During a recent scientific talk at Tandem 2024 in San Antonio, TX, the spotlight was on the debate between CAR T-cell and bispecific antibody therapies for relapsed or refractory Diffuse Large B-cell Lymphoma (DLBCL). Two dynamic and competitive PharmD experts, Emilie Aschenbrenner and Katie Gatwood, took center stage, with Aschenbrenner advocating for bispecific therapies and Gatwood championing CAR T-cell therapies in a presentation titled Taking a Bite out of CAR-T: Debating Use of CAR T-Cell Therapy Vs Bispecific Antibodies in Lymphoma.
With approximately half of DLBCL patients ineligible for stem cell transplant and a pressing need for novel treatments, the discussion focused on the efficacy, safety, and practical considerations of these cutting-edge therapies.
Current Landscape of CAR T-Cell Therapies
Currently, three CAR T-cell therapies are approved for DLBCL in the third-line setting, all targeting CD19. “Selecting the appropriate CAR-T option for a patient is an individualized decision based on patient-specific factors as well as treatment center capabilities and priorities.”- Katie Gatwood
- Axi-Cel (ZUMA-1):
- 5-year overall survival: 43%
- Overall response rate (ORR): 83%
- Median Overall Survival (OS): 25.8 months
- Progression-Free Survival (PFS): 6 months
- Severe Cytokine Release Syndrome (CRS) > grade 3: 13%
- Severe Immune effector cell-associated neurotoxicity syndrome (ICANS) > grade 3: 28%
- Tisa-Cel (JULIET):
- ORR: 53%
- OS median: 12 months
- PFS median: 3 months
- Severe CRS > grade 3: 23%
- Severe ICANS > grade 3: 11%
- Liso-Cel (TRANSCEND-NHL 001):
- ORR: 73%
- PFS: 7 months
- OS median: 27 months
- 2-year overall survival: 51%
- Severe CRS > grade 3: 2%
- Severe ICANS > grade 3: 10%
Axi-Cel has the greatest efficacy but with the highest toxicity. Liso-Cel presented a close second in efficacy with a safer toxicity profile.
Bispecific Antibodies
Bispecifics, targeting CD20 on tumor cells and CD3 on T-cells, offer an alternative approach.“Bispecific antibodies represent a promising new treatment strategy for DLBCL patients who are unable to receive CAR-T cell therapy or relapse post-CAR-T cell therapy”- Emilie Aschenbrenner
- Epcoritamab (EPCORE NHL-1):
- ORR: 63%
- PFS: 4.4 months
- 45% achieved MRD negativity
- CRS in 50% of patients primarily with the first full 48 mg dose Cycle 1 Day 15 (C1D15)
- One fatal case from ICANS
- Subcutaneous injection
- Glofitamab (NP30179 trial):
- ORR: 52%
- PFS: 4.9 months
- CRS in 66% primarily with the first 2.5 mg dose Cycle 1 Day 8 (C1D8)
- One fatal case from ICANS
- Fixed duration of 12 cycles, 2-4 hour infusions
- Mosnetuzamab:
- ORR: 42% in DLBCL patients
- PFS: 3.2 months
The Odronextamab trial (REGN1979) is anticipating approval soon.
Bispecifics present promising results, but data on survival and duration of therapy is still evolving.
Comparative Analysis
Similarities:
- Costs: Both therapies are comparable in cost, although the cost of CAR-T is higher upfront.
- In-patient vs. outpatient: Both can be potentially administered on an outpatient basis, depending on the infrastructure of the healthcare facility.
Differences:
- CAR T-cell strengths: Long-term survival data and duration of therapy.
- Bispecific strengths: Off-the-shelf availability, lower toxicity, and easier access.
Sequencing Considerations
The debate shifted from a winner-takes-all scenario to a focus on sequencing for relapse. CAR T-cell trials with prior antibodies maintained efficacy even with prior bispecific exposures, though noting lower response rates in patients refractory to prior CAR T-cell treatment. However, data for bispecific post-CAR T-cell therapy has yet to be collected. First-line CAR T-cell trials without prior exposures are underway, potentially offering a chemo-free option.
Conclusion:
Both CAR T-cell and bispecific therapies exhibit strengths and limitations. Given high relapse rates, the critical question becomes: What is the best sequence based on individual patient circumstances? As research evolves, the treatment landscape for DLBCL is on the brink of a paradigm shift, offering renewed hope for patients in need.
