Table 2.
Summary of reported results from key clinical trials of zanubrutinib in lymphoproliferative disorders.
| Trial name | Phase | Line | N | Patients | Treatment/median duration of treatment | Follow-up a | Efficacy | Safety |
|---|---|---|---|---|---|---|---|---|
| Mantle cell lymphoma | ||||||||
| NCT0234312050,51
BGB-3111-AU-003 |
1/2 | R/R | 32 | Age ⩾ 18 years, no prior BTKi | Zanu 160 mg BID or 320 mg QD/15.4 mo | 18.8 | 25% CR, 59% PR mDOR 18.5 mo mPFS 21.1 mo 24-mo OS 64% |
Gr ⩾ 3 AEsb,c: anemia 13%, neutropenia 9%, pneumonia 9%, myalgia 9%; 25% discontinued due to AEs; atrial fibrillation/flutter 6% |
| TN | 8 | 8.6 | 38% CR, 50.0% PR | Any-Gr AEs c : diarrhea 35%, petechia/purpura/contusion 31%; 21% discontinued due to AEs | ||||
| NCT0320697052,53
BGB-3111-206 |
2 | R/R | 86 | Age 18–75 years, ⩾ 1 prior treatment, no prior BTKi, Chinese trial | Zanu 160 mg BID/NA | 18.4 | 69% CR, 15% PR mDOR 19.5 mo mPFS 22.1 mo |
Gr ⩾ 3 AEs b : neutropenia d 20%, lung infection/pneumonia 9%; 9% discontinued due to AEs; no atrial fibrillation reported |
| Waldenström macroglobulinemia | ||||||||
| ASPEN54,55
NCT03053440 BGB-3111-302 |
3 | TN R/R |
101 | Age ⩾ 18 years, R/R with ⩾ 1 prior therapy or TN unsuitable for standard ICT; no prior BTKi | Zanu 160 mg BID/NA | 19.4 | In TN: 0% CR, 26% VGPR, 47% PR, 18-mo PFS 78% In R/R: 0% CR, 29% VGPR, 49% PR, 18-mo PFS 86% |
Gr ⩾ 3 AEs b : neutropenia/neutrophil count decreased 20%, hypertension 6%; 4% discontinued due to AEs; no atrial fibrillation/flutter reported |
| TN R/R |
98 | Ibr 420 mg QD/NA | 19.4 | In TN: 0% CR, 17% VGPR, 50% PR, 18-mo PFS 94% In R/R: 0% CR, 20% VGPR, 61% PR, 18-mo PFS 82% |
Gr ⩾ 3 AEs b : hypertension 11%, neutropenia/neutrophil count decreased 8%; 9% discontinued due to AEs; Gr ⩾ 3 atrial fibrillation/flutter 4% | |||
| NCT03332173
56
BGB-3111-210 |
2 | R/R | 44 | Age ⩾ 18 years, at least 1 prior therapy, Chinese trial | Zanu 160 mg BID/NA | 33.0 | CR 0%, VGPR 33%, PR 37% 24-mo PFS 61% mDOMR NR |
Gr ⩾ 3 AEs b : neutrophil count decreased 32%, thrombocytopenia 21%, pneumonia 21%; 14% discontinuation due to AEs; no atrial fibrillation/flutter reported |
| NCT02343120e,57
BGB-3111-AU003 |
1/2 | R/R | 49 | Age ⩾ 18 years, no prior BTKi | Zanu 160 mg BID or 320 mg QD (except for 3 pts starting at <320 mg zanu/day)/NA | 35.8 | CR 2.0%, VGPR 49.0%, PR 28.6% 24-mo PFS 76.2% 24-mo OS 91.5% |
Gr ⩾ 3 AEsb,c: neutropenia
d
15.6% anemia 9.1%; 14% discontinuation due to AEs; atrial fibrillation 6.1% |
| TN | 24 | Zanu 160 mg BID or 320 mg QD/NA | 23.5 | CR 0%, VGPR 33.3%, PR 54.2% 24-mo PFS 91.5% 24-mo OS 100% |
Gr ⩾ 3 AEsb,c: neutropenia d 15.6%; anemia 9.1%; 13% discontinuation due to AEs; atrial fibrillation 4.2% | |||
| Marginal zone lymphoma | ||||||||
| MAGNOLIA
58
NCT03846427 BGB-3111-214 |
2 | R/R | 68 | Age ⩾ 18 years, at least 1 therapy including ⩾ 1 anti-CD20 | Zanu 160 mg BID/NA | 6.8 | CR 15%, PR 45% mDOR and mPFS NR |
Gr ⩾ 3 AEs b : neutropenia 73%; 2.9% discontinuation due to AEs; atrial flutter 1.5% |
| NCT03520920
59
BGB-3111-213 |
2 | R/R | 5 | Age ⩾ 18 years, at least 1 prior therapy, Chinese trial | Zanu 160 mg BID + R 375 mg/m2 on D1, 8, 15, 22 (C1), then D1 of C4, C6, C8, and C10/NA | 10.3 | CR 20%, PR 40% mPFS NE 12-mo PFS 75% |
Gr ⩾ 3 AEsb,c: neutrophil count decrease 14.6%, white blood cell count decrease 9.8%; no discontinuations due to TEAEs |
| Chronic lymphocytic leukemia/small lymphocytic lymphoma | ||||||||
| ALPINE60,61
NCT03734016 BGB-3111-305 |
3 | R/R | 207 | Age ⩾ 8 years, ⩾ 1 prior treatment, no prior BTKi therapy | Zanu 160 mg BID/NA | 15.3 f | CR/CRi 1.9%, PR/nPR 76.3% 12-mo PFS 94.9% 12-mo OS 97.0% |
Gr ⩾ 3 AEs b : neutropenia 18.6%, infections 12.7%; 7.7% discontinued due to AEs; atrial fibrillation/flutter 2.5% |
| 208 | Ibr 420 mg QD/NA | 15.4 f | CR/CRi 1.4%, PR/nPR 61.1% 12-mo PFS 84.0% 12-mo OS 92.7% |
Gr ⩾ 3 AEs b : infections 17.9%, neutropenia 15.0%; 13.0% discontinued due to AEs; atrial fibrillation/flutter 10.1% | ||||
| SEQUOIA
62
NCT03336333 BGB-3111-304 (Arms A & B) |
3 | TN | 240 | Without del(17p), either aged ⩾ 65 years or 18–65 years and unsuitable for FCR | Zanu 160 mg BID/NA | 26.4 | CR 6.6% ORR 94.6% 24-mo PFS 85.5% 24-mo OS 94.3% |
Gr ⩾ 3 AEs b : neutropenia 11.3%, thrombocytopenia 1.7%; 8.3% discontinued due to AEs: atrial fibrillation 3.3% |
| 227 | B (90 mg/m2 D1 & D2) + R (375 mg/m2 C1, then 500 mg/m2C2-C6)/NA | 25.9 | CR 15.1% ORR 85.3% 24-mo PFS 69.5% 24-mo OS 94.6% |
Gr ⩾ 3 AEs b : neutropenia 51%, thrombocytopenia 7.0%; 13.7% discontinued due to AEs; atrial fibrillation 2.6% | ||||
| SEQUOIA
63
NCT03336333 BGB-3111-304 (Arm C) |
3 | TN | 109 | With centrally confirmed del(17p), either aged ⩾ 65 years or 18–65 years and unsuitable for FCR | Zanu 160 mg BID/NA | 18.2 | CR/CRi 3.7%, PR/PR-L 90.8% 12-mo DOR 92.8% 24-month PFS 88.9% 18-mo OS 95.1% |
Gr ⩾ 3 AEs b : neutropenia/decreased neutrophil count 12.9%, pneumonia (3.7%); 3.7% discontinued due to AEs; atrial fibrillation/flutter 2.8% |
| SEQUOIA
64
NCT03336333 BGB-3111-304 (Arm D) |
3 | TN | 49 | With centrally confirmed del(17p), either aged ⩾ 65 years or 18–65 years and unsuitable for FCR | Zanu 160 mg BID, V starting at C4, ramped up to 400 mg QD/NA | 12.0 | 13.9% CR/CRi, 77.8% PR, 5.6% PR-L |
Gr ⩾ 3 AEs b : neutropenia ~15%, diarrhea ~6%; 2.0% discontinued due to AEs; atrial fibrillation 2.9% |
| BOVene,65
NCT03824483 |
2 | TN | 39 | Age ⩾ 18 years, untreated, but prior local RT and short-course corticosteroids allowed | Zanu (160 mg BID) + G (1000 mg IV D1, 8, 15 of C1, then D1 C2-8) + V (targeting 400 mg PO daily)/NA | 14 + | uMRD (10-4) 92% (PB), 84% (BM); CR/CRi 49%, OR 100%; 77% achieved prespecified MRD endpoint and discontinued treatment |
Gr ⩾ 3 AEs b : neutropenia 15%, thrombocytopenia 5%, rash 5%, pneumonia 5% |
| NCT04116437e,66
BGB-3111-215 |
2 | R/R | 17 | Age ⩾ 18 years, CLL/SLL intolerant to but not progressing on ibr or acala | Zanu 160 mg BID or 320 mg QD/3.0 mo | NA | 10/10 efficacy-evaluable patients had SD or better; 6/10 had deepening of response since Zanu initiation | Gr ⩾ 3 AEs b : neutropenia, 5.9%, syncope 5.9%; 96.8% of AEs associated with prior BTKi intolerance did not recur; 94% of patients remained on treatment |
| NCT02569476e,67
BGB-3111-GA101 |
1b | TN R/R |
45 | Age ⩾ 18 years, TN, or R/R | Zanu 160 mg BID or 320 mg QD + G/29 mo | 29 | In TN: 30% CR, 70% PR. In R/R: 28% CR, 64% PR. 24-mo event-free rate for DOR 90% mPFS NR |
Gr ⩾ 3 AEs b : neutropenia 31%, pneumonia 9%; 9% discontinued due to AEs; no atrial fibrillation/flutter reported |
| NCT02343120e,48
BGB-3111-AU-003 |
1 | TN R/R |
94 | Age ⩾ 18 years, no prior BTKi | Zanu 40 mg QD–320 mg QD or 160 mg BID/NA | 13.7 | In TN: 4.5% CR, 95.5% PR/PR-L. In R/R: 1.8% CR, 92.9% PR/PR-L |
Gr ⩾ 3 AEs b : neutropenia 6.4%, hypertension 2.1%; 2.1% discontinued due to AEs; atrial fibrillation 1.1% |
| Diffuse large B-cell lymphoma | ||||||||
| NCT03145064
68
BGB-3111-207 |
2 | R/R | 41 | Age ⩾ 18 years, non-GCB DLBCL ineligible for intensive CT and BM transplantation, Chinese trial | Zanu 160 mg BID/NA | 6.8 | CR 17.1%, PR 12.2% mDOR 4.5 mo mPFS 2.8 mo mOS 8.4 mo |
Gr ⩾ 3 AEs in 48.8%; 9.8% discontinuations due to AEs; no atrial fibrillation reported |
| NCT02795182
69
BGB-3111-A317 |
1b | R/R | 27 | Age ⩾ 18 years, R/R DLBCL | Zanu 160 mg BID + tislelizumab IV 200 mg Q3W/3.0 mo | 4.1 | CR 15%, PR 22% | Gr ⩾ 3 AEsb,c: neutropenia 13%, anemia 9%; 13% discontinuations due to AEs |
| NCT03520920
59
BGB-3111-213 |
2 | R/R | 20 | Age ⩾ 18 years, non-GCB DLBCL with ⩾ 1 prior therapy, Chinese trial | Zanu 160 mg BID + R 375 mg/m2 on D1, 8, 15, 22 (C1), then D1 of C4, C6, C8, and C10/NA | 10.3 | CR 5%, PR 30% mDOR 8.8 mo mPFS 3.4 mo |
Gr ⩾ 3 AEsb,c: neutrophil count decrease 14.6%, white blood cell count decrease 9.8%; no discontinuations due to TEAEs; 15% Gr 5 AEs in DLBCL pts |
| Follicular lymphoma | ||||||||
| NCT02569476e,67
BGB-3111-GA101 |
1 | R/R | 36 | Age ⩾ 18 years, R/R FL | Zanu 160 mg BID or 320 mg QD + G/20 mo | 20.1 | CR 39%, PR 33% 24-mo DOR 62% mPFS 25 mo |
Gr ⩾ 3 AEs b : neutropenia 14%, hypertension 8%; 3% discontinuations due to AEs; no atrial fibrillation reported |
Acala, acalabrutinib; AE, adverse event; B, bendamustine; BID, twice daily; BM, bone marrow; BTKi, Bruton tyrosine kinase inhibitor; C, cycle; CR, complete response; CRi, CR with incomplete hematologic recovery; CT, chemotherapy; D, day; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; FCR, fludarabine-cyclophosphamide-rituximab; G, obinutuzumab; GCB, germinal center B-cell; Gr, grade; ibr, ibrutinib; ICT, immunochemotherapy; m, median; mDOMR, median duration of major response; mo, months; MRD, minimal residual disease; NA, not available; NE, not estimable; nPR, nodular partial response; NR, not reached; OR, overall response; OS, overall survival; PB, peripheral blood; PFS, progression-free survival; PO, by mouth; PR, partial response; PR-L, PR with lymphocytosis; pts, patients; Q3W, once every 3 weeks; QD, once daily; R, rituximab; R/R, relapsed or refractory; RT, radiotherapy; SD, stable disease; TEAE, treatment-emergent adverse event; TN, treatment naïve; uMRD, undetectable minimal residual disease; V, venetoclax; VGPR, very good partial response; Zanu, zanubrutinib.
a
Median follow-up time in months.
b
The most common AEs of grade ⩾ 3 are shown.
c
Safety events are reported for the full study population, including patients with other indications/lines.
d
Includes preferred terms neutropenia, febrile neutropenia, and neutrophil count decrease.
e
Study also enrolled patients with other malignancies and/or lines. Only results for patients in the category indicated are shown here.
f
Per investigator assessment at interim analysis.