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Table 1 Key clinical trials of approved and investigational BTK inhibitors for the treatment of CLL

From: Current and future treatment strategies in chronic lymphocytic leukemia

Agent Trial name Trial design and patients Outcomes Citation
Approved agents
 Ibrutinib (second-line or later monotherapy) RESONATE (NCT01578707) Phase 3 study of the efficacy and safety of ibrutinib versus ofatumumab in patients with relapsed or refractory CLL Ibrutinib versus ofatumumab:
 Median PFS (9.4-month median follow up): not reached versus 8.1 months
 12-month OS: 90% versus 81%
 ORR: 42.6% versus 4.1%
 Grade ≥ 3 AEs: 57% versus 47%
[28]
 Ibrutinib (first-line monotherapy) RESONATE-2 (NCT01722487) Phase 3 study of the efficacy and safety of ibrutinib versus chlorambucil in treatment-naïve patients (≥ 65 years of age) with CLL Ibrutinib versus chlorambucil:
 Median PFS (18.4-month median follow up): not reached versus 18.9 months
 24-month OS: 98% versus 85%
 ORR: 86% versus 35%
[29]
 Ibrutinib (first-line combination) iLLUMINATE (NCT02264574) Phase 3 study of the efficacy and safety of ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in treatment-naïve patients with CLL/SLL Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab:
Median PFS (31.3-month median follow up): not reached versus 19.0 months
30-month PFS: 79% versus 31%
SAEs: 58% versus 35%
[30]
 Ibrutinib (first-line combination) ECOG1912 (NCT02048813) Phase 3 study of the efficacy and safety of ibrutinib plus rituximab or fludarabine plus cyclophosphamide plus rituximab (chemo-immunotherapy) in treatment-naïve patients (≤ 70 years of age) with CLL Ibrutinib plus rituximab versus fludarabine plus cyclophosphamide plus rituximab:
 3-year PFS: 89.4% versus 72.9%
 3-year OS: 98.8% versus 91.5%
 Subgroup analysis of patients without IGHV mutation:
  3-year PFS: 90.7% versus 62.5%
 Grade ≥ 3 AEs: 80.1% versus 79.7%
[31]
 Ibrutinib (first-line monotherapy or combination) ALLIANCE (NCT01722487) Phase 3 study of the efficacy of ibrutinib, ibrutinib plus rituximab, or bendamustine plus rituximab in treatment-naïve patients (≥ 65 years of age) with CLL Ibrutinib, ibrutinib plus rituximab, bendamustine plus rituximab:
 Median PFS: not reached, not reached, 43 months
 2-year PFS: 87%, 88%, 74%
 No differences in OS
 Grade ≥ 3 hematological AEs: 41%, 39%, 61%
[32]
 Acalabrutinib (second-line or later monotherapy) NCT02029443 Phase 1b/2 study of the safety and efficacy of acalabrutinib in patients with relapsed CLL  Median PFS (41-month median follow up): not reached
 Median duration of response: not reached
 45-month estimated PFS: 62%
 ORR: 94%
  Responses were similar regardless of the presence of del(11q), del(17p), complex karyotype, of IGHV mutation status
 Most AEs were mild or moderate
[41, 42]
 Acalabrutinib (first-line monotherapy or combination therapy) ELEVATE TN (NCT02475681) Phase 3 study of the efficacy and safety of acalabrutinib or acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in treatment-naïve patients with CLL Acalabrutinib, acalabrutinib plus obinutuzumab, chlorambucil plus obinutuzumab:
 Median PFS (28.3-month median follow up): not reached, not reached, 22.6 months
 Estimated 24-month PFS: 87%, 93%, 47%
  Consistent across subgroups, including del(17p)
 Median OS: not reached in any arm
 Estimated 24-month OS: 95%, 95%, 92%
 ORR: 86%, 94%, 79%
[43]
 Acalabrutinib (second-line or later monotherapy) ASCEND (NCT02970318) Phase 3 study of the efficacy and safety of acalabrutinib versus rituximab plus idelalisib or bendamustine in patients with relapsing or refractory CLL Interim analysis (acalabrutinib versus rituximab plus idelalisib/bendamustine):
 Median PFS (16.1-month median follow-up): not reached versus 16.5 months
 12-month PFS rate: 88% versus 68%
  Improvement was seen across subgroups, including del(17p) and TP53 mutation
 12-month OS: 94% versus 91%
 ORR: 81% versus 75%
[44]
Investigational agents
 Zanubrutinib (second-line or later monotherapy) NCT02343120 Phase 1 study of the safety and efficacy of zanubrutinib in patients with CLL  ORR: 96%
 Estimated 12-month PFS rate: 100%
 Most AEs were grade 1/2
[38]
 Zanubrutinib (first-line monotherapy [Arm C]) SEQUOIA (NCT03336333) Phase 3 study of zanubrutinib versus bendamustine plus rituximab in treatment-naïve patients with CLL/SLL Interim analysis (Arm C: del(17p)):
 Median PFS (18.2 month median follow-up): not reached
 Estimated 18-month PFS: 89%
 Median duration of response: not reached
 Estimated 18-month duration of response: 84%
 Median OS: not reached
 Estimated 18-month OS: 95%
 ORR: 95%
 Low rate of discontinuation due to AEs
[76]
 Zanubrutinib (second-line or later monotherapy) ALPINE (NCT03734016) Phase 3 study of zanubrutinib versus ibrutinib in patients with relapsing or refractory CLL/SLL Trial is ongoing [74]
 Orelabrutinib (second-line or later monotherapy)   Phase 2 study of orelabrutinib in Chinese patients with relapsing or refractory CLL/SLL  Median PFS (median follow-up 14.3 months): not reached
 Estimated 12-month PFS: 81.1%
 Median duration of response: not reached
 Estimated 12-month duration of response: 77.1%
 Estimated 12-month OS: 86.3%
 ORR (≥ 12 cycles): 91.3%
  del(17p): 100%
  del(11q): 94.7%
  TP53 mutation: 100%
  Unmutated IGHV: 93.9%
 Most AEs were mild to moderate
[79]
 LOXO-305 (any-line monotherapy) BRUIN (NCT03740529) Phase 1/2 study of LOXO-305 in treatment-naïve patients or those with previously treated CLL or NHL Interim analysis (patients with CLL):
 ORR: 57% among 65 efficacy-evaluable patients
  ORR with ≥ 6 months follow-up: 77%
 Median follow-up: 3 months for all patients; 6.7 months for responders
[81]
 ARQ 531 (second-line or later monotherapy) NCT03162536 Phase 1/2 study of ARQ 531 in patients with relapsing or refractory hematologic malignancies (including CLL) Trial is ongoing  
  1. AE adverse event, BTK Bruton tyrosine kinase, CLL chronic lymphocytic lymphoma, IGHV immunoglobulin heavy chain, NHL non-Hodgkin lymphoma, ORR overall response rate, OS overall survival, PFS progression-free survival, SAE serious adverse event, SLL small lymphocytic lymphoma