Table 1 BTKi monotherapy outcomes from phase II/III trials.

Ibrutinib

Treon et al. [24, 25]

Phase II, R/R (N = 63)

Median FU 59 months:

ORR: 90.5%

MRR: 79.4%

PFS: 2 years, 69.1%

OS: 2 years, 95.2%

OS: 5 years, 87%

Median time to response: 4 weeks

59 months median FU:

Grade ≥3 AEs: neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). AF: all grades 12.7%.

Dimopoulos et al. [29]

Phase III, rituximab-refractory (N = 31)

Median FU 18.1 months:

ORR: 90%

MRR: 71%

PFS: 18 months, 86%

OS: 18 months, 97%

Common Grade ≥3 AEs: neutropenia (13%); hypertension (10%); and anemia, thrombocytopenia, and diarrhea (all 6%).

Castillo et al. [30]

Phase II, TN (N = 30)

Median FU 50 months:

ORR: 100%

MRR: 87%

VGPR: 30%

PFS: 4-year, 76%

OS: 4-year, 100%

Grade 2–4 AEs:

Fatigue (33%); upper respiratory tract infection (30%); hematoma (27%); atrial fibrillation and urinary tract infection (both 20%); hypertension, lower tract respiratory infection, and rash (all 17%)

Zanubrutinib

Trotman et al. [95]

Phase I/II, TN (n = 24) and R/R (n = 53)

Median FU 30 months:

ORR: 95.9%

MRR: 82.2%

VGPR + CR: 45.2%

PFS: 3-year, 81%

OS: 3-year, 85%

The most common all-grade AEs: upper respiratory tract infection (51.9%), contusion (32.5%), and cough (22.1%).

Grade ≥3 AEs: neutropenia 15.6%; anemia 9.1%; and basal cell carcinoma and cellulitis (both 5.2%).

Zanubrutinib versus ibrutinib

Tam et al. [32], ASPEN trial

Phase III, R/R (n = 164) and TN (n = 37)

Median FU 19.4 months: Zanubrutinib

ORR: 94%

MRR: 77%

VGPR: 28%

PFS: 18 months, 85%

OS: 18 months, 97%

Ibrutinib

ORR: 93%

MRR: 78%

VGPR: 19%

PFS: 18 months, 84%

OS: 18 months, 93%

AEs (zanubrutinib versus ibrutinib):

All-grade neutropenia: 13% vs 19%

Pneumonia: 2% vs 12%

AF: 2% vs 15%

Zanubrutinib

Dimopoulos et al. [33], ASPEN trial extension

Phase III, MYD88^WT (23 R/R and 5 TN)

Median FU 17.9 months:

ORR: 81%

MRR: 50%

VGPR: 27%

AEs similar to those reported by Tam et al [32] in the head-to-head arm of the ASPEN trial

Acalabrutinib

Owen et al. [34]

Phase II, R/R (n = 92) and TN (n = 14)

Median FU 27.4 months:

R/R ORR: 93%

TN ORR: 93%

Grade 3–4 AEs >5%: neutropenia (16%) and pneumonia (7%). Grade 3–4 AF: 1%. Grade 3–4 bleeding: 3%.

Tirabrutinib

Sekiguchi et al. [35]

Phase II, TN (n = 19) and R/R (n = 9)

Median FU 6.5–8.3 months:

MRR: 88.9%

ORR: 96.3%

Common all-grade AEs: rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%).

Grade ≥3 AEs: neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). All bleeding events were Grade 1; no AF or hypertension.

Pirtobrutinib

Mato et al. [37]

Phase I/II, R/R B-cell malignancies (N = 323); WM (n = 19)

In WM patients (n = 19): ORR: 68%

MRR: 47%

In all patients (N = 323): Grade ≥3 neutropenia: 10%; all grade AF: 1%.