Acalabrutinib vs Rituximab plus Idelalisib or Bendamustine by Investigator Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Phase 3 ASCEND Study

November 2019 Vol 10, No 11
Paolo Ghia, MD
Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele,
Milano, Italy
Andrzej Pluta, MD
Department of Hematological Oncology, Oncology Specialist Hospital,
Brzozow, Poland
Malgorzata Wach, MD
Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin,
Lublin, Poland
Daniel Lysak, MD
Fakultní Nemocnice Plzeň,
Pilsen, Czech Republic
Tomas Kozak, MD
Fakultní Nemocnice Královske Vinohrady,
Prague, Czech Republic
Martin Simkovic, MD
University Hospital Hradec Kralove, Charles University,
Hradec Kralove, Czech Republic
Polina Kaplan, MD
Dnipropetrovsk City Clinical Hospital No. 4,
Dnipropetrovsk, Ukraine
Iryna Kraychok, MD
National Cancer Institute,
Kiev, Ukraine
Arpad Illes, MD
University of Debrecen, Faculty of Medicine, Department of Hematology, Hungary
Javier de la Serna, MD
Hospital Universitario 12 de Octubre,
Madrid, Spain
Sean Dolan, MD
Saint John Regional Hospital, University of New Brunswick,
New Brunswick, Canada
Philip Campbell, MD
Barwon Health, University Hospital Geelong,
Geelosng, Victoria, Australia
Gerardo Musuraca, MD
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori,
Meldola, Italy
Abraham Jacob, MD
The Royal Wolverhampton NHS Trust,
Wolverhampton, United Kingdom
Eric J. Avery, MD
Nebraska Hematology Oncology,
Lincoln, NE
Jae Hoon Lee, MD
Gachon University Gil Medical Center,
Incheon, South Korea
Tianling Chen, MD
Acerta Pharma,
South San Francisco, CA, USA
Wei Liang, PhD
Acerta Pharma,
South San Francisco, CA, USA
Priti Patel, MD
Acerta Pharma,
South San Francisco, CA, USA
Wojciech Jurczak, MD
Department of Hematology, Jagiellonian University Medical College,
Krakow, Poland

Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor that has shown clinical benefit in patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL).

Objective: This randomized, global, multicenter, open-label phase 3 study assessed the efficacy and safety of acalabrutinib monotherapy versus the investigator’s choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in RR CLL (NCT02970318).

Methods: Eligible patients with RR CLL were randomized 1:1 to 100 mg oral acalabrutinib twice daily (BID) until progression versus IdR (150 mg oral Id BID combined with ≤8 IV infusions of R [375 or 500 mg/m2]), or BR (70 mg/m2 IV B on days 1 and 2 of each cycle combined with R [375 or 500 mg/m2 IV] on day 1 of each 28-day cycle for ≤6 cycles). Stratification was by del(17p) status (yes vs no), ECOG status (0-1 vs 2), and prior therapy lines (1-3 vs ≥4). The primary end point was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary end points included overall survival (OS), overall response rate (ORR, by IRC), and safety. Patients with confirmed progression on IdR/BR could cross over to receive acalabrutinib monotherapy.

Results: A total of 310 patients were randomized to acalabrutinib (n = 155) or IdR/BR (n = 155 [IdR, n = 119; BR, n = 36]); median age was 67 years (range, 32-90); 16% had del(17p); 27% had del(11q); 42% had Rai stage III/IV CLL. Median (range) number of prior therapies was 1 (1-8) for acalabrutinib and 2 (1-10) for IdR/BR. Discontinuation due to adverse events (AEs) occurred in 11% of patients on acalabrutinib versus 49% Id, 12% R in IdR, 11% B, and 17% R in BR.

At a median follow-up of 16.1 months, acalabrutinib significantly prolonged IRC-assessed PFS versus IdR/BR (median not reached vs 16.5 months; hazard ratio 0.31, 95% CI 0.20-0.49, P <.0001). PFS rates at 12 months were 88% with acalabrutinib and 68% with IdR/BR; improvement was seen across subgroups, including del(17p), TP53 mutation, and Rai stage.

ORR by IRC was similar with acalabrutinib versus IdR/BR (81% vs 75%; P <.22); 12-month OS rates were 94% and 91% (with 15 and 18 deaths) for acalabrutinib and IdR/BR, respectively. Of IdR/BR patients, 23% crossed over to acalabrutinib monotherapy.

All-grade AEs (≥15%) with acalabrutinib were headache (22%), neutropenia (19%), diarrhea (18%), anemia and cough (15% each); with IdR, diarrhea (47%), neutropenia (45%), pyrexia (18%), and cough (15%); with BR, neutropenia (34%), infusion-related reaction and fatigue (23% each), nausea (20%), and pyrexia (17%). Grade ≥3 AEs (≥5%) with acalabrutinib were neutropenia (16%), anemia (12%), and pneumonia (5%); with IdR (≥15%), neutropenia (40%) and diarrhea (24%); with BR (≥5%), neutropenia (31%), anemia (9%), and constipation (6%).

AEs of interest were atrial fibrillation (5.2% of patients on acalabrutinib vs 3.3% on IdR/BR), bleeding AEs (26% vs 7.2%; including major hemorrhage [1.9% vs 2.6%]); grade ≥3 infections (15% vs 24%), and second primary malignancies, excluding nonmelanoma skin cancer; (6.5% vs 2.6%).

Conclusion: Acalabrutinib monotherapy significantly improved PFS with a more tolerable safety profile versus IdR/BR in patients with RR CLL.

Note: This abstract has been presented at EHA and ICML 2019.

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