High complete response rates and minimal residual disease (MRD) negativity, with durable responses, in high-risk mantle cell lymphoma (MCL) with GLPG5101, a fresh, early memory-enriched CAR T-cell therapy with a 7-day vein-to-vein time: Results from the ATALANTA-1 MCL cohort

Abstract

Abstract Introduction:MCL remains incurable, and patients (pts) with relapsed/refractory (R/R) disease following Bruton tyrosine kinase inhibitor (BTKi) therapy face a poor prognosis and have a high unmet medical need. Anti-CD19 CAR T-cell therapy offers an effective therapeutic option in this setting. Currently approved CAR T-cell products demonstrate higher overall response rates than conventional therapies. However, their use is limited by restricted accessibility, prolonged vein-to-vein (VTV) times, considerable attrition rates, high rates of CRS and ICANS, and suboptimal durability of responses. Recently, a manageable safety profile of GLPG5101 with a median 7-day VTV time was reported in 61 pts with R/R non-Hodgkin lymphoma (NHL; 58/61 received a fresh product), demonstrating low rates of high-grade toxicities. Here, we present Phase 1/2 efficacy and safety data for pts with MCL in the ATALANTA-1 study. Methods: ATALANTA-1 (CTIS: 2022-502661-23-00; NCT06561425) is a Phase 1/2 study of GLPG5101 in pts with R/R NHL; Cohort 4 enrolled pts with R/R MCL. Primary objectives were safety and determination of the recommended Phase 2 dose in Phase 1, and efficacy in Phase 2. MRD was assessed using the clonoSEQ assay (Adaptive Biosciences, Seattle, WA, USA) in plasma and whole blood. Safety data are presented for the safety analysis set while efficacy and T-cell phenotypes of infused product are reported for the intention-to-treat (ITT) population across all doses received (50–110×10⁶ CAR T cells). GLPG5101 is a fresh, early memory-enriched phenotype CD19 CAR T-cell therapy, manufactured using a rapid decentralized platform enabling a 7-day VTV time. Results: As of 21 April 2025, 20 pts underwent leukapheresis. At the time of data cutoff, 18/19 (95%) pts had received an infusion and 1 pt was pending infusion. One pt discontinued the study prior to infusion due to progressive disease; a dropout rate of 1/19 (5%). A fresh product was received by 17/18 pts (94%) with a VTV time of 7 days; no pts required cytotoxic bridging chemotherapy. In the ITT analysis (n=20), median (range) pt age was 67 (57–81) years and median (range) number of prior systemic lines of therapy was 2 (1–6). All pts had received a BTKi, with 85% refractory to or relapsed while on BTKi. 14/20 (70%) pts had high-risk MCL International Prognostic Index scores; the remaining 6/20 (30%) had intermediate risk. 11/16 (69%) pts had a TP53 mutation, 8/12 (67%) pts had a Ki67 index ≥30%, and 3/20 (15%) pts had blastoid morphology. At the time of data cutoff, median (95% CI) follow-up duration was 8.7 (3.4, 16.1) and 6.9 (3.4, 15.1) months for infused pts and the ITT population, respectively. For the ITT population, excluding the pt yet to be infused, 18/19 pts responded with a complete response (CR), a 95% CR rate (CRR). All 18 infused pts achieved a CR (CRR 100%); 8/9 evaluable pts (89%) were MRD negative at the time of CR. The Kaplan–Meier (KM)-estimated 9-month duration of response rate was 82%; the KM-estimated 12-month progression-free survival (PFS) rate was 83%. During the treatment period (≤14 weeks post-infusion), the most common Grade (G) ≥3 adverse events were hematologic; serious infections were reported in 3/17 (18%) pts. G1/2 CRS was reported in 11/17 (65%) pts and G1 ICANS in 5/17 (29%) pts. There were no G≥3 CRS or ICANS events. G≥3 cytopenia was reported in 5/17 (29%), 4/17 (24%), and 4/15 (27%) pts at 30, 60, and 90 days post-infusion, respectively. One death occurred due to E. coli sepsis 6 months post-infusion, while the pt was in CR during the follow-up period (>14 weeks post-infusion). Compared with the starting material, the proportion of early memory phenotype CD8+CAR T cells increased significantly in the final product, and increased moderately within CD4+ CAR T cells, in 93% (13/14) of evaluable pts. These increases drove a corresponding reduction of terminally differentiated effectors. Conclusions: GLPG5101 achieved deep and durable responses in pts with high-risk, aggressive R/R MCL. GLPG5101, characterized by an early memory-enriched T-cell phenotype, was well tolerated, with no G≥3 CRS or ICANS, and demonstrated a 100% CRR, achieving 89% MRD negativity across both plasma and blood, and 83% 12-month PFS in infused pts. GLPG5101's short VTV time (7 days) and low dropout rate (5%) enabled a timely and well-tolerated treatment for pts with aggressive disease. These data support further development of GLPG5101 in a pivotal study for R/R MCL.