A phase 2, multicentre, open‐label trial (ACE‐LY‐003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma

Abstract

Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5).Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%).Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients.Acalabrutinib was active and well tolerated in patients with R/R MZL.

Managing Ibrutinib-Intolerant Patients With B-Cell Malignancies

“…Results from 40 evaluable patients with R/R MZL receiving acalabrutinib 100 mg twice daily showed an ORR of 53% (95% CI, 36%-69%), and 5 (13%) patients had complete responses (median follow-up was 13.3 months). 49 In this study, there were 5 deaths ( n = 4 disease progression, n = 1 septic shock), and the most common ≥ Grade 3 AEs were neutropenia (14%), anemia (7%), dyspnea (7%), fatigue (5%), and thrombocytopenia (5%). Further studies are needed to compare the efficacy and safety of acalabrutinib to other current standard treatments of B-cell malignancies, and to investigate acalabrutinib in ibrutinib-intolerant patients.…”

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open‐label study

“…In other phase 2 BTK inhibitor studies in r/r MZL patients, ibrutinib, zanubrutinib, and acalabrutinib had ORRs of 48% (95% CI, 35–62) at median follow‐up of 19.4 months; 68% (95% CI, 56–79) at median follow‐up of 15.7 months; and 53% (95% CI, 36–69) at median follow‐up of 13.3 months, respectively 7,8,15 . Of note, responses reported in the MAGNOLIA trial of zanubrutinib were based on positron emission tomography evaluations, while the CT‐based response rate was 56% (95% CI, 43–68) in the same study 17 .…”

“…BTK inhibitors are a positive addition to the treatment landscape for r/r MZL due to their targeted inhibition of B cell receptor signaling, which is implicated in the pathogenesis of lymphomas. Current second‐line treatment options approved by the FDA for MZL include ibrutinib and zanubrutinib, while acalabrutinib is undergoing phase 2 studies 15 . Phosphoinositide 3‐kinase (PI3K) inhibitors such as copanlisib and anti‐CD19 chimeric antigen receptor (CAR) T cell therapy constitute other available novel therapies under investigation, but the safety profiles can be quite concerning with a limited eligible population 5 .…”

Unmet clinical needs in the use of zanubrutinib in malignant lymphomas (Waldenström macroglobulinemia, marginal zone lymphoma and mantle cell lymphoma): A consensus‐based position paper from an ad hoc expert panel

“…More recently, in a phase II study including 40 patients with R/R MZL, 43 acalabrutinib was found to have activity, though ORR and CR rates as well as 12‐month PFS rates seem lower than those reported with zanubrutinib.…”