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

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 = 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.

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

“…This is based on a phase III trial in which acalabrutinib was superior to either bendamustine plus rituximab or idelalisib plus rituximab. 131 In this trial, prior ibrutinib therapy was not allowed, but a separate trial has shown that 85% of patients who were intolerant to ibrutinib were subsequently able to take acalabrutinib, with a 76% response rate. 132 Despite all recent therapeutic advances, a proportion of patients will still fail to respond and should be considered for curative therapy.…”

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents

“…These drugs have improved response rates, progression-free survival (PFS), and overall survival (OS), including in patients with high-risk disease. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] AlloHCT carries risks including graft-versushost disease (GVHD), organ toxicity, and nonrelapse mortality (NRM); in light of the potential for long-term disease control with sequential administration of NAs, the necessity of pursuing longterm disease control with alloHCT is less defined. 25 Despite effective NAs, drug intolerance, progression, primary resistance, and high-grade transformation remain as serious limitations for many patients.…”

Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

“…ELEVATE-TN reported that acalabrutinib alone or acalabrutinib-chlorambucil is superior to obinutuzumabobinutuzumab [81]. ASCEND reported that acalabrutinib improved PFS compared with idelalisib-rituximab or BR [82]. Several phase III clinical trials of acalabrutinib in CLL/SLL are ongoing, including ELEVATE-RR, which compares acalabrutinib to ibrutinib, and ACE-CL-311, which compares acalabrutinib-venetoclax with/without obinutuzumab versus chemoimmunotherapy.…”