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

Michael Wang (1, 2) , Simon Rule (3) , Pier Luigi Zinzani (4) , Andre Goy (5) , Olivier Casasnovas (6, 7) , Stephen D Smith (8) , Gandhi Damaj (9) , Jeanette Doorduijn (10, 11) , Thierry Lamy (12) , Franck Morschhauser (13) , Carlos Panizo (14) , Bijal Shah (15) , Andrew Davies (16, 17) , Richard Eek (18) , Jehan Dupuis (19) , Eric Jacobsen (20, 21) , Arnon P Kater (11, 22) , Steven Le Gouill (23, 24) , Lucie Oberic (25) , Taduesz Robak (26) , Todd Covey (27) , Richa Dua (27) , Ahmed Hamdy (27) , Xin Huang (27) , Raquel Izumi (27) , Priti Patel (27) , Wayne Rothbaum (27) , Greg Slatter (27) , Wojciech Jurczak (28)

1 Department of Lymphoma and Myeloma [Houston, TX, USA]
2 Department of Stem Cell Transplantation and Cellular Therapy [Houston, TX, USA]
3 Plymouth University
4 The Institute of Hematology and Oncology L. and A. Seràgnoli [Bologna, Italy]
5 John Theurer Cancer Center [Hackensack, NJ, USA]
6 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
7 Service d'Hématologie Clinique (CHU de Dijon)
8 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
9 IHBN - Institut d'Hématologie de Basse-Normandie
10 Erasmus Medical Centre [Rotterdam, The Netherlands]
11 HOVON Lunenburg Lymphoma Phase I/II Consortium [Amsterdam, The Netherlands]
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
13 GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365
14 Clínica Universidad de Navarra [Pamplona, Spain]
15 H. Lee Moffitt Cancer Center and Research Institute
16 Cancer Research UK Centre - Cancer Sciences Unit [Southampton, UK]
17 Faculty of Medicine [Southampton, UK]
18 Border Medical Oncology [Wodonga, VIC, Australia]
19 Unité des hémopathies lymphoïdes [CHU Henri Mondor]
20 Dana-Farber Cancer Institute [Boston]
21 HMS - Harvard Medical School [Boston]
22 Academic Medical Center [Amsterdam, Netherlands]
23 Hôpital Hôtel-Dieu de Nantes - CHU de Nantes - Hôpital Hôtel-Dieu de Nantes - Centre Hospitalier Universitaire de Nantes
24 CRCINA-ÉQUIPE 10 - Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma
25 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
26 MUL - Medical University of Łódź
27 Acerta Pharma (Redwood City, CA)
28 Department of Hematology [Krakow, Poland]

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.

Domaines: Cancer

Michael Wang, Simon Rule, Pier Luigi Zinzani, Andre Goy, Olivier Casasnovas, et al.. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. The Lancet, 2018, 391 (10121), pp.659-667. ⟨10.1016/S0140-6736(17)33108-2⟩. ⟨inserm-01980627⟩