Safety and Efficacy of Bispecific Antibodies in Adults with Large B-Cell Lymphomas: A Systematic Review of Clinical Trial Data
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Eligibility Criteria
2.3. Data Extraction
2.4. Quality and Risk of Bias Assessment
2.5. Data Synthesis
3. Results
3.1. Study Selection
3.2. Study Characteristics
Citation | Intervention | Trial Design | Key Eligibility Criteria | Subject Demographics |
---|---|---|---|---|
Viardot et al., 2016 [29] | Blinatumomab (CD19/CD3) as monotherapy | Phase II Multicenter Open label Single arm Dose escalation | Relapsed or refractory to ≥1 prior line and ineligible or failed autologous HSCT ECOG performance status 0–2 Life expectancy ≥ 12 weeks | 23 patients with DLBCL (cohort I and III combined) Median age 66 years 52.2% male participants Median three prior lines of therapy |
Gaballa et al., 2023 [30] | AZD0486 (CD19/CD3) as monotherapy | Phase I Multicenter Open label Single arm Dose escalation | Relapsed or refractory CD19+ B-NHL failing ≥2 prior lines of therapy, including prior CD19 CAR T and/or CD20 TCE | 62 patients with B-cell NHL (including 27 patients with DLBCL) Median age 68 years 58% male participants Median three prior lines of therapy |
Hawkes et al., 2022 [31,51] | TG-1801 (CD19/CD47) in combination with ublituximab | Phase I Multicenter Open label Multi-arm Dose escalation | Relapsed or refractory B-cell lymphoma after ≥1 prior line of therapy ECOG performance status 0–2 | 16 patients with B-Cell NHL (including nine patients with DLBCL) Median age 71 years 68.8% male participants Median three prior lines of therapy |
Bannerji et al., 2022 [32] | Odronextamab (C20/CD3) as monotherapy | Phase I Multicenter Open label Single arm Dose escalation and expansion | Relapsed or refractory with ≥1 prior line of therapy, including an anti-CD20 therapy ECOG performance status 0–1 Life expectancy ≥ 6 months | 145 patients with CD20+ B-cell malignancies (including 85 patients with DLBCL) Median age 67 years 70% male participants Median three prior lines of therapy |
Melchardt et al., 2023 [33] | Glofitamab (CD20/CD3) in combination with polatuzumab vedotin | Phase II Multicenter Open label Single arm Feasibility trial | Treatment naïve ≥60 years and not eligible for full dose R-CHOP Allowed lymphoma related ECOG performance status ≤3 and reduced renal function | 10 patients with DLBCL Median age 79 years |
Hutchings et al., 2019 [34] | Glofitamab (CD20/CD3) in combination with atezolizumab | Phase Ib Multicenter Open label Single arm | Relapsed or refractory with ≥1 prior line of therapy, ineligible for or had exhausted standard therapeutic options * ECOG performance status 0–2 * | 38 patients with B-NHL (including 33 patients with aggressive B-NHL) 52.6% male participants Median age 67 years Median three prior lines of therapy |
Hutchings et al., 2023 [35] | Glofitamab (CD20/CD3) in combination with RO7227166 | Phase I/II * Multicenter * Open label Single arm * Dose escalation | Relapsed or refractory with ≥2 prior lines of therapy, ineligible for or had exhausted standard therapeutic options * ECOG performance status 0–1 * Life expectancy ≥ 12 weeks * | 104 patients enrolled, including 57 patients with LBCL Median age 63 years 61% male participants Median three prior lines of therapy |
Dickinson et al., 2022 [36] | Glofitamab (CD20/CD3) as monotherapy | Phase II Multicenter Open label Single arm Dose escalation/expansion | Relapsed or refractory to ≥2 prior lines of therapy including anti-CD20 antibody and an anthracycline ECOG performance status 0–1 Life expectancy ≥ 12 weeks | 154 patients with LBCL Median age 66 years 65% male participants Median three prior lines of therapy |
Falchi et al., 2023 [37] | Epcoritamab (CD20/CD3) in combination with R-CHOP | Phase Ib/II Multicenter * Open label Dose escalation and expansion * | Treatment naïve CD20+ DLBCL IPI score ≥ 3 | 47 patients with DLBCL Median age 64 years |
Vermaat et al., 2023 [38] | Epcoritamab (CD20/CD3) in combination with R-mini-CHOP | Phase Ib/II Multicenter Open label Dose escalation and expansion | Treatment naïve Not a candidate for full dose R-CHOP due to age ≥75 years or ≥65 years with comorbidities | 28 patients with CD20+ DLBCL Median age 81 years |
Brody et al., 2023 [39] | Epcoritamab (CD20/CD3) in combination with GemOx | Phase Ib/II Multicenter * Open label Dose escalation and expansion * | Relapsed/refractory disease Ineligible for HDT-ASCT * | 34 patients with DLBCL Median age 71 years Median two prior lines of therapy |
Abrisqueta et al., 2022 [40] | Epcoritamab (CD20/CD3) in combination with R-DHAX/C | Phase Ib/II Multicenter * Open label Dose escalation and expansion * | Relapsed/refractory CD20+ DLBCL Eligible for HDT-ASCT | 29 patients with DLBCL Median age 58 years 72% of patients had received one prior line of therapy, 28% had received two or three prior therapies |
Thieblemont et al., 2023 [41] | Epcoritamab (CD20/CD3) as monotherapy | Phase I/II Multicenter Open label Single arm Dose expansion | Relapsed or refractory to ≥2 prior lines of therapy including anti-CD20 antibody Failed or ineligible for ASCT ECOG performance status 0–2 | 157 patients with LBCL Median age 64 years 59.9% male participants Median three prior lines of therapy |
Vose et al., 2023 [42] | Epcoritamab (CD20/CD3) as monotherapy | Phase IIa Multicenter Open label Single arm Dose optimization | Relapsed or refractory to ≥2 prior lines of therapy including an anti-CD20 monoclonal antibody containing regimen * Failed or ineligible for ASCT * | 24 patients with CD20+ DLBCL Median age 65 years Median three prior lines of therapy (range 2–10) |
Patel et al., 2022 [43] | Plamotamab (CD20/CD3) as monotherapy | Phase I Multicenter Open label Dose escalation | Relapsed or refractory disease, ineligible for or had exhausted standard therapeutic options ECOG performance status 0–2 | 36 patients with B-cell NHL (including 19 patients with DLBCL) Median age 67 years 61% male participants Median four prior lines of therapy |
Song et al., 2023 [44] | GB261 (CD20/CD3) as monotherapy | Phase I/II Multicenter Open label Single arm Dose escalation and expansion | CD20+ r/r B-NHL or CLL with no available standard-of-care treatments ECOG performance status 0–1 * | 47 patients with B-cell NHL (including 36 patients with DLBCL) Median age 60 years 55.3% male participants Median three prior lines of therapy |
Olszewski et al., 2023 [45] | Mosunetuzumab (CD20/CD3) in combination with CHOP | Phase II Multicenter Open label Single arm Dose expansion | Treatment naïve IPI score 2–5 ECOG performance status 0–2 Life expectancy ≥ 24 weeks | 40 patients with DLBCL Median age 65 years 55% male participants |
Matasar et al., 2024 [46] | Mosunetuzumab (CD20/CD3) as monotherapy | Phase I/II Multicenter Open label Single arm Dose escalation | Relapsed or refractory to ≥2 prior lines including ≥1 prior anthracycline, and ≥1 anti-CD20-directed therapy) (DLBCL/tFL) | 218 patients with B-cell NHL (including 102 patients with LBCL) Median age 64 years 66.5% male participants Median three prior lines of therapy |
Budde et al., 2024 [47] | Mosunetuzumab (CD20/CD3) in combination with polatuzumab vedotin | Phase Ib/II Multicenter Multi-arm Open label Single arm Dose escalation and expansion | Relapsed or refractory to ≥1 prior line of therapy including anti-CD20 antibody Transplant ineligible ECOG performance status 0–2 Life expectancy ≥ 12 weeks | 120 patients with B-cell NHL (including 117 patients with LBCL) Median age 68 years 67.5% male participants Median two prior lines of therapy |
3.3. Treatment-Emergent Adverse Events
3.3.1. Cytokine Release Syndrome (CRS)
3.3.2. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
3.3.3. Infections, Fever, and Fatigue
3.3.4. Cytopenias
3.3.5. Other Frequently Reported Adverse Events
3.4. Efficacy Outcomes
3.5. Quality Assessment
4. Discussion
4.1. Limitations
4.2. Future Directions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
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Bispecific Antibody | CRS | ICANS | Infection | Fever/Pyrexia | Fatigue | |||||
---|---|---|---|---|---|---|---|---|---|---|
Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | |
Blinatumomab [29] | 0 | 0 | NR | NR | NR | NR | 43.5 | 4.3 | 26.1 | 0 |
AZD0486 [30] | 48 | 0 | 27 | 9.7 | NR | NR | NR | NR | NR | NR |
TG-1801 [31,51] | 0 | 0 | 0 | 0 | NR | NR | NR | NR | 25 | 0 |
Odronextamab [32] | 61 | 7 | 12 | 3 | 49 | 23 | 73 | 1 | 33 | 5 |
Glofitamab [33,34,35,36] | 50.2 | 2.6 | 4 | 1.5 | 49 | 17.5 | 18.2 | 0 | 17.9 | 0.6 |
Epcoritamab [37,38,39,40,41,42] | 46.4 | 2.3 | 2.5 | 0 | 41.6 | 14.6 | 31.8 | 0 | 25 | 1.9 |
Plamotamab [43] | 72.2 | 0 | NR | NR | NR | NR | 38.9 | NR | NR | NR |
GB261 [44] | 12.8 | 0 | 0 | 0 | NR | NR | NR | NR | NR | NR |
Mosunetuzumab [45,46,47] | 39.4 | 2.5 | 4.9 | 1.6 | 46.8 | 15.1 | 20 | 0.9 | 46.7 | 6.7 |
Bispecific Antibody | Anemia | Thrombocytopenia | Neutropenia | Leukopenia | Lymphopenia | |||||
---|---|---|---|---|---|---|---|---|---|---|
Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | Any Grade | Grade ≥ 3 | |
Blinatumomab [29] | 4.4 * | NR | 21.7 | 17.4 | 4.4 | NR | 17.4 | 17.4 | NR | NR |
AZD0846 [30] | 34 | 0 | NR | NR | 32 | NR | 20.9 | NR | 29 | NR |
TG-1801 [31,51] | 31 | 6 | 25 | 13 | 19 | 19 | NR | NR | NR | NR |
Odronextamab [32] | 38 | 25 | 28 | 14 | 25 | 19 | 19 | 9 | 22 | 19 |
Glofitamab [33,34,35,36] | 25.8 | 6 | 25 | 8 | 28.6 | 22.5 | NR | NR | NR | 3.2 |
Epcoritamab [37,38,39,40,41,42] | 33 | 10.2 | 40.7 | 5.7 | 36.5 | 14.6 | NR | NR | NR | NR |
Plamotamab [43] | 44.5 | 19.4 | NR | 11.1 | NR | 16.7 | NR | NR | NR | NR |
GB261 [44] | NR | NR | NR | NR | 31.9 | 17 | NR | NR | NR | NR |
Mosunetuzumab [45,46,47] | 15.1 | 19.2 | 11.5 | 12.2 | 35 | 25 | 7.5 | 7.5 | 8.4 | 10 |
Bispecific Antibody | Any Grade, Occurring in >20% of Participants | Grade ≥ 3, Occurring in >5% of Participants | ||
---|---|---|---|---|
Adverse Event | Median Rate, % | Adverse Event | Median Rate, % | |
Blinatumomab [29] | Tremor | 47.8 | Device-related infection | 13 |
Oedema | 26.1 | Pneumonia | 13 | |
Device-related infection | 21.7 | C-reactive protein increased | 13 | |
Pneumonia | 21.7 | Encephalopathy | 8.7 | |
Diarrhea | 21.7 | Aphasia | 8.7 | |
Hyperglycemia | 8.7 | |||
AZD0486 [30] | N/A | N/A | NR | NR |
TG-1801 [31,51] | Headache | 25 | Fall | 6 |
Abdominal pain | 25 | |||
COVID-19 | 25 | |||
Odronextamab [32] | Chills | 47 | Hypophosphatemia | 19 |
Hypophosphataemia | 29 | Aspartate transaminase increased | 10 | |
C-reactive protein increased | 28 | Pneumonia | 9 | |
Cough | 28 | Hypotension | 8 | |
Hypotension | 28 | Alanine transaminase increased | 7 | |
Headache | 25 | Hypoxia | 6 | |
Nausea | 24 | Hyperglycemia | 6 | |
Infusion-related reaction | 24 | |||
Decreased appetite | 23 | |||
Dyspnea | 22 | |||
Blood creatinine increased | 21 | |||
Tachycardia | 21 | |||
Oedema peripheral | 21 | |||
Glofitamab [33,34,35,36] | COVID-19 | 25 | Bleeding | 10 |
Diarrhea | 21 | Renal toxicity | 10 | |
Decreased appetite | 21 | Hypophosphatemia | 5.8 | |
Epcoritamab [37,38,39,40,41,42] | Diarrhea | 39.7 | NR | NR |
Nausea | 34 | |||
COVID-19 | 32 | |||
Injection site reactions | 28 | |||
Constipation | 21 | |||
Hypokalema | 21 | |||
Plamotamab [43] | Nausea | 38.9 | NR | NR |
Asthenia | 27.8 | |||
Diarrhea | 25 | |||
Hypophosphatemia | 25 | |||
Aspartate transaminase increased | 25 | |||
GB261 [44] | COVID-19 infection | 40.4 | COVID-19 infection | 12.8 |
Mosunetuzumab [45,46,47] | Nausea | 42.5 | Febrile neutropenia | 20 |
Constipation | 37.5 | Hypophosphatemia | 14.7 | |
Hypokalemia | 32.5 | Pneumonia | 7.5 | |
Peripheral neuropathy | 31.7 | Hypokalemia | 7.5 | |
Diarrhea | 31.7 | Decreased appetite | 7.5 | |
Decreased appetite | 30 | |||
Vomiting | 30 | |||
Alopecia | 30 | |||
Dizziness | 25 | |||
Headache | 23.4 | |||
Hypotension | 22.5 | |||
Hypophosphatemia | 22.5 |
Bispecific Antibody | Sample Size | MFU, Months | ORR, % | CRR, % | PRR, % | mDoR, Months | mPFS, Months | Response Criteria |
---|---|---|---|---|---|---|---|---|
Front-line setting | ||||||||
Epcoritamab [37,38] | n = 66 | 11.5 | 100 | 80.5 | NR | Not reached | Not reached | Lugano |
Mosunetuzumab [45] | n = 40 | 32 | 95 | 90 | 5 | Not reached | NR | Lugano |
Relapsed/refractory setting | ||||||||
Blinatumomab [29] | n = 20 | 15 | 40 | 20 | 20 | 11.6 | 3.7 | Cheson |
TG-1801 [31] | n = 9 | NR | 56 | 0 | 56 | NR | NR | NR |
Odronextamab [32] | n = 82 | 4.2 | 36 | 24 | 11.5 | 4.4 | 6.8 | Lugano |
Glofitamab [34,35,36] | n = 243 | 12.6 | 52 | 39 | NR | 18.4 | 4.9 | Lugano |
Epcoritamab [39,40,41] | n = 206 | 10 | 91 | 59 | 22.1 | 12 | 4.4 | Lugano |
Plamotamab [43] | n = 19 | NR | 47.4 | 26.3 | NR | NR | NR | NR |
GB261 [44] | n = 22 | 4.5 | 73 | 45.5 | NR | Not reached | NR | Lugano and LYRIC 2016 |
Mosunetuzumab [46,47,52] | n = 227 | 17.9 | 47 | 32.7 | 15.5 | 20.8 | 11.4 | Cheson and Lugano |
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Bayly-McCredie, E.; Treisman, M.; Fiorenza, S. Safety and Efficacy of Bispecific Antibodies in Adults with Large B-Cell Lymphomas: A Systematic Review of Clinical Trial Data. Int. J. Mol. Sci. 2024, 25, 9736. https://doi.org/10.3390/ijms25179736
Bayly-McCredie E, Treisman M, Fiorenza S. Safety and Efficacy of Bispecific Antibodies in Adults with Large B-Cell Lymphomas: A Systematic Review of Clinical Trial Data. International Journal of Molecular Sciences. 2024; 25(17):9736. https://doi.org/10.3390/ijms25179736
Chicago/Turabian StyleBayly-McCredie, Elena, Maxine Treisman, and Salvatore Fiorenza. 2024. "Safety and Efficacy of Bispecific Antibodies in Adults with Large B-Cell Lymphomas: A Systematic Review of Clinical Trial Data" International Journal of Molecular Sciences 25, no. 17: 9736. https://doi.org/10.3390/ijms25179736