Background: Acalabrutinib is a next-generation, highly selective, covalent Bruton tyrosine kinase inhibitor approved for patients with CLL, including those with R/R CLL.
Objectives: The efficacy and safety of acalabrutinib alone versus IdR or BR were shown in patients with R/R CLL in a preplanned interim analysis of ASCEND; final results are reported herein.
Methods: In this randomized, multicenter, phase 3, open-label study (NCT02970318), patients with R/R CLL were randomized 1:1 to receive oral (PO) acalabrutinib 100 mg twice daily (bid) or investigator’s choice of IdR (Id: 150 mg PO bid until progression or toxicity; R: 375 mg/m2 × 1, then 500 mg/m2 IV for 8 total infusions) or BR (B: 70 mg/m2 IV and R: 375 mg/m2 × 1, then 500 mg/m2 IV for 6 total cycles) until progression or toxicity. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. All patients provided informed consent.
Results: A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled (median age: 67 years; del[17p] 16%, del[11q] 27%, Rai stage 3/4 42%). At a median follow-up of 22.0 months, acalabrutinib significantly prolonged investigator-assessed PFS versus IdR/BR (median: not reached vs 16.8 months; hazard ratio: 0.27; P <.0001); 18-month PFS rates were 82% for acalabrutinib and 48% for IdR/BR. The 18-month OS rate was 88% for both treatment regimens. The ORR was 80% with acalabrutinib versus 84% with IdR/BR; ORR including partial response with lymphocytosis was 92% versus 88%, respectively. The most common adverse events (AEs; any grade [grade ≥3]) by treatment group were: acalabrutinib, headache (22% [1%]), neutropenia (21% [17%]), and diarrhea (20% [2%]); IdR, diarrhea (49% [25%]) and neutropenia (46% [40%]); BR, neutropenia (34% [31%]), fatigue (23% [3%]), infusion-related reaction (23% [3%]), and nausea (20% [0%]). AEs led to drug discontinuation in 16% of acalabrutinib, 56% of IdR, and 17% of BR patients. AEs of interest included atrial fibrillation (acalabrutinib 6%, IdR/BR 3%), major hemorrhage (all grade; acalabrutinib 3%, IdR/BR 3%), grade ≥3 infections (acalabrutinib 20%, IdR/BR 25%), and second primary malignancies excluding nonmelanoma skin cancer (acalabrutinib 5%, IdR/BR 2%).
Conclusions: Final ASCEND results with additional follow-up confirm earlier findings and support the favorable efficacy and safety of acalabrutinib compared with standard-of-care regimens in patients with R/R CLL.
Support: This study was sponsored by Acerta Pharma, a member of the AstraZeneca group.