Rapcabtagene autoleucel (YTB323) for patients with first line high-risk large B-cell lymphoma: Phase II interim results

Abstract Introduction: Although ~70% of patients (pts) with large B-cell lymphoma (LBCL) respond to frontline (1L) chemoimmunotherapy, outcomes are poor in patients with high-risk (HR) disease, defined as an International Prognostic Index (IPI) score 3-5 or double-hit LBCL (DHL), and in those not achieving complete response (CR) at the interim evaluation during 1L therapy. Chimeric antigen receptor (CAR)-T cells, a practice-changing therapy in the relapsed/refractory setting, may have potential in 1L HR LBCL. Rapcabtagene autoleucel (YTB323) is an investigational CD19-directed CAR-T cell therapy utilizing the T-Charge™ platform to rapidly manufacture product (2 days), preserving T-cell stemness and enhancing in vivo expansion. We report a descriptive interim analysis of the ongoing phase 2 trial of rapcabtagene autoleucel in pts with 1L HR LBCL (NCT03960840). Methods: Eligible pts had histologically confirmed LBCL with an IPI score of 3-5, and/or MYC and BCL2 and/or BCL6 rearrangement (DHL per WHO 2016). After 2 cycles of 1L therapy R-CHOP, R-CHP-Pola, or R-EPOCH (which was required for pts with DHL), pts were eligible if a positron emission tomography (PET) scan per Lugano classification showed stable disease (SD) or partial response (PR) with a Deauville score of 4 or 5. Pts with progressive disease or CR were not eligible. A third cycle of 1L therapy as bridging after leukapheresis could be administered. Pts received lymphodepletion followed by a single dose of rapcabtagene autoleucel (12.5×106 cells). The primary endpoint was investigator-assessed CR rate (CRR) defined as best overall response of CR post rapcabtagene autoleucel infusion. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), adverse events (AEs), and cellular kinetics. Results: As of January 22, 2025 (enrollment ongoing at data cutoff), 37 pts received rapcabtagene autoleucel (median follow-up: 4.2 months range 0.3-17.1). Median age was 59 y (range 26-76); 78.4% of pts were White and 10.8% were Asian; 10.8% of patients were Hispanic or Latino. At diagnosis, 86% had an IPI score ≥3, 38% had DHL per local assessment, and 95% had stage III-IV disease. Germinal center B-cell (GCB) LBCL was reported in 51% of pts, 41% had non-GCB, and information was missing for 8%. In total, 57% of pts had an IPI of 4-5 or DHL and 43% had IPI 3 without DHL. After 2 cycles of 1L therapy, 86% of pts had PR and 14% had SD. Among 31 infused pts who had ≥1 months post-infusion follow-up, CRR was 74% and ORR was 90%. AEs (any grade) were reported in 100% of the 37 infused pts. AEs of interest included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. CRS occurred in 38% of pts (all grade 1); ICANS occurred in 8% of pts (all grade ≤3); infections occurred in 49% of pts (grade ≥3, 8%). Median time to CRS onset was 9.5 days (range, 1–18) and median time to resolution was 4 days (range 1–5). Of the pts with CRS, 50% (7/14) received tocilizumab, and none were admitted to ICU. Median time to ICANS onset was 17 days (range, 10–18), and median time to resolution was 19 days (range, 3–27+; 1 case-ongoing as of cutoff). One pt was reported by the treating investigator to have immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (grade 2), which resolved after treatment with tocilizumab and anakinra. Among pts with grade 3 or 4 cytopenias (based on laboratory results) at 1 month post infusion, the probability of resolution by month 3 for neutropenia, leukopenia and anemia was 100%; for thrombocytopenia, the probability of resolution by month 3 was 87%. There were no reported deaths or secondary malignancies as of data cutoff. Cellular kinetics showed robust in vivo expansion by qPCR with a median Cmax of 31,000 copies/µg DNA, similar to the expansion previously reported in pts with 3L r/r DLBCL (median Cmax 41,800/µg DNA). Conclusions: A single dose of rapcabtagene autoleucel (12.5×106 CAR+ cells) showed promising initial efficacy and a manageable safety profile in pts with 1L HR LBCL. At the time of presentation, CAR-T cell immunophenotyping data and efficacy data for the final pt population with longer follow-up (≥6 months for most pts) will be available, allowing initial assessment of DOR.