Table 1.
Clinical trials investigating tyrosine kinase inhibitors in CLL/SLL, FL, MCL, MZL, WM, HCL, and plasma cell dyscrasias.
| TYROSINE KINASE INHIBITOR [TARGETED TYROSINE KINASE*]/TREATMENT REGIMEN | PHASE OF THE CLINICAL TRIAL | MALIGNANCY/DISEASE STATUS (N) | OUTCOME | REFERENCE(S) |
|---|---|---|---|---|
| AZD2171 (cediranib) [VEGFR] | II | CLL/SLL, relapsed/refractory (n = 15) | OR: none (trial closed early due to lack of efficacy) | 82 |
| Bafetinib [diverse kinases like Bcr-Abl, Lyn, Fyn] | II | CLL, relapsed/refractory (n = 16) | OR: none [partial nodal response in 7/11 patients (64%)] | 83 |
| CC-292 [Btk] | I | CLL/SLL (n = 57), WM (n = 6), other B-NHL (n = 23), updated results for CLL/SLL (n = 83), relapsed/refractory | CLL/SLL: PR: 34%; all 17 efficacy-evaluable B-NHL patients reached SD, updated results for CLL/SLL: OR (PR): 31–67% (depending on dosage) | 84,85 |
| Dasatinib [diverse kinases like Bcr-Abl, Src and Btk] | II | MM, relapsed/‘plateau phase’ (n = 21) | OR: 5% (subgroup of 6 patients after dose escalation: 17%) | 86 |
| II | CLL/SLL, relapsed/refractory (n = 15) | OR (PR): 20% | 29 | |
| Dasatinib [diverse kinases like Bcr-Abl, Src and Btk] + fludarabine | II | CLL, fludarabine-refractory (n = 20) | OR (PR): 17% | 30 |
| Dovitinib [FGFR] | II | MM, relapsed/refractory (n = 43) | OR: none, SD: 62% (patients with t(4;14)) vs 35% (patients without t(4;14)) | 72 |
| Entospletinib [Syk] | II | CLL, relapsed/refractory (n = 41) | OR (PR): 61% | 25 |
| II | FL, relapsed/refractory (n = 41) | 55% with reduced tumor bulk (10% decreased in tumor bulk ≥50%), no CR | 33 | |
| Fostamatinib [Syk] | I/II | phase II part: CLL/SLL (n = 11), FL (n = 21), MCL (n = 9), MZL (n = 3), DLBCL (n = 23), LPL (n = 1), relapsed/refractory | OR (phase II part): CLL/SLL: 55% (PR), FL: 10% (PR), MCL: 11% (PR), DLBCL: 22% (1 patient with CR), none of 3 evaluable patients with MZL or LPL responded | 24 |
| Ibrutinib (single agent) [Btk] | I | CLL/SLL (n = 16), FL (n = 16), MCL (n = 9), MZL (n = 4), WM (n = 4), DLBCL (n = 7), relapsed/refractory | OR (evaluable patients): 60% (CR 16%); ITT population: CLL/SLL: 69%, FL: 38%, MCL: 78%, MZL: 25%, WM: 75%, DLBCL: 29% | 34 |
| I/II | CLL/SLL, treatment naïve (n = 31) | OR: 71% (CR: 13%) | 87 | |
| I/II | CLL/SLL, relapsed/refractory (n = 85) | OR: 71% (CR: 2%), no difference between the patient groups (420 mg vs 840 mg ibrutinib daily), PFS 75% at 26 months | 13 | |
| II | CLL/SLL, presence of TP53 aberration, different disease stages (n = 51) | OR: previously untreated: 97% (PR: 55%, PR with lymphocytosis: 42%), relapsed/refractory: 80% (PR: 40%, PR with lymphocytosis: 40%) | 10 | |
| II | MCL, relapsed/refractory (n = 111) | OR: 68% (CR: 21%), estimated median PFS: 13.9 months | 42 | |
| II | FL, relapsed/refractory (n = 40) | OR: 30% (CR: 3%) | 35 | |
| II | WM, relapsed/refractory (n = 63) | OR: 81%, major response rate (PR or better): 57% | 57 | |
| II | HCL, relapsed or ‘unfit’ (n = 8) | No detailed efficacy data available | 60 | |
| II** | MM, relapsed/refractory (n = 69) | OR (PR): 5%, up to 25% clinical benefit rate (depending on dosage) | 88 | |
| Ibrutinib [Btk] (vs ofatumumab) | III | CLL/SLL, relapsed/refractory (n = 391) | OR (PR): 43% vs 4%, OS (at 12 months): 90% vs 81% | 16 |
| Ibrutinib [Btk] + bendamustine + rituximab | I | FL (n = 12), MCL (n = 17), MZL (n = 1), DLBCL (n = 16), transformed (n = 2), different disease stages | OR: 72% (FL: 90%, MCL: 94%, MZL: 100%, DLBCL: 37%, transformed: 50%); CR: 52% | 36 |
| I | CLL/SLL, relapsed/refractory (n = 30) | OR: 93% (CR: 17%) | 89 | |
| Ibrutinib [Btk] + lenalidomide | I | FL (n = 2), MCL (n = 2), LPL (n = 1), DLBCL (n = 4), transformed (n = 4), relapsed/refractory | No detailed efficacy data available | 38 |
| I | CLL/SLL, relapsed/refractory (n = 11) | OR (PR): 100% | 90 | |
| Ibrutinib [Btk] + ofatumumab | I/II | CLL/SLL (n = 66), PLL (n = 2), transformed (n = 3), relapsed/refractory | OR (CLL/SLL): 83% | 91 |
| Ibrutinib [Btk] + rituximab | II | CLL, high risk, different disease stages (n = 40) | OR: 95% (CR: 8%) | 92,93 |
| II | MCL, relapsed/refractory (n = 50) | OR: 87% (CR: 38%) | 44 | |
| Ibrutinib [Btk] + R-CHOP | I | FL (n = 4), MCL (n = 5), DLBCL (n = 24), treatment-naïve | OR: 91% (PR: 21%, CR: 70%) | 37 |
| Imatinib [Bcr-Abl, ckit] | II | MM, relapsed/refractory (n = 23) | OR: none, treatment ended in 18/23 patients (78%) due to PD | 75 |
| Imatinib [Bcr-Abl, ckit]*** + chlorambucil | I | CLL, relapsed/refractory (n = 11) | OR: 45% | 94 |
| Nintedanib (BIBF 1120) [VEGFR/FGFR/PDGFR] | I | MM, relapsed/refractory (n = 17) | OR: none, SD: 13% (evaluable patients) | 95 |
| ONO-4059 [Btk] | I | CLL, relapsed/refractory (n = 25) | OR (including modified PR with lymphocytosis): 84%, 89% responses in the 17p-deleted subgroup | 18,19 |
| I | SLL (n = 1), FL (n = 3), MCL (n = 7), WM (n = 1), DLBCL (n = 2), relapsed/refractory | OR (PR): 42%, OR for MCL: 50% | 96 | |
| SB1518 [JAK2] | I | SLL (n = 1), FL (n = 10), MCL (n = 5), HL (n = 14), DLBCL (n = 4), relapsed/refractory | OR at the highest dose level (n = 22): 14%, median PFS (all evaluable patients): 120 days | 40 |
| Sorafenib [different kinases such as VEGFR, PDGFR, ckit] | II | CLL (n = 2), FL (n = 4), MCL (n = 2), LPL (n = 1), DLBCL (n = 11), T-cell lymphoma (n = 1), relapsed/refractory | OR: 10%, SD: 42% | 97 |
| Sunitinib [different kinases such as VEGFR, PDGFR, ckit] | II | CLL/SLL, relapsed/refractory (n = 18) | OR: none (trial closed early due to lack of efficacy) | 82 |
| Vandetanib (ZD6474) [VEGFR/EGFR] | II | MM, relapsed/refractory (n = 18) | OR: none | 80 |
Notes: Tyrosine kinase inhibitors are shown in an alphabetic order.
*
Some of the tyrosine kinase inhibitors inhibit further structures than those specified in this table.
**
Ibrutinib ± dexamethasone.
***
Might also inhibit DNA repair.
Abbreviations: Btk, Bruton’s tyrosine kinase; CLL, chronic lymphocytic leukemia; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FL, follicular lymphoma; HCL, hairy cell leukemia; HL, Hodgkin lymphoma; ITT, intention to treat; JAK2, Janus kinase 2; LPL, lymphoplasmocytic lymphoma; MCL, mantle-cell lymphoma; MM, multiple myeloma; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; OR, objective response; OS, overall survival; PD, progressive disease; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival; PLL, prolymphocytic leukemia; PR, partial response; R-CHOP, rituximab together with cyclophosphamide, doxorubicin, vincristine, and prednisolone; SD, stable disease; SLL, small lymphocytic lymphoma; VEGFR, vascular endothelial growth factor receptor; WM, Waldenstrom macroglobulinemia.