As reported in the Journal of Clinical Oncology by Ghia et al, the phase III ASCEND trial has shown prolonged progression-free survival with acalabrutinib monotherapy vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
The trial supported the November 2019 U.S. Food and Drug Administration approval of acalabrutinib for treatment of adults with chronic CLL or small lymphocytic lymphoma (SLL).
Study Details
In the open-label trial, 310 patients from sites in 25 countries in North America, Europe, the Middle East, and the Asia-Pacific region were randomly assigned between February 2017 and January 2018 to receive acalabrutinib monotherapy at 100 mg twice daily (n = 155) or investigator’s choice of idelalisib/rituximab (n =119) or bendamustine/rituxumab (n = 36). 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 the first cycle, 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 the first cycle and 500 mg/m2 thereafter on day 1 of cycles 2 through 6.
Randomization was stratified by del(17p) status, Eastern Cooperative Oncology Group performance status, and number of prior lines of therapy. Patients receiving investigator’s choice therapy who had confirmed disease progression were permitted to cross over to receive acalabrutinib monotherapy. Acalabrutinib was given until disease progression or unacceptable toxicity.
The primary endpoint was progression-free survival on independent review committee (IRC) assessment in the intent-to-treat population.
Progression-Free Survival
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 rates were 88% vs 68%. In post hoc analysis, median durations were 15.8 months in patients receiving idelalisib/rituximab and 16.9 months in those receiving bendamustine/rituximab.
The progression-free survival benefit of acalabrutinib was consistent across subgroups examined. Hazard ratios were:
- 0.30 (95% CI = 0.18–0.48) and 0.36 (95% CI = 0.10–1.37) for performance status 0/1 and 2
- 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 a TP53 mutation
- 0.32 (95% CI = 0.11–0.94) and 0.32 (95% CI = 0.19–0.52) for unmutated and mutated IGHV
- 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 four or more.
Overall, 23% of patients initially randomly assigned to investigator’s choice crossed over to receive acalabrutinib at 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 at 12 months was 94% vs 91%. Overall response rates on independent review committee assessment were 81% vs 75% (P = .22), with median response durations of not reached vs 13.6 months (P < .0001).
KEY POINTS
- Acalabrutinib significantly prolonged progression-free survival vs investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab.
- Median progression-free survival was not reached vs 16.5 months.
Adverse Events
Grade 3 or 4 adverse events occurred in 45% of patients in the acalabrutinib group, 86% of patients receiving idelalisib/rituximab, and 43% of those receiving bendamustine/rituximab. The most commonly reported adverse events were neutropenia (16%), anemia (12%), and pneumonia (5%) in patients receiving acalabrutinib; neutropenia (40%), diarrhea (24%), pneumonia (9%), and increased alanine aminotransferase (9%) in patients receiving idealisib/rituximab; and neutropenia (31%), anemia (9%), and constipation ( 6%) in those receiving bendamustine/rituximab. Atrial fibrillation occurred in 5% of patients in 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 common = pneumonia in 8 patients), 56% of patients receiving idealisib/rituximab (most common = diarrhea in 16, pneumonia in 10), and 26% of those receiving bendamustine/rituximab (no type of event occurring in more than 1 patient). Adverse events led to discontinuation of treatment in 11% of the acalabrutinib group and in 47% of the idelalisib/rituximab group.
Adverse events led to death in 10% of the acalabrutinib group, 11% of patients receiving idelalisib/rituximab, and 14% of those receiving bendamustine/rituximab.
The authors concluded, “Acalabrutinib significantly improved progression-free survival compared with idelalisib/rituximab or bendamustine/rituximab and has an acceptable safety profile in patients with relapsed/refractory CLL.”
Paolo Ghia, MD, PhD, of Università Vita-Salute San Raffaele, Milan, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Acerta Pharma (a member of the AstraZeneca group). For full disclosures of the study authors, visit ascopubs.org.
