As reported in the Journal of Clinical Oncology by Paolo Ghia, MD, PhD, of the Università Vita-Salute San Raffaele, Milan, Italy, and colleagues, the phase III ASCEND trial showed significantly prolonged progression-free survival with acalabrutinib monotherapy vs investigator’s choice of either idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in adults with relapsed or refractory chronic lymphocytic leukemia (CLL).¹ The trial supported the November 2019 approval of acalabrutinib in the treatment of adults with chronic CLL or small lymphocytic lymphoma.

Paolo Ghia, MD, PhD

Study Details

This open-label trial was conducted between February 2017 and January 2018 and enrolled 310 patients from 102 sites in 25 countries across North America, Europe, the Middle East, and the Asia-Pacific region. The patients were randomly assigned to receive either acalabrutinib monotherapy at 100 mg orally twice daily (n = 155) or investigator’s choice of IdR (n = 119) or BR (n = 36). Randomization was stratified by del(17p) status, TP53 and IGHV mutation status, Eastern Cooperative Oncology Group (ECOG) performance status, and number of prior lines of therapy.

Patients with significant cardiovascular disease and those with previous treatment with BTK, PI3K, SYK, or BCL-2 inhibitors were excluded. Concomitant treatment with warfarin or equivalent vitamin K antagonists was prohibited. Patients who had previously
received bendamustine were eligible to receive bendamustine if the duration of prior response was at least 24 months. Patients receiving investigator’s choice of therapy, and who then had confirmed disease progression, were permitted to cross over to receive acalabrutinib monotherapy.

Acalabrutinib was administered until disease progression or unacceptable toxicity. The investigator’s choice of therapy consisted of: idelalisib at 150 mg, twice daily, until disease progression or unacceptable toxicity in combination with rituximab at 375 mg/m² on day 1 of cycle 1, followed by 500 mg/m² every 2 weeks for four doses and then every 4 weeks for three doses for a total of eight infusions; or bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle in combination with rituximab at 375 mg/m² on day 1 of cycle 1 and 500 mg/m² thereafter on day 1 of cycles 2 through 6. The primary endpoint was progression-free survival per independent review committee assessment in the intent-to-treat population.

For the acalabrutinib vs combined investigator’s choice group, the median patient ages were 68 vs 67 years (22% vs 20% were aged ≥ 75 years) and 70% vs 65% were male, respectively. The ECOG performance status was 0 for 37% vs 35% of patients, 1 for 50% vs 51%, and 2 for 12% vs 14%, respectively. In the acalabrutinib vs investigator’s choice group, 18% vs 14% of patients had del(17p); 26% vs 22% had TP53 mutation; 77% vs 82% had unmutated IGHV; and the median number of prior therapies was one vs two, with 79% vs 73% of patients having had one or two prior therapies, 11% vs 15% having had three, and 10% vs 12% having had at least four, respectively.

Progression-Free Survival

The median follow-up was 16.1 months (range = 0.03–22.4 months). Median progression-free survival was not reached in the acalabrutinib group vs 16.5 months (95% confidence interval [CI] = 14.0–17.1 months) in the investigator’s choice group (hazard ratio [HR] = 0.31, 95% CI = 0.20–0.49, P < .0001). Estimated 12-month progression-free survival rates for the acalabrutinib group vs the investigator’s choice group were 88% vs 68%, respectively. In a post hoc analysis of the investigator’s choice subgroups, median progression-free survival durations were 15.8 months in patients receiving IdR and 16.9 months in those receiving BR.

The progression-free survival benefits of acalabrutinib were consistent across examined patient subgroups. Hazard ratios were 0.30 (95% CI = 0.18–0.48) and 0.36 (95% CI = 0.10–1.37) for an ECOG performance status of 0 or 1 and 2, respectively; 0.21 (95% CI = 0.07–0.68) and 0.33 (95% CI = 0.21–0.54) for patients with and without del(17p), 0.24 (95% CI = 0.11–0.56) and 0.33 (95% CI = 0.20–0.57) for patients with and without TP53 mutation, 0.32 (95% CI = 0.11–0.94) and 0.32 (95% CI = 0.19–0.52) for unmutated and mutated IGHV, and 0.27 (95% CI = 0.16–0.44) and 0.64 (95% CI = 0.23–0.80) in patients with one to three prior lines of therapy and those with at least four.

Overall, 23% of patients who were initially randomly assigned to the investigator’s choice of therapy crossed over to receive acalabrutinib after disease progression. At the time of analysis, median overall survival had not been reached in either group, with 10% of patients in the acalabrutinib group and 12% in the investigator’s choice group having died (HR = 0.84, 95% CI = 0.42–0.66). Overall survival rates at 12 months for the two groups were 94% and 91%. Overall response rate per independent review committee assessment was 81% vs 75% (P = .22), with median response durations of not reached vs 13.6 months (P < .0001).

Adverse Events

Grade 3 or 4 adverse events occurred in 45% of the acalabrutinib group, 86% of
patients receiving IdR, and 43% of those receiving BR. The most common side effects were neutropenia (16%), anemia (12%), and pneumonia (5%) in the acalabrutinib group; neutropenia (40%), diarrhea (24%), pneumonia (9%), and increased alanine aminotransferase levels (9%) in patients receiving IdR; and neutropenia (31%), anemia (9%), and constipation (6%) in those receiving BR. Atrial fibrillation occurred in 5% of the acalabrutinib group and 3% of the investigator’s choice group. Bleeding of any grade occurred in 26% vs 7% of patients. Second primary malignancies occurred in 14% vs 5% of patients.

Serious adverse events occurred in 29% of the acalabrutinib group (most commonly, pneumonia in 8 patients), 56% of patients receiving IdR (most commonly diarrhea in 16, pneumonia in 10), and 26% of those receiving BR (no type of event occurring in more than 1 patient). Adverse events led to discontinuation of treatment in 11% of the acalabrutinib group and 47% of the IdR group.

Adverse events led to death in 10% of the acalabrutinib group, 11% of patients receiving IdR, and 14% of those receiving BR.

The authors concluded: “Acalabrutinib significantly improved [progression-free survival] compared with IdR or BR and has an acceptable safety profile in patients with [relapsed/refractory] CLL.” 

DISCLOSURE: The study was supported by Acerta Pharma (a member of the AstraZeneca group). Dr. Ghia has received honoraria from AbbVie, BeiGene, Janssen Oncology, Gilead Sciences, Juno Therapeutics, Sunesis Pharmaceuticals, ArQule, Adaptive Biotechnologies, Dynamo, MEI Pharma, and Acerta Pharma/AstraZeneca; has served as a consultant or advisor to AbbVie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo, MEI Pharma, and Acerta Pharma/AstraZeneca; and has received research funding from AbbVie, Janssen Oncology, Gilead Sciences, Sunesis Pharmaceuticals, and Novartis. For complete disclosures of the other study authors, visit ascopubs.org.

REFERENCE

1. Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 38:2849-2861, 2020.