Table 2.
Current clinical trials of Bruton tyrosine kinase inhibitors in haematological malignancies and the latest extended follow-up results.
| Trials | Intervention | Comparison | Numbers | Median age | ORR | CR | Median PFS | Median OS | Study design (Phase) |
|---|---|---|---|---|---|---|---|---|---|
| R/R CLL/SLL | |||||||||
| O’Brien et al. [53] (PCYC-1103) | Ibru | 101 | 64 | 89% | 10% | 51 mon; 5 years: 44% | NR | Ib/II, 5 years extended follow-up | |
| Munir et al. [55] (RESONATE, PCYC-1112) | Ibru | Ofatumumab | 195 vs 196 | 67 vs 67 | 91% vs 11% | Ibru: 10.8% | 44.1 vs 8.1 mon | 67.7 vs 65.1 mon | III, 6 years extended follow-up |
| Jain et al. [56] | Ibru-R | 40 | 65 | 95% | 23% | 45 mon | NR | II, 47 months extended follow-up | |
| Brown et al. [62] (PCYC-1108) | Ibru-BR | 30 | 62 | 97% | 40% | 12 mon:86.3%, 36 mon:70.3% | N/A | Ib | |
| Fraser et al. [63] (HELIOS) | Ibru-BR | Placebo-BR | 289 vs 289 | 64, 63 | 87.2% vs 66.4% | 38.1% vs 8% | NR vs 14.3 mon; 36 mon: 68% vs 13.9% | NR | III, 34.8 months extended follow-up |
| Jaglowski et al. [57] | Ibru- Ofatumumab | Concurrent start; Ofatumumab lead-in | 27 vs 20 vs 24 | 64 | 100% vs 79% vs 71% | N/A | 12 mon: 89% vs 85% vs 75% | N/A | Ib/II |
| Hillmen et al. [58] (CLARITY) | Ibru-Venetoclax | 47 | 64 | 89% | 51% | N/A | N/A | II | |
| Byrd et al. [59, 77] (ACE-CL-001) | Acala | 134 | 66 | 94% | 4% | N/A | N/A | I/II, 41 months extended follow-up | |
| Awan et al. [79]a | Acala | 33 | 64 | 76% | 3% | N/A | N/A | II, 18.5 months extended follow-up | |
| Ghia et al. [82] (ASCEND) | Acala | IR or BR | 155 vs 155 | N/A | 81% vs 75% | 0% vs 1% | NR vs 16.5 mon; 12 mon-PFS:88% vs 68% | 20 mon: 94% vs 91% | III |
| Xu et al. [83] | Zanu | 91 | 61 | 91% | 4% | 1 year: 80.9% | N/A | II | |
| Naive CLL/SLL | |||||||||
| O’Brien et al. [53, 65](PCYC-1102) | Ibru | 31 | 71 | 87% | 29% | 5 years: 92% | 5 years: 92% | Ib/II, 5 years extended follow-up | |
| Burger et al., [66] (Resonate-2) | Ibru | Chlorambucil | 136 vs 133 | 73 vs 72 | Ibru: 92% | Ibru: 30% | 5 years: 70% vs 12% | 5 years: 83% vs 68% | III, 5 years extended follow-up |
| Woyach et al. [70] | Ibru | Ibru-R, BR | 182 vs 182 vs 183 | 71 vs 71 vs 70 | 93% vs 94% vs 81% | 7% vs 12% vs 26% | NR vs NR vs 43 mon | 2 years: 90% vs 94% vs 95% | III |
| Davids et al. [75] | Ibru-FCR | 85 | 55 | 96% | 36% | 2 years: 100% | 2 years: 100% | II | |
| Moreno et al. [76] (iLLUMINATE) | Ibru- obinutuzumab | Chlorambucil - obinutuzumab | 113 vs 116 | 70 vs 72 | 100% vs 85% | 19% vs 8% | NR vs 19 mon; 30 mon: 79% vs 31% | N/A | III |
| Shanafelt et al. [52] (E1912) | Ibru-R | FCR | 354, 175 | 56.7 vs 56.7 | 95.8% vs 81.1% | 17.2%vs 30.3% | 3 year: 89.4% vs 72.9% | 3 years: 98.8% vs 91.5% | III |
| Sharman et al. [81] (ELEVATE TN) | Acala, Acala+ obinutuzumab | Obinutuzumab+ chlorambucil | 179 vs 179 vs 177 | N/A | 85.5% vs 93.9% vs 78.5% | 1% vs 14% vs 5% | NR vs NR vs 22.6 mon; 2 year: 87% vs 93% vs 47% | 2 years: 95% vs 95% vs 92% | III |
| Naive and R/R CLL/SLL | |||||||||
| Woyach et al. [80] | Acala | 19 vs 22 | 61 vs 63 | 95% vs 92% | N/A | 39 mon: 94.4% (Naive); 42 mon: 72.7% (R/R) | 39 mon: 100% (Naive;) 42 mon: 82% (R/R) | Ib/II | |
| Cull et al. [113] ASH | Zanu | 22 vs 98 | 67 | 100% vs 95.9% | 13.6%vs 14.3% | 2 year: 95% vs 88% | N/A | I/II, 25.1 months extended follow-up | |
| Tam et al. [18, 32] | Zanu-obinu | 45 | 68 | 96% | 27% | N/A | N/A | Ib | |
| High risk (del 17p, TP53 mutation) naive or R/R CLL/SLL | |||||||||
| Ahn et al. 2015, [72] | Ibru naive | R/R | 35 vs 16 | 62 vs 62 | 96% | 0% | 5 year: 74.4% vs 19.4% | 5 years: 85.3% vs 53.7% | II, 4.8 years extended follow-up |
| O’Brien et al. [73] (RESONATE-17) | Ibru | 154 | 64 | 83% | 10% | 24 mon: 64% | 24 mon:74% | II, 27.6 months extended follow-up | |
| Sun et al. [114] | Acala 100 mg BID | Acala 200 mg QD | 48 | N/A | 79.2% vs 85.8% | N/A | 24 mon: 87.2% vs 91.5% | N/A | II |
| Tam et al. [18, 32] ASH (SEQUOIA) | Zanu | 109 | 70 | 92% | 0% | N/A | N/A | III | |
| R/R MCL | |||||||||
| Wang et al. 2015, [26] (PCYC-1104-CA) | Ibru | 111 | 68 | 67% | 23% | Median: 13 mon | Median: 22.5 mon | II, 26.7 months extended follow-up | |
| Rule et al. [115] (RAY) | Ibru | Temsiromlimus | 139 vs 141 | 67 vs 68 | 77% vs 47% | 23% vs 3% | 15.6 vs 6.2 mon | 30.3 vs 23.5 mon | III, 3 years extended follow-up |
| Jain et al. 2016, [41] | Ibru-rituximab | 50 | 67 | 88% | 58% | 43 mon; 3 year: 54% | NR; 3 years: 69% | II, 47 months extended follow-up | |
| Tam et al. [116] | Ibru-venetoclax | 24 | 68 | 76% | 57% | 12 mon: 75%; 18 mon: 57% | 12 mon: 79%; 18 mon: 74% | II | |
| Jerkeman et al. [43] (PHILEMON) | Ibru-Len-rituximab | 50 | 69 | 75% | 56% | 16 mon | 20 mon | II | |
| Martin et al. [39] | Ibru-palbociclib | 27 | 65 | 67% | 37% | 2 years: 59.4% | 2 years: 60.6% | I | |
| Wang et al. [31, 46] (ACE-LY-004) | Acala | 124 | 68 | 81% | 42% | 20 mon; 24 mon: 49% | 24 mon: 72.4% | II, 26 months extended follow-up | |
| Tam et al. [18, 32] | Zanu naive | R/R | 45 | 71 | 87.5% vs 86.5% | 37.5%vs 29.7% | R/R 14.7mon | N/A | I |
| Song et al. [33] | Zanu | 86 | 60.5 | 84% | 68.6% | 22.1 mon | N/A | II | |
| Naive MCL | |||||||||
| Wang et al. [46] Lugano (WINDOW -1) | Ibru-RCVAD | 50 | N/A | 100% | 92% | 3 years: 88% | 3 years: 100% | II | |
| Naive and R/R WM | |||||||||
| Treon et al. [87]b | Ibru | 63 | 63 | 91% | 73% | 2 years: 69.1% | 2 years: 95.2% | II | |
| Dimopoulos et al. [117] (INNOVATE) | Ibru-R | Placebo-R | 75 vs 75 | 70 vs 68 | 92% vs 47% | 72% vs 32% | NR vs 20.3 mon; 24 mon: 80% vs 37% | NR vs NR; 30 mon: 94% vs 92% | III |
| Treon et al. [88]c | Ibru | 30 | 67 | 100% | 83% | 18 mon: 92% | N/A | II | |
| Owen et al. [89] | Acala naive | R/R | 14 vs 92 | 73 vs 69 | 93% vs 93% | 0% vs 0% | 2 years: 90% vs 82% | 2 years: 92% vs 89% | II |
| Trotman et al. [118] EHA | Zanu | 24 vs 49 | 67 | 96% vs 90% | 0% vs 2% | 2 years: 81% | N/A | I | |
| Dimopoulos et al. [119] (ASPEN cohort 2) | Zanu naive | R/R | 5, 21 | N/A | 80% vs 76.2% | 0% vs 0% | N/A | N/A | III |
| Tam et al. [120] (ASPEN cohort1) | Zanu | Ibru | 102 vs 99 | N/A | 28.4% vs 19.2% | N/A | 1 year: 89.7% vs 87.2% | 1 year: 97% vs 93.9% | III |
| R/R MZL | |||||||||
| Noy et al. [90] | Ibru | 63 | 66 | 48% | 3% | 14.2 mon | 18 mon: 81% | II | |
| R/R DLBCL | |||||||||
| Wilson et al. [94] | Ibru | 80 | 64 | 37% | 10% | 1.64 mon | 6.41 mon | I/II | |
| Maddocks et al. [40] | Ibru-BR | 16 | 62 | 37% | 31% | N/A | N/A | I | |
| Sauter et al. [95] | Ibru-R-ICE | GCB/Non-GCB/PMBL | 3 vs 8 vs 4 | 59 | 33% vs 100% vs 100% | 0% vs 0% vs 100% | N/A | N/A | I |
| Goy et al. [91] | Ibru-Len-R | non-GCB | 23 | 64 | 65% | 41% | N/A | N/A | I |
| Younes et al. [96, 104] | Ibru-Nivo | 45 | 64 | 36% | 16% | 2.6 mon | N/A | I/IIa | |
| Naive DLBCL | |||||||||
| Younes et al. [121] | Ibru-RCHOP | 18 | 61 | 100% | 83% | N/A | N/A | I | |
| Younes et al. [96, 104] (non-GCB) | Ibru-RCHOP | Placebo-RCHOP | 419 vs 419 | 63 vs 61 | 89.3% vs 93.1% | 67.3% vs 68% | 36 mon: 70.8% vs 68.1% | 36 mon: 82.8% vs 81.4% | III |
| R/R PCNSL | |||||||||
| Grommes et al. [122] | Ibru | 13 | 69 | 77% | 37% | N/A | N/A | I | |
| Soussain et al. [97] | Ibru | 52 | 67.5 | 52% | 19% | 4.8 mon | 19.2 mon | II | |
| R/R FL | |||||||||
| Bratlett et al. [123] (P2C) | Ibru | 40 | 64 | 38% | 13% | 14 mon; 2 years: 20.4% | 2 years: 79% | II | |
| Gopal et al. [99] (DAWN) | Ibru | 110 | 61.5 | 21% | 11% | 4.6 mon | 12 mon: 78%; 30-mon: 61% | II | |
| Tam et al. [18, 32] | Zanu-obinu | 36 | 59 | 72% | 36% | N/A | N/A | Ib | |
| Naive FL | |||||||||
| Ujjani et al. [124] | Ibrutinib-Len-R | 22 | 53.5 | 95% | 36% | N/A | N/A | I | |
| R/R MM | |||||||||
| Richardson et al. [103] | Ibru | 92 | 65 | 28% | N/A | 4.6 mon | N/A | II | |
| Chari et al. [102] | Ibru-carfilzomib- dexamethasone | 43 | 63 | 76% | 2% | 20.5 mon | NR | I | |
ORR overall response rate, CR complete response, PFS progressive-free survival, OS overall survival, AE adverse events, Ibru Ibrutinib, Acala acalabrutinib, Zanu zanubrutinib, B bendamustine, R rituximab, Len lenalidomide, FCR fludarabine-cyclophosphamide-rituximab, ICE ifosfamide-carboplatin-etoposide, Obinu obinutuzumab, Nivo nivolumab, RCHOP rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone, CVAD cyclophosphamide-vincristine-doxorubicin-dexamethasone, mon, Months, N/A not available, NR not reach, R/R refractory or relapse.
aIncluded R/R CLL who intolerant to ibrutinib.
bOnly included R/R WM.
cOnly included Naive WM.