Research Summary
Acalabrutinib, a next-generation covalent Bruton tyrosine kinase (BTK) inhibitor, has shown efficacy and tolerability in the treatment of chronic lymphocytic leukemia (CLL). In the Phase III, randomized, multicenter, open-label ASCEND trial, acalabrutinib was compared to investigator’s choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in the treatment of relapsed/refractory (R/R) CLL. Primary analysis of ASCEND showed that acalabrutinib therapy was associated with significantly superior progression-free survival (PFS) and acceptable tolerability among patients, compared to IdR and BR. Ghia et al1 analyzed four-year follow-up data from the ASCEND trial to determine the long-term efficacy and safety of acalabrutinib. Their findings are summarized below.
To be included in the trial, patients needed to be aged 18 years or older, have received at least one prior systemic therapy, have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and have adequate renal, hematologic, and hepatic function. Exclusion criteria included significant cardiovascular disease requiring vitamin K antagonist treatment and previous treatment with B-cell lymphoma 2, BTK, phosphoinositide 3-kinase, or tyrosine-protein kinase inhibitors.
Patients in the acalabrutinib group received oral acalabrutinib 100mg twice daily until progressive disease (PD) or unacceptable toxicity. Patients in the IdR group received oral idelalisib 150mg twice daily until PD or unacceptable toxicity and intravenous (IV) rituximab 375mg/m2 on Day 1 of the first cycle, followed by 500mg/m2 every two weeks for four doses, then every four weeks for three doses. Patients in the BR group received IV bendamustine 70mg/m2 on Days 1 and 2 of cycles 1 to 6 and IV rituximab 375mg/m2 on Day 1 of the first cycle, then 500mg/m2 on Day 1 of cycles 2 to 6. Patients in the IdR and BR groups could cross over to acalabrutinib therapy upon confirmed disease progression.
Among 310 patients, median age was 67 years. Unmutated immunoglobulin heavy chain variable region (IGHV) genes were found in 228 patients (74%). Chromosome 17p deletion (del17p) and/or TP53 mutation were present in 86 patients (28%).
At data cutoff, 112 of 154 patients (73%) in the acalabrutinib group had completed 24 months or more of treatment. Of 118 patients in the IdR group, 92 (78%) and 27 (23%) had completed six months or more of rituximab treatment and 24 or more months of idelalisib treatment, respectively. Of 35 patients in the BR group, 28 (80%) and 29 (83%) had completed six or more cycles of rituximab and bendamustine therapy, respectively. Eighty patients (52%) in the investigator’s choice arm switched to acalabrutinib treatment.
Ninety-three patients (60%) in the acalabrutinib arm were alive and disease progression-free at median 46.5-month follow-up, compared to 36 (23%) in the investigator’s choice arm at median 45.3-month follow-up. PFS was significantly longer in the acalabrutinib group (median: not reached) compared to the investigator’s choice group (median: 16.8 months); the difference was still significant when comparing the IdR and BR groups alone, with median PFS of 16.2 and 18.6 months, respectively. In patients with del17p and/or TP53 mutation, median PFS was superior in the acalabrutinib arm, at 45.5 months, compared to 11.1 months in the investigator’s choice arm. Median PFS was not reached with acalabrutinib treatment in patients without del17p and/or TP53 mutation, compared to 23.3 months with IdR/BR therapy. Among patients with unmutated IGHV, median PFS was not reached in the acalabrutinib arm, compared to16.2 months in the investigator’s choice arm.
In both arms, median overall survival (OS) was not reached. The 42-month OS rate was higher in the acalabrutinib arm than the investigator’s choice arm (78% vs. 65%), with similar rates in high-risk subgroups. Additionally, objective response rate (ORR) was similar between groups, at 83 and 84 percent for the acalabrutinib and investigator’s choice arms, respectively. Complete response was five percent (n=8) in both arms.
The most common adverse events (AEs) of any grade were neutropenia (24%), headache (23%), diarrhea (21%), and upper respiratory tract infection (20%) in the acalabrutinib group; diarrhea (53%), neutropenia (47%), and pyrexia (19%) in the IdR group; and neutropenia (34%), fatigue (23%), infusion-related reaction (23%), and nausea (20%). A total of 108 patients (92%) in the IdR group experienced a Grade 3 or higher AE, followed by 104 (68%) in the acalabrutinib group and 17 (49%) in the BR group. Neutropenia was the most common Grade 3 or higher AE in all groups.
Drug discontinuation due to AEs occurred in 79 (67%), 36 (23%), and 6 (17%) patients in the IdR, acalabrutinib, and BR groups, respectively. Rates of most events of clinical interest, including atrial fibrillation, major hemorrhage events, and hypertension, and second primary malignancies, were similarly low in all groups. The most common event of clinical interest was infection of any grade, occurring in 73, 68, and 49 percent of patients in the IdR, acalabrutinib, and BR groups, respectively.
Based on these results, Ghia et al demonstrated that acalabrutinib monotherapy showed superior efficacy with consistent, adequate tolerability in patients with R/R CLL, compared to IdR and BR therapies, at a follow-up of about four years.
Reference
- Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: final ASCEND trial results. Hemasphere. 2022;6(12):e801. Â