Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Five-year follow-up of ELEVATE-TN.

Abstract

7539 Background: For ELEVATE-TN (NCT02475681), we previously reported superior efficacy of acalabrutinib (A) ± obinutuzumab (O) vs O + chlorambucil (Clb) in patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL) at 28.3 and 46.9 months (mo) median follow-up. Now, we report results from a 5-y update. Methods: Pts were randomized to A+O, A, or O+Clb. Pts who progressed on O+Clb could cross over to A monotherapy. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: A total of 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) had a median age of 70 y. At a median follow-up of 58.2 mo (range, 0.0–72.0; data cutoff Oct 1, 2021), median PFS was not reached (NR) (hazard ratio [HR]: 0.11) for A+O and A (HR: 0.21) vs 27.8 mo for O+Clb (both P<0.0001). Estimated 60-mo PFS rates were 84% (A+O), 72% (A), and 21% (O+Clb). Median OS was NR in any treatment arm, and significantly longer in the A+O vs O+Clb arms (HR: 0.55; P=0.0474); estimated 60-mo OS rates were 90% (A+O), 84% (A), and 82% (O+Clb). ORR was significantly higher with A+O (96%; 95% CI 92–98) and A (90%; 85–94) vs O+Clb (83%; 77–88; P<0.0001 [A+O], P=0.0499 [A]). Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were higher with A+O (29%/3%) vs O+Clb (13%/1%); 13%/1% had CR/CRi with A; CR increased since the interim analysis (previously 21% [A+O] and 7% [A]). Adverse events (AEs) and treatment exposure are shown in the Table. Treatment is ongoing in 65% (A+O) and 60% (A) of pts; the most common reasons for treatment discontinuation were AEs (17% [A+O], 16% [A], 14% [O+Clb]) and progressive disease (6%, 10%, 2%, respectively). Crossover from O+Clb to A occurred in 72 (41%) patients; 25% of these pts discontinued A (10% due to AEs and 11% due to progressive disease). Conclusions: After a 5-y follow-up, efficacy and safety of A+O and A monotherapy were maintained, with significantly longer OS in the A+O arm compared with O+Clb. Clinical trial information: NCT02475681. [Table: see text]

Real-World Persistence and Time to Next Treatment With Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Including Patients at High Risk for Atrial Fibrillation or Stroke

“…23 In a nationally representative population of privately insured adult patients in the US with a CLL diagnosis (July 2012-June 2015), AF was observed in 11% of patients receiving ibrutinib monotherapy 24 ; and in a metaanalysis of 6 studies of patients with CLL treated with ibrutinib monotherapy, the pooled estimate of the risk of any-grade AF was 7.0 per 100 person-years. 25 Similar rates of any-grade AF as an adverse event of acalabrutinib have also been reported in previous clinical trials (3%-7%) 26 , including 5-year follow-up data from ELEVATE-TN (6%-7%), 27 as well as in real-world studies (1%). 26,28 More recently, in the ELEVATE-RR trial (in patients treated with ibrutinib or acalabrutinib who had ≥1 previous line of therapy), the rate of any-grade AF was 9.0% and 15.6% for acalabrutinib and ibrutinib, respectively, while a numerically higher rate of grade ≥3 AF was observed with acalabrutinib (4.5%) than with ibrutinib (3.4%), 29 providing further evidence that AF is a class effect of BTKis.…”

Selecting initial therapy in CLL

“…The stron gest data sup port the addi tion of obinutuzumab to acalabrutinib, which improved 5-year PFS by 12% in the ELEVATE-TN study. 20 Intriguingly, the addi tion of rituximab to ibrutinib did not lead to any improve ment in PFS in 2 ran dom ized tri als. 9,21 These dif fer ences in out come may be explained by greater cell kill ing and greater anti body-depen dent cel lu lar cyto tox ic ity (ADCC) of the type 2 mAb obinutuzumab.…”

Novel combination approaches with targeted agents in frontline chronic lymphocytic leukemia

“…Notably, prolonged PFS also was demonstrated with acalabrutinibobinutuzumab versus acalabrutinib in a post-hoc analysis, and this difference persisted at 5 years of follow-up, with PFS estimates of 84% for the combination versus 72% for monotherapy (HR, 0.51; p = .0259). 15 The most common AEs were headache and diarrhea for acalabrutinib monotherapy, and a higher incidence of AEs was observed for combination therapy with obinutuzumab, particularly on account of neutropenia (grade ≥3, 31%).…”