Key points: - Bispecific T-cell-engaging antibodies (TCEs) are a significant advance in the treatment of diffuse large B-cell lymphoma (DLBCL), demonstrating robust clinical activity with manageable toxicity profiles. - TCEs function by crosslinking T cells and lymphoma cells, resulting in major histocompatibility complex -independent, T-cell–mediated target cell cytotoxicity. - Their integration into third line (3L) as monotherapy (complete responses [CR] in as high as 40%), and now second line (2L) in combination (CR 59% [STARGLO trial]), as well as recent data in the first line (1L) underscores their therapeutic potential (CR in as high as 96% [NP40126 study]). ● 3L: Single-arm trials led to the regulatory approval of glofitamab and epcoritamab for this setting in both the United States and the European Union (EU). The EU recently granted approval for odronextamab monotherapy in the same setting. ○ Unfortunately, the majority of patients will have resistant disease or will relapse after TCE monotherapy. ○ The efficacy of bispecific antibodies depends on sustained target antigen expression and preserved T-cell function; the loss of either of these factors, or intrinsic tumour and microenvironment biology, contributes to therapeutic resistance. Combination strategies aim to overcome these resistance mechanisms, enhance anti-tumour efficacy and potentially reduce treatment-related adverse events. ● 2L: STARGLO trial is the first study of a CD20xCD3 TCE (Glofitamab plus gemcitabine and Oxaliplatin [GemOs]) with an overall survival benefit and supports the use of this combination as a new “standard of care” in relapse and refractory (R/R) DLBCL in transplant-ineligible patients. The similar regimen in transplant-ineligible R/R DLBCL patients of epcoritamab and GemOx has promising response. ● 1L: Preliminary reports from phase I/II trials of CD20xCD3 TCEs in combination with either CHOP(cyclophosphamide, doxorubicin, vincristine, and prednisone), Rituximab (R)-CHOP or Polatuzumab (Pola)-R-CHP(cyclophosphamide, doxorubicin, and prednisone) -in first-line- are promising. The favourable adverse effect profile and high efficacy of these combinations lend themselves to first-line treatment of populations not suitable for chemotherapy. ○ The superior efficacy of the Mosunetuzumab-Pola combination versus standard salvage chemotherapy (R-GemOx) in R/R DLBCL was demonstrated by the phase III SUNMO trial which reported a higher CR rate (51 vs. 24%) that was associated with a significant improvement in progression-free survival (PFS) with a median PFS of 11.5 months. The combination was safe and well tolerated. - The TCEs drive T-cell activation through CD3 engagement, but T-cell activation in normal physiology requires a second co-stimulatory molecule such as 4-1BBL or CD28. The use of co-stimulatory bispecific antibodies may be able to improve T-cell responses without leading to an increase in cytokine release syndrome. - Small molecules including the Bruton tyrosine kinase inhibitors (BTKi) and cereblon E3 ligase modulators (i.e., golcadomide) lead to increases in T-cell activation and cytotoxic activity in addition to their direct anti-lymphoma effect. ● BTKi are already being explored in combination with TCEs in other B-No Hodgkin lymphoma histologies and have activity in DLCBL, particularly in the ABC subtype with CD5 gene signature. ● Immunomodulatory imide (IMiD) drugs like lenalidomide also have preferential single-agent activity in the ABC subtype. - While there is ongoing uncertainty on the correct sequencing of TCEs and chimeric antigen receptor (CAR) T-cell therapy, it is difficult to disentangle the impact of patient selection; retrospective data suggest that CAR T-cell efficacy is not impacted by previous TCE therapy. ● A phase II trial that incorporates the anti-CD19 axicabtagene ciloleucel between cycles of glofitamab is currently recruiting and will provide important clinical and translational data to help answer some of the key questions (NCT06213311). |
