Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland
Wojciech Jurczak , Andrzej Pluta , Malgorzata Wach , Daniel Lysak , Martin Simkovic , Iryna Kriachok , Árpád Illés , Javier De La Serna , Sean Dolan , Philip Campbell , Gerardo Musuraca , Abraham Jacob , Eric Joseph Avery , Jae Hoon Lee , Ganna Usenko , Min Hui Wang , Ting Yu , Paolo Ghia
Background: Acalabrutinib (acala) is a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor approved for patients (pts) with chronic lymphocytic leukemia (CLL). In the primary analysis of ASCEND (median follow-up 16.1 mo), acala showed superior efficacy with an acceptable tolerability profile vs idelalisib (Id) plus rituximab (R) (IdR) or bendamustine (B) plus R (BR) in pts with relapsed/refractory (R/R) CLL (Ghia et al. J Clin Oncol. 2020;38:2849-2861). We report the results of the ASCEND study at ~4 years of follow-up. Methods: In this multicenter, randomized, open-label, phase 3 study (NCT02970318), pts with R/R CLL received oral (PO) acala 100 mg BID until progression or unacceptable toxicity or investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or unacceptable toxicity; R: 375 mg/m2 x1 then 500 mg/m2 IV [8 total infusions]) or BR (B: 70 mg/m2 IV; R: 375 mg/m2 x1 then 500 mg/m2 IV [6 cycles]). Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. Results: A total of 310 pts (acala, n=155; IdR, n=119; BR, n=36) were randomized (median age 67 y; del(17p) 15%, unmutated IGHV 74%, Rai stage 3/4 42%). At median follow-up of 46.5 mo (acala) and 45.3 mo (IdR/BR), acala significantly prolonged INV-assessed PFS vs IdR/BR (median not reached [NR] vs 16.8 mo; P<0.0001); 42-mo PFS rates were 62% for acala vs 19% for IdR/BR. In pts with del(17p), median PFS was NR (acala) vs 13.8 mo (IdR/BR; P<0.0001). In pts with unmutated IGHV, median PFS was NR (acala) vs 16.2 mo (IdR/BR; P<0.0001). Median OS was NR in both arms; 42-mo OS rates were 78% (acala) vs 65% (IdR/BR). ORR was 83% (acala) vs 84% (IdR/BR) (ORR + partial response with lymphocytosis: 92% [acala] vs 88% [IdR/BR]). AEs led to drug discontinuation in 23% of acala, 67% of IdR, and 17% of BR pts. Events of clinical interest (acala vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), and grade ≥3 infections (29% vs 29%). Conclusions: At ~4 years of follow-up, acala maintained efficacy compared with standard-of-care regimens and a consistent tolerability profile in R/R CLL. Clinical trial information: NCT02970318.
Acala (n=154) | IdR (n=118) | BR (n=35) | ||||
---|---|---|---|---|---|---|
Median treatment exposure (mo) | 44.2 | 11.5 (Id), 5.5 (R) | 5.6 (B), 5.5 (R) | |||
Common AEsa, n (%) | Any Grade | Grade ≥3 | Any Grade | Grade ≥3 | Any Grade | Grade ≥3 |
Neutropenia | 37 (24) | 29 (19) | 55 (47) | 47 (40) | 12 (34) | 11 (31) |
Headache | 36 (23) | 1 (1) | 7 (6) | 0 | 0 | 0 |
Diarrhea | 33 (21) | 3 (2) | 62 (53) | 31 (26) | 5 (14) | 0 |
Upper respiratory tract infection | 31 (20) | 3 (2) | 20 (17) | 4 (3) | 4 (11) | 1 (3) |
Fatigue | 19 (12) | 2 (1) | 10 (8) | 1 (1) | 8 (23) | 1 (3) |
Nausea | 13 (8) | 0 | 17 (14) | 1 (1) | 7 (20) | 0 |
Infusion-related reaction | 1 (1) | 0 | 9 (8) | 2 (2) | 8 (23) | 1 (3) |
aAny grade in ≥20% of pts. AE reporting period: up to 30 days after last study drug dose or at disease progression, whichever comes first.
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