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

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