Acalabrutinib has demonstrated durable responses as a single agent or combined with obinutuzumab in treatment-naïve (TN) chronic lymphocytic leukemia (CLL).

Jeff P Sharman, MD, and colleagues presented interim results of the multicenter, open-label Phase 3 ELEVATE-TN study (NCT02475681) at the 2019 ASH Annual Meeting & Exposition. This study evaluated the efficacy and safety of acalabrutinib + O vs acalabrutinib alone vs O + chlorambucil (Clb) in patients with TN CLL.

Eligible patients had TN CLL requiring treatment per iwCLL criteria and were aged ≥65 years or <65 years with coexisting conditions. Patients were randomized 1:1:1 to receive oral acalabrutinib (100 mg twice daily continuously) alone or combined with intravenous O (1000 mg on Days 1, 2 [split 100/900], 8, and 15 of Cycle 2, and Day 1 of subsequent 28-day cycles for a total of 6 cycles), or O plus oral Clb (0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles). 

Patients were stratified by del(17p) status, ECOG status (≤1 vs 2), and geographic region. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) with acalabrutinib + O vs O + Clb. Key secondary endpoints included IRC-assessed PFS with acalabrutinib vs O + Clb, IRC-assessed overall response rate (ORR), overall survival (OS), and safety.

From September 14, 2015, to February 8, 2017, 535 patients were randomized to the acalabrutinib + O (n=179), acalabrutinib (n= 179), or O + Clb (n=177) arms. The median age was 70 y (range, 41-91); 69% had high- and 12% had very high-risk CLL IPI scores.

At a median follow-up of 28 months, acalabrutinib + O significantly prolonged PFS vs O + Clb (median not reached [NR] vs 22.6 mo; HR 0.10, 95% CI 0.06–0.18, P<.0001), reducing the risk of progression or death by 90%. 

Acalabrutinib (median NR) also prolonged PFS vs O + Clb (HR 0.20, 95% CI 0.13–0.31, P<.0001). Estimated 30-months PFS rates with acalabrutinib + O, acalabrutinib, and O + Clb were 90%, 82%, and 34%, respectively. 

PFS improvement with acalabrutinib + O or acalabrutinib vs O + Clb was consistent across subgroups examined including del(17p) (HR [95% CI]; 0.13 [0.04–0.46]; 0.20 [0.06–0.64]).

Median OS was not reached in any arm; (HR [95% CI]; acalabrutinib + O vs O + Clb, 0.47 [0.21-1.06], P=.0577; acalabrutinib vs O + Clb, 0.60 [0.28-1.27], P=.1556). In the acalabrutinib + O, acalabrutinib, and O + Clb arms, the estimated 30-month OS rates were 95%, 94%, and 90%, respectively. Five patients (3%) in the acalabrutinib + O arm, 11 patients (6%) in the acalabrutinib arm, and 55 patients (31%) in the O + Clb arm had received a next therapy; 45 patients (25%) in the O + Clb arm crossed over to the acalabrutinib monotherapy arm.

In conclusion, study results showed that acalabrutinib + O and acalabrutinib monotherapy significantly improved PFS vs O + Clb, with tolerable safety in patients with TN CLL. Despite cross over for disease progression in the O + Clb arm, a trend toward improved OS was observed in both acalabrutinib arms, though longer follow-up is needed, authors said.—Amanda Del Signore

Sharman J, Banerji V, Fogliatto LM. et al. ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Presented at: the 2019 ASH Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 31.