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.