CD20xCD3 Bispecific Antibodies As Standard of Care (SOC) for Relapse/Refractory (R/R) Large B-Cell Lymphoma (LBCL) - a Multicenter Retrospective Study
Authors: Dong Ning , Khadka Sushmita , Sandoval-Sus Jose , Rondon Carlos Silva , Perez Ariel , Al Sagheer Tiba , Iqbal Madiha , Alderuccio Juan Pablo , Rodriguez Arocho Cristian , Kareem Syeda Saba , Jain Michael D. , Chavez Julio C. 
Published: December 2024

Introduction:
CD20xCD3 bispecific antibodies (BsAbs) represent a major advance in the treatment of relapsed or refractory (r/r) large B-cell lymphoma (LBCL). In their pivotal trials, epcoritamab (Epcor) and glofitamab (Glofi) showed an overall response rate (ORR) and complete response rate (CRR) of 52-63% and 39%, respectively, in patients (pts) with r/r LBCL after 2 or more prior lines of therapy (LOT). Data on the efficacy and safety of BsAbs in standard of care (SOC) setting is limited. Here, we report our multicenter retrospective study on SOC BsAbs for the approved indication in r/r LBCL.
Methods:
All pts who received SOC BsAbs for r/r LBCL at four cancer centers in Florida were included. Pts who died before the first response evaluation were considered to have disease progression. Median follow up time was calculated using reverse Kaplan Meier (KM) method. Univariate analysis (UVA) and multivariate analysis (MVA) of response rates were done using logistic regression. UVA and MVA of PFS and OS were done using Cox proportional hazard model. Median PFS (mPFS) and median OS (mOS) were estimated using KM method.
Results:
As of June 1, 2024, a total of 69 pts received SOC BsAbs for r/r LBCL (43 epcor and 26 glofi). Forty pts (58.0%) were male; median age was 66 years (range 32-89); ECOG &gt;= 3 in 14 (20.3%) pts; transformed indolent lymphoma in 20 (29.0%); Richter transformation in 3 (4.4%); HGBL with MYC/BCL2 rearrangements (double-hit lymphoma [DHL]) in 12 (17.4%); bulky disease&gt;10cm in 33 (47.8%); IPI score &gt;= 4 in 15 (21.7%). Pts received a median of 3 prior LOT (range 2-12); 46 (66.7%) had primary refractory disease; 40 (58.0%) received prior CD19 CAR-T therapy; 35 pts (50.7%) would not have met the inclusion criteria of the pivotal trials due to: ECOG&gt;=3 (n=14), thrombocytopenia (n=11), neutropenia (n=2), CNS involvement (n=6), recent infection (n=6), prior CAR-T within 30 days (n=1), and CrCL&lt;45 (n=2).
Among the 69 pts, 65 were evaluable for response. At a median follow up of 7 months, the ORR and CRR were 52.3% and 26.2%, respectively. Median PFS was 4.2 months (m) (95%CI: 2.8-6.9). Median OS was 6.2m (95%CI: 5.9-not reached [NR]).
The ORRs in pts without prior CAR-T (CART-naive), progressed after achieving CR/PR to prior CAR-T (CART-R), and not achieving CR/PR to prior CAR-T (CART-NR) were 13/25 (52.0%), 18/24 (75%), and 3/16 (18.8%), respectively, p&lt;0.01.
In the UVA of ORR, the following factors were associated with lower response: CART-NR (18.8% vs 63.3%, p&lt;0.01) and ECOG &gt;=3 (21.4% vs 60.8%, p=0.01). Bulky disease, IPI &gt;=4, DHL, &gt;=4 prior lines of therapy, DLBCL subtype or BsAb type was not associated with response. In MVA, only CART-NR was a significant predictor of lack of response to BsAb (odds ratio 5.6, 95%CI: 1.3-24).
In the UVA of PFS, CART-NR and ECOG &gt;=3 were associated with shorter mPFS (1.9m [95%CI: 0.6-3] vs 5.4m [95%CI: 4.0-NR] in CAR-T non-responders vs responders; 1.1m [95%CI: 0.4-3.2] vs 5.4m [95%CI: 3.2-NR] in ECOG&gt;=3 vs &lt;3). In the MVA, CART-NR and ECOG&gt;=3 were associate with shorter PFS (HR 2.7, p&lt;0.01 and 2.5, p&lt;0.02, respectively). One of the 3 pts with Richter transformation had continuous PR at 5 months.
Cytokine release syndrome (CRS) occurred in 21 pts (36.2%), including 4 (5.8%) grade (Gr) &gt;= 3. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 12 pts (17.4%) with 6 (8.7%) Gr &gt;= 3. Gr3-4 neutropenia was observed in 18 pts (26.1%); Gr3-4 thrombocytopenia in 10 (14.5%). Infection all grades and Gr &gt;= 3 occurred in 26 pts (37.7%) and 19 pts (27.5%), respectively. Among them, bacterial infection was identified in 13, COVID in 5, fungal in 2, and CMV in 1 patient.
Conclusion:
BsAbs had comparable efficacy in SOC setting as in the pivotal trials. CRS and ICANS were mostly low-grade; however, a high incidence of serious infection was observed. Pts with no response to prior CAR-T also had poor BsAbs response. This could reflect a common mechanism of resistance to immunotherapy, either due to tumor characteristics or host T-cell exhaustion. Longer follow-up is needed to evaluate the durability of response.