Introduction. Chimeric antigen receptor T-cells (CAR T-cells) have improved outcomes for patients (pts) with relapse or refractory diffuse large B-cell lymphoma (R/R DLBCL). However, relapse or progression after CAR T-cell therapy is associated with a short overall survival (mOS), especially when CAR T-cell therapy was administered in the third line or later. We then conducted a phase II trial (BiCAR study, LYSA) testing glofitamab, a 2:1 CD20xCD3 bispecific antibody, with a rapid ramp-up in patients with DLBCL relapsing immediately after CAR T-cells. The primary endpoint was met in June 2023 with a mOS of 14.7 mo (Cartron et al. Nat Cancer 2025). We report the final analysis of the BiCAR study and a prespecified comparison with a synthetic control arm, including patients who were enrolled in the DESCAR-T registry & in phase II ALYCANTE and contemporaneously received a treatment after CAR T-cell failure other than CD20xCD3 bispecific antibody.

Patients and Methods. Patients with biopsy-confirmed CD20+ DLBCL who showed no metabolic response (i.e., stable disease) or experienced progression/relapse at least one month (first assessment) after CAR T-cell infusion received obinutuzumab (1000 mg) three days before (Day -3) the first glofitamab dose. Intravenous glofitamab was administered with a rapid step-up dosing schedule on D1 (2.5 mg), D3 (10 mg), and D8 (30 mg) of Cycle (C) 1, and at 30 mg on D1 of C2–11 (21-day cycles). The primary endpoint was OS and the study was designed to detect an improvement in median OS from 6.3 months (null hypothesis) to 12.6 months (alternative hypothesis) assuming 90% power at a 5% (one-sided) significance level. The objective of the prespecified comparison with synthetic control arm was to compare OS in patients treated with glofitamab (BICAR study) and those not treated by bispecifics (DESCAR-T registry & ALYCANTE study) after CAR T-cell failure, using the stabilized inverse probability of treatment weighting (sIPTW). The two populations were balanced on inclusion criteria of BiCAR after weighting. Absolute standardized mean differences (SMD) of less than 0.2 were required for OS comparison. The main analysis was performed on a weighted multiple imputation dataset (missing values imputed using the MICE method).

Results All patients in the BiCAR trial completed their follow-up on May 21, 2025. The median follow-up was 30.4 mo (95% CI: 23.0-31.4). A total of 46 patients were included, of whom 31 (67%) were male. The median number of prior lines of therapy was 3 (range 2–5). Most patients received axi-cel (26/46), and 14 (30%) were refractory to prior CAR T-cell therapy. Median overall survival (mOS) was 17.3 months (95% CI: 9.0–28.4), with a 2-year OS rate of 38.3%. Median progression-free survival (PFS) was 3.8 months (95% CI: 2.4–15.9), and the 2-year PFS rate was 29.1%. The overall best response rate was 76.1% (95% CI: 61.2-87.4) including 45.7% with complete response (CR), with a median response duration (DOR) of 16.1 months (95% CI: 4.0–NA) and a 2-y DOR rate of 41.8% (95% CI: 36.9–58.7). Median duration of CR (DOCR) was not reached (95% CI: 19.7–NA), with a 2-y DOCR rate of 64.9% (95% CI: 39.9–82.9). Median OS was not reached (95% CI: 27.4-NA) for patients in CR after C2 compared to 9 mo (95% CI: 4.9-20.1) for those who did not reach CR after C2 (P=0.001). Additionally, mOS was not reached (95% CI: 10.2-NA) for patients with late relapse (>6 mo) after CAR T-cells therapy compared to 11.1 mo (95% CI: 5.5-20.0) for refractory and early relapse patients (P=0.01).

The OS comparison with the synthetic arm from the DESCAR-T registry (n=125) & ALYCANTE study (n=8) demonstrated that OS was improved with glofitamab compared to patients who did not receive anti-CD3xCD20 bispecific antibody after CAR T-cell failure. After sIPTW: median OS was 19.6 months (95% CI: 10.2-NR) in glofitamab arm versus 7.6 months (95% CI: 5.5-9.8) in the control arm; HR 0.490 [0.306;0.786], p-value 0.0072, e-value: 2.654. Sensitivity analyses using different weighting, missing data handling methods and testing impact of heterogeneity of data soucres confirmed the robustness of the results.

Conclusion The final analysis of the BiCAR study confirmed that glofitamab used for DLBCL in the first relapse or progression after CAR T-cell therapy significantly improves OS. An indirect comparison with patients included in the DESCAR-T registry showed that glofitamab is the best option for those patients.

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2025
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