Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial

Abstract

Background: Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity.

Methods: In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926.

Findings: From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]).

Interpretation: Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.

Funding: Acerta Pharma, a member of the AstraZeneca Group.

Conflict of interest statement

Declaration of interests

MW reports grants and personal fees from Pharmacyclics, Janssen, and Acerta Pharma, outside the submitted work. SR reports personal fees from AstraZeneca and Acerta Pharma, outside the submitted work. PLZ reports personal fees from Celgene, Roche, Janssen, Gilead, Takeda, Servier, Bristol-Myers Squibb, and Merck, outside the submitted work. AG reports non-financial support from Celgene, Genentech, and Pharmacyclics, during the conduct of the study; and personal fees from Celgene, Pharmacyclics, Acerta Pharma, and Takeda outside the submitted work. OC reports grants, personal fees, and non-financial support from Roche, Gilead, and Takeda; personal fees and non-financial support from Bristol-Myers Squibb, MSD, and Celgene; and personal fees from AbbVie, outside the submitted work. SDS reports grants from Acerta Pharma, during the conduct of the study; and grants from Seattle Genetics, Merck Sharpe and Dohme, Janssen Research and Development, Pharmacyclics, Genentech, and Portola Pharmaceuticals, outside the submitted work. FM reports personal fees from Roche Genetech; and personal fees from Celgene, Bristol-Myers Squibb, Janssen, and Gilead, outside the submitted work. CP reports personal fees and non-financial support from MundiPharma; grants, personal fees, and non-financial support from Roche Pharma; grants and personal fees from Janssen, Bristol-Myers Squibb; personal fees from Takeda; and grants from Acerta Pharma, during the conduct of the study. BS reports personal fees from Celgene, Bayer, Amgen, Baxalta, Jazz, and Pfizer; grants from Rosetta Genomics, Clonoseq, DeBartolo Institute for Personalized Medicine, and Incyte, outside the submitted work. AD reports grants from Acerta Pharma during the conduct of the study; grants, personal fees, and non-financial support from F Hoffmann-La Roche, Celgene, Takeda Pharma, Gilead Sciences; personal fees and non-financial support from CTI BioPharma; grants from Bayer and GlaxoSmithKline; grants and personal fees from Janssen, Pfizer, and Karyopharma; personal fees and non-financial support from Mundipharma; and personal fees from Kite Pharma, outside the submitted work. JDu reports personal fees from AbbVie and Roche, outside the submitted work. EJ reports personal fees from Merck, Seattle Genetics, Spectrum, and Pharmacyclics, outside the submitted work. SLG reports personal fees and non-financial support from Roche; grants and personal fees from Janssen-Cilag; and personal fees from Celgene, outside the submitted work. TR reports grants from Acerta Pharma and Pharmacyclics, and grants and personal fees from Janssen, during the conduct of the study. WR reports personal fees and non-financial support from Acerta Pharma, is an investor in Acerta at Quogue BioVentures II, outside the submitted work, and is an inventor for acalabrutinib patents pending or issued. TC is currently employed by Acerta Pharma and is a shareholder of AstraZeneca. AH is currently an employee of Acerta Pharma; and has a patent pending for acalabrutinib. RI is currently an employee of Acerta Pharma; and has a patent pending for acalabrutinib. JGS is currently an employee of Acerta Pharma with stock options in the company. WJ reports grants from Acerta Pharma during the conduct of the study; and grants from Janssen, Merck, Gilead, TG Therapeutics, Sandoz, Pfizer, and Takeda, outside the submitted work. JDo, RD, AH, XH, RI, PP, WR, and JGS are employees of Acerta Pharma. GD, TL, RE, APK, and LO declare no competing interests.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Pharmacokinetics and pharmacodynamics of acalabrutinib in mantle cell lymphoma

(A) Mean acalabrutinib plasma concentrations over time on day 1 and day 8 after a 100 mg dose. Three (7%) of 44 patients had anomalous initial concentrations on day 1 that were not below the limit of quantification. (B) BTK occupancy on day 1, and predose and post dose during steady-state. Box and whisker plots show median and IQR (Tukey method). BTK=Bruton tyrosine kinase.

Figure 2:. Efficacy of acalabrutinib in mantle cell lymphoma

(A) Maximum change from baseline in the SPD of target lesions for all treated patients with baseline and one or more post-baseline lesion measurements. Percentage change in SPD is shown by best response achieved in each patient. (B) Kaplan-Meier curve for duration of response in patients with a complete response versus those with a partial response. Kaplan-Meier curves are shown for progression-free survival (C) and overall survival (D). SPD=sum of the product diameters.

Figure 3:. Subgroup analysis of overall response

Forest plot containing overall response by prespecified subgroups according to baseline demographic and clinical characteristics. 95% CIs were based on exact binomial distribution. MIPI=Mantle Cell Lymphoma International Prognostic Index. ECOG=Eastern Cooperative Oncology Group.