AbbVie, Celgene, Emergent, Genentech/Roche, Genzyme, Gilead, GlaxoSmithKline/Novartis, Sanofi, Merck, and Pharmacyclics; and has received research funding from Acerta Pharma, AbbVie, Emergent, Genentech, Gilead, GlaxoSmithKline/Novartis, Janssen, Juno, Karyopharm, Kite, and Pharmacyclics. A.S. has been a consultant for and has received honoraria from AbbVie, Gilead, GlaxoSmithKline, Janssen, Novartis, and Roche. S.D. has been a consultant for AbbVie, Gilead, GlaxoSmithKline, Janssen, MSD, and Roche; has received honoraria from AbbVie, Gilead, Janssen, and MSD; has received travel expenses from Gilead, Janssen, and Roche; is a member of speakers’ bureaus for Gilead and Janssen; and is on an advisory board for Servier. J.M.C. is an employee of Northwest Medical Specialties, PLLC. J.R.B. has been a consultant for AbbVie, Astellas Pharma, AstraZeneca, BeiGene, Loxo, Sunesis, Celgene, TG Therapeutics, Gilead, Verastem Pharmaceuticals, Janssen, Pfizer, Pharmacyclics, Redx, Roche/Genentech, and Sun BioPharma; has received research funding from Gilead, Verastem, Loxo, and Sun; and serves on a data safety monitoring board for Morphosys and Invacs. P.H. has been a consultant for and has received honoraria from AbbVie, Acerta Pharma, Alexion Pharmaceuticals, Gilead, and Janssen; and his institution has received research funding from AbbVie, Gilead, Janssen, GlaxoSmithKline, Pharmacyclics, and Roche. P.M. has been a consultant for Bayer, Genentech, Gilead, Janssen/Pharmacyclics, Novartis, and Verastem; and has received research funding from Celgene and Teva. F.T.A. has been a consultant for AbbVie, Janssen, Gilead, AstraZeneca, Sunesis, Genentech, Celgene, Blueprint Medicines, and Pharmacyclics; has received research funding from Innate Pharma and Pharmacyclics; and has served on speakers’ bureaus for AbbVie and AstraZeneca. D.M.S. has received research funding from Acerta, Gilead, Karyopharm, and the Lymphoma Research Foundation. P.G. has been a consultant for AbbVie, Acerta Pharma, AstraZeneca, Adaptive, ArQule, BeiGene, Dynamo, Gilead, Janssen, and Sunesis; and has received research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. J.B. has served as a board or advisory committee member for AbbVie/Pharmacyclics, Gilead, and Janssen; and has received research funding from AbbVie/Pharmacyclics, Acerta Pharma, and Gilead. J.M.P. has been a consultant for Gilead and Pharmacyclics, and has equity ownership in and has received research funding from Actinium Pharmaceuticals, Inc. J.A.W. has been a consultant for Janssen, and received research funding from Acerta, AbbVie, Karyopharm, and Morphosys. P.P. is a current employee of and has equity ownership in Acerta Pharma; and has equity ownership in AstraZeneca. A.H., R.I., T.C., and M.G. are employees of, have equity ownership in, and hold related patents with Acerta Pharma. M.M.F. is an employee of, patent holder with, and equity owner of AstraZeneca. K.B. is an employee and equity owner of AstraZeneca. W.R. has equity ownership in, holds related patents with, and serves on the board of directors of Quogue BioVentures II LLC. M.H.W. is an employee of and has equity ownership in Acerta Pharma; and has equity ownership in AstraZeneca. S.O. has been a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, and Alexion; has received research support from Kite Pharma, Regeneron, and Acerta Pharma; and has been a consultant for and received research support from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis. R.R.F. has been a consultant for AbbVie, Acerta Pharma, AstraZeneca, BeiGene, Celgene, Gilead, TG Therapeutics, Verastem Pharmaceuticals, Janssen, Pfizer, Pharmacyclics, Roche/Genentech, Sunesis, and Loxo Pharmaceuticals; has served on the data safety monitoring boards of Incyte; has received research funding from Acerta Pharma, TG Therapeutics, Verastem, and Celgene; and has received speaker fees from Janssen.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Twice-daily dosing results in near-complete target coverage over the dosing interval. BTK target occupancy enzyme-linked immunosorbent assay was performed on PBMC lysates using a biotin-tagged covalent analog of acalabrutinib as a molecular probe. Drug trough was 12 or 24 hours after dosing for the twice-daily (BID) and once-daily (QD) regimens, respectively. Box and whiskers show the median using the Tukey method for whisker range. Statistical significance was determined using an unpaired, parametric, 2-tailed Student t test.

Figure 2.

Frequency of grade ≥3 AEs. (A) All grade ≥3 nonhematologic AEs occurring in ≥5% of patients. (B) All grade ≥3 hematologic events. (C) All grade ≥3 infections. (D) Serial assessment of grade ≥3 AEs over time. The dashed line denotes 5% rate; time to onset is based on first occurrence of grade ≥3 event.

Figure 3.

PFS and EFS. (A) Kaplan-Meier curves for PFS for all patients, and patients with del(17)(p13.1), del(11)(q22.3), or complex karyotype. (B) Kaplan-Meier curves for PFS based on IGHV mutational status. (C) Kaplan-Meier curve for EFS for all patients.

Figure 4.

Analysis of BTK mutations in patients with R/R CLL who progressed during acalabrutinib treatment. (A) Summary of mutations detected in BTK across 2 different platforms. Text in parentheses indicates limits of mutation allele frequency (AF) detection. Each triangle represents a sample assessed at pretreatment baseline (left) or at progression (right); gray indicates wild-type BTK and green indicates BTK C481X mutation. (B) AF of BTK mutations in 6 patients with mutations at progression. Three time points are shown as a line plot for each patient and for each BTK mutation. The inset shows raw next-generation sequencing data from the integrated genome viewer of the BTK mutation at the progression time point. If 2 mutations coexisted in a single patient sample, separate reads are provided for each independent clone. Raw variant allele frequency (VAF) in Integrative Genomics Viewer (IGV) inset where filtered VAF plotted in line charts. PtID, patient identifier; WES, whole-exome sequencing.