Atalanta-1: A Phase 1/2 Trial of GLPG5101, a Fresh, Stem-like, Early Memory CD19 CAR T-Cell Therapy with a 7-Day Vein-to-Vein Time, for the Treatment of Relapsed/Refractory Non-Hodgkin Lymphoma
Authors: Kersten Marie José , Saevels Kirsten , Willems Evelyne , Liefaard Marte C. , Milatos Stavros , Pont Margot J. , Vennin Claire , Santermans Eva , van Muyden Anna D. D. , Shetty Jeevan , Hoefsmit Esmée P. , Fasan Omotayo , Kuipers Maria T. , Anguille Sébastien , Vermaat Joost S.P. 
Published: December 2024

Background:CD19-targeted CAR T-cell therapies offer the potential for durable remission in patients (pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), who typically have poor prognoses. Shorter vein-to-vein time, robust in vivo expansion, and preservation of early T-cell phenotypes during manufacturing may improve safety and efficacy in pts with NHL. GLPG5101 is a fresh, stem-like, early memory phenotype CD19 CAR T-cell therapy manufactured using a rapid decentralized platform enabling a 7-day vein-to-vein time. Here, we present updated results from the ongoing ATALANTA-1 study of GLPG5101 for R/R NHL.

Methods: ATALANTA-1 (CTIS: 2022-502661-23-00) is a Phase (Ph)1/2 study of GLPG5101 in pts with R/R diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), Burkitt lymphoma, or primary central nervous system lymphoma. Primary objectives are safety, establishment of a recommended Ph2 dose in Ph1, and efficacy (objective response rate [ORR]) in Ph2. Secondary objectives encompass manufacturing feasibility, safety, efficacy (including duration of response and minimal residual disease [MRD]), and pharmacokinetics. The expansion and persistence of GLPG5101 were quantified in peripheral blood using PCR. MRD in plasma was evaluated using the clonoSEQ assay.

Results: As of April 25, 2024, 53 pts had undergone leukapheresis: 49 had received an infusion, with 47 (96%) receiving a fresh product. A 7-day vein-to-vein time was achieved in 43/47 (91%) pts. In Ph1, 2 pts received less than the prespecified minimum dose and were not included in the analyses. Data for 45 pts receiving a fresh infusion were analyzed (R/R DLBCL n=13 [all Ph1]; MCL n=8; FL n=19; MZL n=5). Median (range) age was 66.5 (25-78) years in Ph1 and 67.0 (40-81) years in Ph2. Median (range) number of prior therapies was 2.5 (1-7) in Ph1 and 3.0 (2-11) in Ph2.

Most Grade ≥3 treatment-emergent adverse events (reported up to 14 weeks post-infusion) were hematological. CRS was reported in 9/20 (45%) Ph1 pts (Grade ≤2 n=8; Grade 3 n=1) and 10/25 (40%) Ph2 pts (all Grade ≤2). ICANS was reported in 6/20 (30%) Ph1 pts (all Grade 1) and 4/25 (16%) Ph2 pts (Grade 1 n=3; Grade 3 n=1). Of all 49 pts who received an infusion, 2 died during the treatment period and 1 died during follow-up.

Three pts had not reached first response assessment at data cutoff and were excluded from the efficacy analyses. Median (range) follow-up in the study was 13.0 (0-24) months in Ph1 and 5.4 (1-14) months in Ph2. Across Ph1 and Ph2, 37/42 efficacy-evaluable pts responded to treatment (ORR 88%), with 35/42 achieving complete response (CR; CR rate [CRR] 83%). All pts with MCL (8/8) achieved CR (ORR and CRR 100%); 20/21 pts with FL/MZL responded (ORR and CRR 95%); 9/13 pts with DLBCL responded (ORR 69%) with 7 achieving CR (CRR 54%). Of pts with DLBCL who received the higher dose, 6/7 responded (ORR 86%) with 5 achieving CR (CRR 71%).

At data cutoff, of 11/16 (69%) Ph1 pts who responded to treatment, 10 had an ongoing response and 1 had completed the study while in CR. After an initial response, 3 pts with DLBCL and 1 with MCL progressed. In Ph2, 21/21 (100%) of responding pts had an ongoing response. MRD negativity occurred in 12/15 (80%) evaluable pts who achieved CR (DLBCL n=1; MCL n=2; MZL n=2; FL n=7). All MRD-negative pts with a minimum follow-up of 6 months (n=11) were in ongoing CR at data cutoff.

The proportion of early T-cell phenotypes (naïve/stem cell memory and central memory) of CD4+ and CD8+ CAR T cells was significantly increased in the final product (FP) compared with the starting material (SM). A median increase in the CD4:CD8 ratio of CAR+ T cells in the FP was observed compared with the SM. GLPG5101 demonstrated robust in vivo expansion across all dose levels and indications, and persisting CAR T cells were detected in peripheral blood up to 21 months post-infusion.

Conclusions: Results from the ongoing ATALANTA-1 study show a manageable overall safety profile, with low rates of Grade ≥3 CRS and ICANS and high antitumor activity in all NHL subtypes studied. GLPG5101, a fresh, stem-like, early memory CD19 CAR T-cell therapy manufactured using a rapid decentralized platform, showed robust in vivo expansion and durable persistence. Treatment with GLPG5101 led to promising efficacy and safety across indications in heavily pretreated pts with R/R NHL.