Prospective trials evaluating covalent BTKi monotherapy and covalent BTKi combinations in R/R MCL
| Treatment . | Reference . | Study . | N . | Drug class(es) added . | Median age, y . | Median prior lines (range) . | High risk MIPI . | Response . | Median PFS (mo; 95% CI) . | Key grade 3/4 adverse events ≥10% . |
|---|---|---|---|---|---|---|---|---|---|---|
| Covalent BTK inhibitor monotherapy | ||||||||||
| Ibrutinib | 14 | Phase 2 | 111 | — | 68 | 3 (1-5) | 49% | ORR 68%; CR 21% | 13.9 (7.0-NE) | Neutropenia 16%; thrombocytopenia 11% |
| Ibrutinib | 25 | Phase 3 | 139 | — | 67 | 2 (1-9) | 22% | ORR 72%; CR 19% | 14.6 (10.4-NE) | Neutropenia 13% |
| Ibrutinib | 19 | Pooled analysis | 370 | — | 68 | 2 (1-9) | 32% | ORR 70%; CR 27% | 12.5 (9.8-16.6) | Neutropenia 17%; thrombocytopenia 12.4%; pneumonia 12.7%; anemia 10.0% |
| Acalabrutinib | 27,28 | Phase 2 | 124 | — | 68 | 2 (1-2) | 17% | ORR 81%; CR 40% | 22 (16.6-33.3) | Neutropenia 12%; anemia 12% |
| Zanubrutinib | 30,31 | Phase 2 | 86 | — | 60.5 | 2 (1-4) | 38.4% | ORR 83.7%; CR 77.9% | 33 (19.4-NE) | Neutropenia 18.6%; infection 18.6%; pneumonia 12.8% |
| Zanubrutinib | 32 | Phase 1/2 | 32 | — | 70.5 | 1 (1-4) | 31.3% | ORR 90.6%; CR 31.3% | 21.1 mo (13.2–NE) | Infections 18.8%; anemia 12.5% |
| Covalent BTK inhibitor-based combinations | ||||||||||
| Ibrutinib-rituximab | 26 | Phase 2 | 50 | Anti-CD20 mAb | 67 | 3 (1-9) | 12% | ORR 88%; CR 44% | Median NR; 15-mo PFS 69% (57%–84%) | Atrial fibrillation 12% |
| Ibrutinib-lenalidomide-rituximab | 36 | Phase 2 | 50 | Immunomodulatory agent; anti-CD20 mAb | 69 | 2 (1-7) | 46% | ORR 76%; CR 56% | 16.0 (13.7-20.5) | Neutropenia 36%; infection 22%; cutaneous 14%; gastrointestinal 12%; thrombocytopenia 12% Vascular 10% |
| Ibrutinib-venetoclax | 40 | Phase 2 | 24 | BCL2 inhibitor | 68 | 2 (0-6) | 75% | ORR 71%; CR 71% | 29 (13-NR) | Neutropenia 33%; thrombocytopenia 17%; diarrhea 12%; anemia 12% |
| Ibrutinib-venetoclax-obinutuzumab | 13 | Phase ½ | 24 | Type 2 glycoengineered; anti-CD20 mAb; BCL2 inhibitor | 66 | 1 (1-3) | 29% | ORR 71%; CR 67%; uMRD 71.5%; (10/14) | Median NR; 2-y PFS 69.5% (52.9-91.4) | Neutropenia 71%; thrombocytopenia 54%; diarrhea 12% |
| Ibrutinib-bortezomib | 37 | Phase 1/2 | 55 | Proteosome inhibitor | 71 | 1 (1-5) | Not known | ORR 87.3%; CR 44% | 18.6 (12.4-NR) | G4 hematotoxicity 16.4%; G3 infections 25% Otherwise not available |
| Ibrutinib-umbralisib | 38 | Phase 2 | 21 | PI3K-δ/casein kinase 1ε inhibitor | 68 | 2 (2-3) | Not known | ORR 67%; CR 27% | 10.5 | Infection 17%*; neutropenia 12%; bruising 12%; diarrhea 10% |
| Ibrutinib-palbociclib | 39 | Phase 1 | 27 | CDK4/6 inhibitor | 69 | 1 (1-5) | 26% | ORR 67%; CR 37% | Median NR; 2-y PFS 59.4% (37.9%-80.9%) | Neutropenia 41%; thrombocytopenia 30%; hypertension 15%; febrile neutropenia 15%; pneumonia 11% |
| Treatment . | Reference . | Study . | N . | Drug class(es) added . | Median age, y . | Median prior lines (range) . | High risk MIPI . | Response . | Median PFS (mo; 95% CI) . | Key grade 3/4 adverse events ≥10% . |
|---|---|---|---|---|---|---|---|---|---|---|
| Covalent BTK inhibitor monotherapy | ||||||||||
| Ibrutinib | 14 | Phase 2 | 111 | — | 68 | 3 (1-5) | 49% | ORR 68%; CR 21% | 13.9 (7.0-NE) | Neutropenia 16%; thrombocytopenia 11% |
| Ibrutinib | 25 | Phase 3 | 139 | — | 67 | 2 (1-9) | 22% | ORR 72%; CR 19% | 14.6 (10.4-NE) | Neutropenia 13% |
| Ibrutinib | 19 | Pooled analysis | 370 | — | 68 | 2 (1-9) | 32% | ORR 70%; CR 27% | 12.5 (9.8-16.6) | Neutropenia 17%; thrombocytopenia 12.4%; pneumonia 12.7%; anemia 10.0% |
| Acalabrutinib | 27,28 | Phase 2 | 124 | — | 68 | 2 (1-2) | 17% | ORR 81%; CR 40% | 22 (16.6-33.3) | Neutropenia 12%; anemia 12% |
| Zanubrutinib | 30,31 | Phase 2 | 86 | — | 60.5 | 2 (1-4) | 38.4% | ORR 83.7%; CR 77.9% | 33 (19.4-NE) | Neutropenia 18.6%; infection 18.6%; pneumonia 12.8% |
| Zanubrutinib | 32 | Phase 1/2 | 32 | — | 70.5 | 1 (1-4) | 31.3% | ORR 90.6%; CR 31.3% | 21.1 mo (13.2–NE) | Infections 18.8%; anemia 12.5% |
| Covalent BTK inhibitor-based combinations | ||||||||||
| Ibrutinib-rituximab | 26 | Phase 2 | 50 | Anti-CD20 mAb | 67 | 3 (1-9) | 12% | ORR 88%; CR 44% | Median NR; 15-mo PFS 69% (57%–84%) | Atrial fibrillation 12% |
| Ibrutinib-lenalidomide-rituximab | 36 | Phase 2 | 50 | Immunomodulatory agent; anti-CD20 mAb | 69 | 2 (1-7) | 46% | ORR 76%; CR 56% | 16.0 (13.7-20.5) | Neutropenia 36%; infection 22%; cutaneous 14%; gastrointestinal 12%; thrombocytopenia 12% Vascular 10% |
| Ibrutinib-venetoclax | 40 | Phase 2 | 24 | BCL2 inhibitor | 68 | 2 (0-6) | 75% | ORR 71%; CR 71% | 29 (13-NR) | Neutropenia 33%; thrombocytopenia 17%; diarrhea 12%; anemia 12% |
| Ibrutinib-venetoclax-obinutuzumab | 13 | Phase ½ | 24 | Type 2 glycoengineered; anti-CD20 mAb; BCL2 inhibitor | 66 | 1 (1-3) | 29% | ORR 71%; CR 67%; uMRD 71.5%; (10/14) | Median NR; 2-y PFS 69.5% (52.9-91.4) | Neutropenia 71%; thrombocytopenia 54%; diarrhea 12% |
| Ibrutinib-bortezomib | 37 | Phase 1/2 | 55 | Proteosome inhibitor | 71 | 1 (1-5) | Not known | ORR 87.3%; CR 44% | 18.6 (12.4-NR) | G4 hematotoxicity 16.4%; G3 infections 25% Otherwise not available |
| Ibrutinib-umbralisib | 38 | Phase 2 | 21 | PI3K-δ/casein kinase 1ε inhibitor | 68 | 2 (2-3) | Not known | ORR 67%; CR 27% | 10.5 | Infection 17%*; neutropenia 12%; bruising 12%; diarrhea 10% |
| Ibrutinib-palbociclib | 39 | Phase 1 | 27 | CDK4/6 inhibitor | 69 | 1 (1-5) | 26% | ORR 67%; CR 37% | Median NR; 2-y PFS 59.4% (37.9%-80.9%) | Neutropenia 41%; thrombocytopenia 30%; hypertension 15%; febrile neutropenia 15%; pneumonia 11% |
BCL2, B-cell lymphoma 2; CDK4/6, cyclin-dependent kinase 4 and 6; G, grade; MIPI, mantle cell lymphoma international prognostic index; NR, not reached; PI3K, phosphoinositide 3-kinase; uMRD, undetectable minimal residual disease.
AEs include 21 patients with CLL.