Key Phase 3 Bispecific Antibody Trials
| Trial | Regimen | Sponsor | Setting | Status |
|---|---|---|---|---|
| NCT05083169 MajesTEC-9 | Teclistamab + Daratumumab | Janssen | RRMM vs PVd | Active Phase 3 |
| NCT05572515 MajesTEC-3 | Teclistamab vs PVd | Janssen | R/R Multiple Myeloma | Active Phase 3 |
| NCT05455320 MonumenTAL-6/7 | Talquetamab + Daratumumab vs SoC | Janssen | R/R Multiple Myeloma | Active Phase 3 |
| NCT04628494 EPCORE NHL-2 | Epcoritamab vs IC chemotherapy | Genmab | R/R DLBCL | Active Phase 3 |
| NCT06047080 | Glofitamab + Pola-R-CHP vs R-CHOP | Roche | 1L DLBCL | Active Phase 3 |
| NCT04408638 | Glofitamab + G-DHAX/IC vs R-DHAX/IC | Roche | R/R Follicular Lymphoma | Active Phase 3 |
| NCT04712097 | Mosunetuzumab + Lenalidomide vs RI | Roche | R/R Follicular Lymphoma | Active Phase 3 |
| NCT04487080 MARIPOSA | Amivantamab + Lazertinib vs Osimertinib | Janssen | 1L EGFR-mutant NSCLC | Active Phase 3 |
| NCT04988295 MARIPOSA-2 | Amivantamab + Lazertinib + plat-chemo vs SoC | Janssen | EGFR-mutant NSCLC post-osimertinib | Active Phase 3 |
| NCT04538664 | Amivantamab + CAPOX vs SoC | Janssen | EGFR exon 20 insertion NSCLC | Active Phase 3 |
The Bispecific Revolution: T-Cell Redirecting in Hematology
T-cell engaging bispecific antibodies work by simultaneously binding a tumor surface antigen (one arm) and CD3 on T-cells (the other arm), creating an immune synapse that activates polyclonal T-cells regardless of their antigen specificity. Unlike CAR-T cells, bispecifics do not require patient-specific manufacturing — they are ready-to-use, stored as standard biologics, and accessible at community oncology centers without specialized apheresis infrastructure.
In multiple myeloma, the field has coalesced around two antigen targets:
- BCMA (B-cell maturation antigen): Expressed on myeloma plasma cells but not normal tissues. Teclistamab (Janssen) and elranatamab (Pfizer) are both approved. The BCMA×CD3 class competes directly with BCMA-directed CAR-T therapies (ide-cel/Abecma, cilta-cel/Carvykti).
- GPRC5D (G-protein-coupled receptor class C group 5 member D): Talquetamab (Janssen) targets this orphan receptor, which is expressed on myeloma cells but distinct from BCMA. Critically, GPRC5D expression is maintained in patients who have lost BCMA expression after prior BCMA-directed therapy — making talquetamab viable as a next line for BCMA-refractory patients.
Key toxicity profile: all T-cell engaging bispecifics carry cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) risk, requiring step-up dosing schedules and typically one to two nights of hospitalization for the first cycle. GPRC5D-directed talquetamab additionally causes dysgeusia (taste disturbance) and nail/skin changes due to GPRC5D expression in squamous epithelium.
In B-cell lymphoma, Roche's CD20×CD3 bispecifics are the lead programs. Glofitamab (Columvi) and mosunetuzumab (Lunsumio) are both approved in R/R DLBCL and FL respectively. Genmab's epcoritamab (Epkinly, partnered with AbbVie) received approval in R/R DLBCL and FL, and is now in Phase 3 vs IC chemotherapy (EPCORE NHL-2).
Amivantamab: The Solid Tumor Bispecific
Amivantamab (Rybrevant, Janssen) targets EGFR and MET simultaneously — two receptor tyrosine kinases whose crosstalk drives resistance to EGFR-targeted TKIs. It received initial approval for NSCLC with EGFR exon 20 insertions (2021), a subtype that does not respond to standard EGFR TKIs.
The MARIPOSA program represents Janssen's most significant competitive challenge in oncology:
- MARIPOSA (NCT04487080): Amivantamab + lazertinib (a third-generation EGFR TKI) vs osimertinib monotherapy as first-line treatment for EGFR-mutant NSCLC. This directly challenges AstraZeneca's Tagrisso, which generates over $5B in annual revenue. MARIPOSA reported positive PFS data, showing the combination delayed disease progression longer than osimertinib alone — an unprecedented result that prompted debate about whether osimertinib monotherapy should remain the standard of care.
- MARIPOSA-2 (NCT04988295): Testing amivantamab + lazertinib + chemotherapy vs SoC in patients who progressed on osimertinib. MET amplification is a dominant osimertinib resistance mechanism; amivantamab addresses MET and EGFR simultaneously, potentially reversing resistance.
The clinical rationale for EGFR×MET bispecific inhibition: osimertinib resistance develops primarily through MET amplification (~20%) and EGFR C797S tertiary mutations. By blocking both pathways from day one, the combination may prevent or delay the clonal outgrowth that leads to osimertinib failure.
From "Off the Shelf" to Combination: The Next Phase
The bispecific field is moving rapidly from monotherapy approvals into combination regimens designed to push into earlier treatment lines and improve response depth. The rationale is identical to the evolution of monoclonal antibody therapy in hematology: single agents demonstrate activity, then combinations improve outcomes, then combinations enter first-line therapy.
- Bispecific + CD38 antibody: Teclistamab+daratumumab (MajesTEC-9) and elranatamab+daratumumab (MAGNETISMM-9) both in Phase 3. Daratumumab's myeloma ubiquity makes it the logical combination partner.
- Bispecific vs CAR-T: The competitive question is not "bispecific OR CAR-T" but "which for which patient." Bispecifics are accessible immediately; CAR-T requires manufacturing. But bispecific therapy is continuous (weekly to biweekly dosing) while CAR-T is a one-time infusion. Fatigue and late toxicities from months-long bispecific dosing are emerging as patient-reported concerns.
- Bispecific + ADC: Combining bispecifics with antibody-drug conjugates (e.g., belantamab mafodotin, a BCMA-directed ADC) creates orthogonal mechanisms targeting the same antigen. Phase 1/2 data are emerging; Phase 3 designs are likely to follow.
- Blinatumomab in ALL: Blinatumomab (Blincyto, Amgen/Pfizer) remains the only approved CD19×CD3 bispecific in B-cell ALL. Pfizer's elranatamab and blinatumomab together give Pfizer/Amgen a bispecific position in two hematologic malignancies.
Related Pages
- Multiple Myeloma Clinical Trials — Full Pipeline
- DLBCL Clinical Trials
- Non-Hodgkin Lymphoma Clinical Trials
- CAR-T Cell Therapy Clinical Trials
- Antibody-Drug Conjugate (ADC) Clinical Trials
- Non-Small Cell Lung Cancer Clinical Trials
- HER2-Targeted Cancer Clinical Trials
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Start Free Trial →Frequently Asked Questions
How many bispecific antibody clinical trials are currently active?
As of March 2026, there are 201 active bispecific antibody trials on ClinicalTrials.gov — 112 recruiting, 62 active not recruiting, and 27 not yet recruiting. Janssen (J&J) leads with 39 active trials, followed by Roche (17), NCI (16), Genmab (9), Pfizer (8), and Amgen (6). Janssen controls three approved bispecifics: teclistamab (Tecvayli, BCMA×CD3), talquetamab (Talvey, GPRC5D×CD3), and amivantamab (Rybrevant, EGFR×MET).
What is the difference between teclistamab and talquetamab in multiple myeloma?
Teclistamab (Tecvayli, Janssen) targets BCMA×CD3 — the same antigen as several CAR-T therapies (ide-cel, cilta-cel). Talquetamab (Talvey, Janssen) targets GPRC5D×CD3, a different myeloma antigen that remains expressed on BCMA-refractory or BCMA-antigen-loss cells. This BCMA-independent mechanism is clinically important: patients who relapse after BCMA-directed CAR-T or teclistamab may still respond to talquetamab. The MajesTEC and MonumenTAL trial programs are now combining both bispecifics with daratumumab to build all-oral or outpatient-accessible regimens that compete with CAR-T manufacturing timelines.
How do T-cell engaging bispecific antibodies compare to CAR-T cell therapy?
T-cell engaging bispecifics are off-the-shelf — no apheresis, no vein-to-vein manufacturing time (4-6 weeks for CAR-T), and lower per-dose cost. CAR-T therapies typically show deeper initial responses and potentially longer durability in some patients, but require a manufacturing step that can fail and are available only at certified treatment centers. Bispecifics are administered subcutaneously (teclistamab, talquetamab) or IV (glofitamab, mosunetuzumab) and can be started within days. The competitive question is whether continuous bispecific dosing until progression equals or exceeds the response durability of CAR-T in relapsed/refractory myeloma and lymphoma.