Wang M, et al. ASH 2017:155

Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase II ACE-LY-004 study


The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is efficacious in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL); however, it has been associated with toxicities such as atrial fibrillation, bleeding, and infections.1,2 Off-target activities of ibrutinib may contribute to the incidence of these toxicities.3 Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activities in preclinical studies.4,5 At the 2017 ASH Annual Meeting, a phase II study evaluated the efficacy and safety of acalabrutinib monotherapy in patients with R/R MCL.6

Study design

  • The ACE-LY-004 study enrolled patients between March 12, 2015, and January 5, 2016, at 40 centres across 10 countries.
  • A total of 124 patients with R/R MCL who received 1–5 prior therapies were enrolled.
  • Patients received 100 mg acalabrutinib twice a day in 28-day cycles until disease progression.
  • Primary endpoint was overall response rate (ORR) by investigator assessment based on the Lugano classification.
  • Secondary endpoints included ORR by independent review committee (IRC) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics (PK), and pharmacodynamics.
  • Exploratory endpoints included time to response and IRC-assessed ORR per the 2007 International Harmonization Project (IHP) criteria.
  • Data cutoff was February 28, 2017.
  • Inclusion criteria were:
    • Confirmed MCL with translocation t(11;14)(q13;q32) and/or overexpressed cyclin D1;
    • Relapsed after or refractory to 1–5 prior treatments;
    • Measurable nodal disease (≥1 lymph node ≥2 cm in longest diameter);
    • Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2; and
    • Age ≥18 years.
  • Exclusion criteria were:
    • Significant cardiovascular disease (uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within six months of screening, any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval >480 ms);
    • Concomitant use of warfarin or equivalent vitamin K antagonists; and
    • Previous treatment with BTK inhibitors.

Key findings

Baseline characteristics and disposition

  • Median age was 68 years (range: 42–90).
  • The majority of patients were male (80%) with an ECOG PS ≤1 (93%), Ann Arbor stage IV disease (75%), and extranodal disease (73%).
  • Patients had received a median of two prior therapies.
    • The majority of patients had previously received rituximab as a single agent or as part of a regimen (95%).
    • The majority of patients had previously received a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimen (52%).
  • At a median follow-up of 15.2 months, 56% of patients remained on study therapy.
  • Of the 54 patients (44%) who discontinued acalabrutinib, reasons for discontinuation were:
    • Disease progression (n = 39);
    • Adverse event (AE) (n = 7);
    • Receipt of stem cell transplant (n = 5);
    • Lost to follow-up (n = 1);
    • Withdrawal of consent (n = 1); and
    • Patient decision to stop treatment (n = 1).
  • AEs leading to discontinuation occurred in one patient each and were aortic stenosis, diffuse large B-cell lymphoma, blood blister and petechiae (in a patient with grade 3 acute coronary syndrome treated with clopidrogel), dyspnea and leukostasis syndrome, noncardiac chest pain, pulmonary fibrosis, and thrombocytopenia.


  • Acalabrutinib PK parameters indicated rapid absorption and elimination, and low potential for accumulation.
  • Acalabrutinib dosed at 100 mg twice a day (bid) resulted in a median BTK occupancy of 99% four hours post dose and 95%–97% before next dose.
  • IRC-assessed ORR and complete response (CR) using the Lugano classification were 80% and 40%, respectively. (Table 1)
    • A high concordance was observed between investigator- and IRC-assessed ORR and CR (91% and 94%, respectively).
  • IRC-assessed ORR and CR by 2007 IHP criteria were 75% and 30%, respectively.
  • ORR was consistent across all prespecified subgroups. (Figure 1)
    • No differences were observed by sex, race, Ann Arbor stage, tumour bulk, or prior lenalidomide exposure.
  • Most patients experienced a reduction in lymphadenopathy (94%).
  • Median time to response was 1.9 months (range: 1.5–4.4).
    • Initial response was achieved by the end of Cycle 2 in the majority of responders (92%).
  • Median DOR has not been reached, and the 12-month DOR rate was 72% (95% CI: 62–80).
  • Median PFS and OS have not been reached. (Figure 2)

Table 1. ORR using the 2014 Lugano Classification

Figure 1. Subgroup analysis of ORR

Figure 2. Progression-free survival and overall survival


  • Most common AEs are summarized in Figure 3.
  • Serious AEs (SAEs) occurred in 48 patients (39%).
  • SAEs reported in ≥2 patients included:
    • Pneumonia (n = 5, 4%);
    • Anemia (n = 4, 3%);
    • General physical health deterioration (n = 3, 2%);
    • Sepsis (n = 2, 2%);
    • Tumour lysis syndrome (n = 2, 2%); and
    • Vomiting (n = 2, 2%).
  • One grade 3 gastrointestinal (GI) hemorrhage occurred in a patient with a history of GI ulcers.
  • One grade 5 AE (aortic stenosis) occurred in a patient with a history of aortic stenosis (not treatment related).
  • No cases of atrial fibrillation were observed.
  • Grade 3/4 cardiac AEs included:
    • One grade 3 acute coronary syndrome (treatment related);
    • One grade 3 acute myocardial infarction (not treatment related); and
    • One grade 4 cardiorespiratory arrest (not treatment related).
  • Any grade and grade 3/4 infections occurred in 53% and 13% of patients, respectively.
  • Bleeding events occurred in 31% of patients and were all grade 1/2, with the exception of the grade 3 GI hemorrhage.

Figure 3. Most common adverse events

Key conclusions

  • Acalabrutinib 100 mg bid demonstrated compelling efficacy and a differentiated safety profile, thus providing an alternative therapeutic option for patients with R/R MCL.
    • Responses were durable, and the majority of the most common AEs were grade 1/2.
    • There were few discontinuations due to AEs (6%).
    • No atrial fibrillation was observed and the rate of grade ≥3 hemorrhage was low (1%).
  • The PK and selectivity profiles of acalabrutinib allowed twice-daily dosing with minimal off-target effects while achieving near complete and continuous BTK inhibition over time.

References: 1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369(6):507–16. 2. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, LLC; 2017. 3. Stephens DM, Spurgeon SE. Ibrutinib in mantle cell lymphoma patients: glass half full? Evidence and opinion. Ther Adv Hematol 2015;6(5):242–52. 4. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374(4):323–32. 5. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther 2017;363(2):240–52. 6. Wang M, Rule S, Zinzani PL, et al. Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase 2 ACE-LY-004 study. ASH Annual Meeting Abstracts 2017:155.