ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia

Paolo Ghia, MD, PhD; Andrzej Pluta, PhD; Malgorzata Wach, MD; Daniel Lysak, MD, PhD; Tomas Kozak, PhD; Martin Simkovic, MD, PhD; Polina Kaplan, MD; Iryna Kraychok, MD, PhD; Arpad Illes, PhD, DSc; Javier de la Serna, MD, PhD; Sean Dolan, MD; Phillip Campbell, MBBS; Gerardo Musuraca, MD, PhD; Abraham Jacob, MD; Eric Avery, MD; Jae Hoon Lee, MD; Wei Liang, PhD; Priti Patel, MD; Cheng Quah, MBBS; Wojciech Jurczak, MD

Disclosures

J Clin Oncol. 2020;38(25):2849-2861. 

In This Article

Abstract and Introduction

Abstract

Purpose: Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

Methods: Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator's choice (idelalisib plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety.

Results: From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator's choice (n 5 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1–10). After a median follow-up of 16.1 months (range, 0.03–22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator's choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P < .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator's choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively.

Conclusion: Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.

Introduction

Therapy for chronic lymphocytic leukemia (CLL) is undergoing a paradigm shift, with a change in the use of chemoimmunotherapy to targeted therapy with small-molecule inhibitors.[1] Therapeutic options for relapsed or refractory (R/R) CLL have included combination regimens such as bendamustine plus rituximab (B-R) and idelalisib plus rituximab (I-R).[2–6] B-R is still used in second-line therapy in many countries around the world,[7] and I-R is a viable option for patients intolerant to ibrutinib.[8,9] Studies with B-R showed a median progression-free survival (PFS) or event-free survival of 11–18 months.[4,10,11] The combination of I-R was associated with a median PFS of 19.4 months, but with characteristic treatment-limiting adverse events (AEs).[6,12]

Bruton tyrosine kinase (BTK) is a member of the B-cell receptor signaling pathway and a clinically validated target in B-cell malignancies.[13,14] The BTK inhibitor (BTKi) ibrutinib is approved in front-line and R/R CLL settings.[13,15]

Acalabrutinib is a selective, potent, covalent BTKi[16] that showed a tolerable safety profile and promising efficacy in a phase I/II study in patients with R/R CLL, with an overall response rate (ORR) of 94%, including in patients with high-risk disease characteristics,[16,17] and received US Food and Drug Administration approval in 2019 for the treatment of CLL.[18] In this phase III ASCEND study, we compared the efficacy and safety of acalabrutinib monotherapy versus investigator's choice (I-R or B-R) in patients with R/R CLL (ClinicalTrials.gov identifier: NCT02970318; other study ID no. ACE-CL-309).

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