Dyer MJS, et al. ASCO 2018:7547

Acalabrutinib monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma


Bruton tyrosine kinase (BTK) inhibitors are promising therapies for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), an aggressive B-cell lymphoma that has limited treatment options in the R/R setting.1,2 Acalabrutinib is a second-generation BTK inhibitor with minimal off-target activity.3 This may lead to a tolerable safety profile that can allow the combination of a BTK inhibitor with another therapy. The ACE-LY-002 study was developed to assess the safety and efficacy of acalabrutinib monotherapy in patients with R/R DLBCL. Results from this study were presented at the 2018 ASCO Annual Meeting.4

Study design

  • The ACE-LY-002 study was a phase Ib, multicentre, open-label trial conducted at seven sites in the United States and the United Kingdom.
  • Eligible patients were aged ≥18 years and had pathologically confirmed, non-germinal centre B-cell (GCB)–type R/R DLBCL (per institution immunohistochemistry), an Eastern Oncology Cooperative Group performance status (ECOG PS) of 0–2, and the presence of radiographically measurable disease.
  • Exclusion criteria included:
    • Prior treatment with B-cell receptor inhibitors or B-cell lymphoma 2 inhibitors and concomitant warfarin or equivalent vitamin K antagonists;
    • Central nervous system involvement; and
    • Significant cardiovascular disease, including:
      • Uncontrolled or symptomatic arrhythmias;
      • Congestive heart failure;
      • Myocardial infarction within six months of screening;
      • Any New York Heart Association class III or IV cardiac disease; or
      • A corrected QT interval >480 ms.
    • Patients with prior or concurrent atrial fibrillation were not excluded from the study.
  • A subset of patients with available tissue had central cell-of-origin testing performed by gene expression profiling (NanoString Lymphoma Subtyping Test).
  • Acalabrutinib was given orally twice a day at a dose of 100 mg in 28-day cycles until progressive disease (PD) or unacceptable toxicity.
  • The primary endpoint was safety.
    • Adverse events (AEs) and serious AEs (SAEs) were collected from the time of screening, throughout the treatment period, and up to 30 days after the last dose of acalabrutinib.
    • AEs and SAEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
  • Secondary endpoints included pharmacokinetic (PK) and pharmacodynamic analyses, overall response rate (ORR), duration of response, and progression-free survival (PFS).
    • PK samples were collected during Cycle 1.
    • Blood for pharmacodynamic analyses was collected on days 1, 2, 8, 28, and 56.
      • The percentage occupied BTK was calculated in each sample for each assessment time point using an enzyme-linked immunosorbent assay-based method.
    • ORR was investigator-assessed and based on the Lugano classification.
      • Imaging was performed at the end of Cycle 2, Cycle 4, and Cycle 6, and then every three cycles thereafter (or more frequently at the investigator’s discretion).
    • Kaplan-Meier methods were used to estimate median PFS.

Key findings

Baseline characteristics and disposition

  • A high proportion of patients had poor risk characteristics, including advanced-stage extranodal disease and inadequate response to prior therapy.
  • Ten patients had refractory disease and 11 patients had relapsed disease, for a total study population of 21 patients.
  • The median age was 64 years (range: 32–84).
  • Ten patients were male (48%).
  • The majority of patients were white (71%), had an ECOG PS of 1 (67%), had stage IV disease (57%), and had extranodal involvement (57%).
  • Patients had received a median of three prior therapies (range: 1–5).
    • The most common prior therapy was the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, either on its own or in combination with methotrexate or intrathecal methotrexate (81%).
    • Another commonly received prior therapy was the combination of rituximab, ifosfamide, carboplatin, and etoposide (48%).
  • As of October 30, 2017, the median time on study was 3.9 months (range: 0.8–22.5).
    • Only one patient was continuing treatment at this time.
  • Reasons for treatment discontinuation included disease progression (81%), AEs/SAEs (10%), and initiation of an alternative cancer therapy (5%).
  • Median duration of treatment was 2.3 months (range: 0.5–22.5).


  • AEs of any grade occurred in 95% of patients.
  • Common AEs were primarily grade 1/2. (Figure 1)
    • Six patients (29%) reported grade 3 AEs.
      • Grade 3 AEs included anemia (n = 5), fatigue (n = 2), and abdominal pain (n = 2).
      • All patients with grade 3 anemia had low hemoglobin levels at baseline.
    • No grade 4 AEs were reported.
  • SAEs of any grade occurred in 43% of patients.
    • The most common SAEs were abdominal pain, pyrexia, and respiratory failure (n = 2 each).
  • No atrial fibrillation, hypertension, tumour lysis syndrome, or grade ≥3 bleeding AEs occurred.
  • Infections of any grade occurred in 11 patients (52%), of which three (14%) were grade 3/4.
  • A total of eight patient deaths (38%) were reported on study.
    • Five patients (24%) died due to disease progression, four of whom died more than 30 days after the last dose of acalabrutinib.
    • Three patients (14%) died due to AEs, all of which were unrelated to acalabrutinib.
      • One patient with a history of cystic fibrosis was admitted with pneumonia during the first month of therapy and died due to respiratory failure 27 days after the last dose of acalabrutinib.
      • One patient, who had discontinued treatment due to progression, died of sepsis 32 days after the last dose of acalabrutinib.
      • One patient died of meningeal metastases 32 days after the last dose of acalabrutinib.
  • Acalabrutinib was discontinued due to AEs in two patients (10%).
    • The AEs were respiratory failure (grade 5) and meningeal metastases (grade 5).


  • Investigator-assessed ORR for all patients was 24% (95% CI: 8.2%–47.2%). (Figure 2)
    • Four patients (19%) achieved a complete response (CR).
  • NanoString subtyping was available for 15 patients.
    • Nine patients had an activated B-cell (ABC) subtype of DLBCL, five had the GCB subtype, and one patient had an unclassified subtype.
  • The ORR in patients with ABC subtype was 33%, with 22% achieving a CR.
  • One patient with GCB subtype responded to treatment (20%), and the patient achieved a CR.
  • The median relative dose intensity was 98% (range: 6%–100%).
  • PK was similar in refractory and relapsed patients.
  • Rapid absorption and elimination were observed, indicating a low potential for accumulation.
  • BTK occupancy was conducted in five patients who had evaluable predose and postdose samples.
    • The median steady-state BTK target occupancy was 97%–99% throughout the daily dosing interval at steady-state on Day 8.
    • No patient had <90% BTK occupancy for any assessment.

Figure 1. Adverse events reported in ≥3 patients

Figure 2. Characteristics of the responders and duration of response

Key conclusions

  • Acalabrutinib monotherapy was well tolerated and demonstrated activity in patients with R/R DLBCL.
  • The safety profile was consistent with previous studies.
    • The most common AEs were grade 1/2 and did not lead to treatment discontinuation.
  • Acalabrutinib’s PK and selectivity profiles allowed twice-daily dosing with minimal off-target effects, while achieving near complete and continuous BTK inhibition over the treatment interval.
  • A weak correlation between institution immunohistochemistry and gene expression profiling classification methods may impact future patient selection approaches based on cell-of-origin.
  • These data support the evaluation of acalabrutinib-based combination therapies in patients with R/R DLBCL.

References: 1. Nowakowski GS, Blum KA, Kahl BS, et al. Beyond RCHOP: a blueprint for diffuse large B cell lymphoma research. J Natl Cancer Inst 2016;108(12):djw257. 2. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 2015;21(8):922–6. 3. 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. 4. Dyer MJS, de Vos S, Ruan J, et al. Acalabrutinib monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma. J Clin Oncol (ASCO Annual Meeting) 2018;36(Suppl):abstr 7547.