Durable Responses With GLPG5101 Suggest Feasibility of Decentralized CAR T Manufacturing in R/R NHL

Treatment with GLPG5101 led to high complete response (CR) rates across all indications in heavily pretreated patients with relapsed/refractory non-Hodgkin lymphoma (NHL), suggesting that administering decentralized manufactured autologous anti-CD19 CAR T-cell therapy is a feasible strategy for this population, according to updated results from the ongoing phase 1/2 ATALANTA-1 study (EudraCT 2021-003272-13) presented at the2024 EHA Congress.¹

At the data cutoff date of December 20, 2023, the objective response rate (ORR) among efficacy-evaluable patients in the phase 1 portion of the study (n = 16) was 87.5%, with a complete response (CR) rate of 75%. In the phase 2 portion of the study, 93.3% of efficacy-evaluable patients (n = 15) responded to treatment with GLPG5101 and all achieved a CR.²

Moreover, data from the pooled analysis efficacy set revealed high ORR and CR rates with GLPG5101 across all tumor types assessed. Patients with diffuse-large B-cell lymphoma (DLBCL; n = 9) achieved a 78% ORR, which included a 56% CR rate. For those with follicular lymphoma (FL; n = 15) and marginal zone lymphoma (MZL; n = 2), the ORR and CR rate was 94%. Notably, 1 patient in this cohort did not have a response recorded. The ORR and CR rate was 100% for patients with mantle cell lymphoma (MCL; n = 5).¹

The majority of responses achieved were also durable, with 71% and 100% of patients in the phase 1 and 2 portions of the research, respectively, displaying an ongoing response at the data cutoff. The median follow-up was 13.1 months (range, 0.5-21.0) in phase 1 and 4.2 months (range, 1.0-9.4) in phase 2.

“Our data show that it’s feasible to decentralize CAR T-cell manufacturing, and with a fresh-out/fresh-in procedure, you can have a very short vein-to-vein time,”lead study author Marie José Kersten, MD, professor of Hematology and head of the Department of Hematology at the Amsterdam University Medical Center in the Netherlands, stated in an oral presentation of the data. “These cells expand very well in vivo and also persist for longer periods of time, with relatively low rates of severe cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS] and high CR rates across the different indications.”

CAR T-cell agents targeting CD19 have well-documented efficacy and have demonstrated a clear survival benefit in relapsed/refractory NHL. However, logistical concerns such as manufacturing delays have limited the impact of these agents and their use in clinical practice.

Kersten and colleagues hypothesized that shortening the time from leukapheresis to CAR T infusion could help expedite treatment, thereby decreasing drop-out rates and improving clinical outcomes. Accordingly, ATALANTA-1 was designed to evaluate the safety, efficacy, and feasibility of a decentralized CAR T-cell manufactured product, the second-generation anti-CD19/4-1BB CAR-T candidateGLPG5101, with a short vein-to-vein time for patients with relapsed/refractory NHL.^1,2

The ongoing, open-label, multicenter study included a phase 1 dose-escalation and phase 2 expansion cohort. Patients were eligible for the dose-escalation portion if they had primary refractory or first-relapsed DLBCL; or relapsed/refractory FL, MZL, or MCL after 2 prior treatments. Dose-expansion cohorts included patients with DLBCL, high-risk DLBCL, FL and MZL, Burkitt lymphoma, or primary central nervous system lymphoma (PCNSL). Patients with prior exposure to CD19-targeted therapies were ineligible for enrollment.

After undergoing screening on day –35, patients proceeded to leukapheresis on day –7 and received a conditioning chemotherapy regimen consisting of cyclophosphamide (Cy) and fludarabine (Flu) on days –6 to –4. Decentralized manufacturing of the CAR T-cell product occurred during this time. On day 0, GLPG5101 was administered as a single, fresh, fixed intravenous infusion. In phase 1, patients received GLPG5101 at 1 of 3 dose levels: 50 × 10⁶ CAR T cells (dose level 1), 110 × 10⁶ CAR T cells (dose level 2) and 250 × 10⁶ CAR T cell (dose level 3). The first response assessment was conducted on day 28.

The primary end points in phase 1 were safety and determination of the recommended phase 2 dose (RP2D), and ORR served as the primary end point in phase 2. Key secondary end points included safety, efficacy, pharmacokinetics, pharmacodynamics, and the feasibility of decentralized manufacturing.

Notably, the RP2D in patients with FL, MZL, and MCL was dose level 2; this has yet to be determined in those with DLBCL, Kersten noted.

A total of 20 and 26 patients were screened in phase 1 and phase 2, respectively; 17 and 21 of patients in these respective cohorts underwent leukapheresis and comprised the intention-to-treat (ITT) population. All 17 patients in phase 1 subsequently received lymphodepleting chemotherapy, as did all but 1 patient in the phase 2 cohort.

In phase 1, patients were treated with GLPG5101 at dose levels less than 1 (n = 1), 1 (n = 7), or 2 (n = 9). The 16 patients who received dose levels 1 and 2 comprised the efficacy analysis set. In phase 2, 17 patients received GLPG5101 at the RP2D. These patients were considered the safety analysis set. Of those who were not treated with GLPG5101, 1 patient discontinued the study prior to receiving lymphodepleting chemotherapy due to disease progression, 2 did so prior to treatment with GLPG5101 due to toxicity (n = 1) and an inability to generate CAR T cells at dose level 1 (n = 1); and 1 patient was pending infusion at the time of analysis. Notably, 2 patients were not included in the phase 2 efficacy analysis set, as first response assessment data were not available at the time of data cutoff.

GLPG5101 was administered as a fresh product to 94% of patients. Three patients in phase 1 received dose level 1 instead of the planned dose level 2, and 1 patient in phase 2 was treated with GLPG5101 at less than the RP2D. The median vein-to-vein time was 7 days (range, 7-13), which eliminated the need for bridging therapy. Notably, 2 patients received a cryopreserved product with a vein-to-vein time of 13 days.

The median age of patients was 65 years (range, 25-77) across all dose levels in phase 1 and 67 years (range, 45-81) for the overall patient population in phase 2. Most patients in both phases were male (75% in phase 1; 53% in phase 2) and had stage III/IV disease (94%; 76%). Patients in both arms receive a median of 3 prior lines of therapy (range, 1-7; range, 2-11).

Regarding NHL subtype, 56% of patients in phase 1 had DLBCL, 19% had MCL, 19% had FL, and 6% had MZL. No patients in phase 2 had DLBCL, 24% had MCL, 71% had FL, and 6% had MZL. More patients in phase 2 had high-risk NHL (65%) than phase 1 (38%). The majority of patients in phase 2 had an ECOG performance status of 0 (47%) vs a status of 1 in phase 1 (56%).

Assessment of T-cell subsets showed an increased proportion of naive/stem cell memory and central memory T cells, which are early phenotypes of CD4-positive and CD8-positive CAR T cells, in the final CAR T product vs the apheresis starting material. The median proportion of CD4-positive early phenotypes was 23.7% in the starting material vs 44.3% in the final product. The corresponding proportion of CD8-positive cells was 12.8% vs 42.1, respectively.

“If you look at the pharmacokinetics, we saw a good expansion of the CARs…and there was not really a significant difference [in expansion] between the dose levels.” Kersten noted. At week 14 post-infusion, 73% of patients had detectable GLPG5101 in peripheral blood work and persisting CAR T cells were detected up to 12 months after infusion.

GLPG5101 displayed an acceptable safety profile, and no unexpected safety findings were observed. All patients in both phases experience a treatment-emergent adverse effect (TEAE) up to 14 weeks after infusion, and the majority of grade 3 or higher TEAEs were hematological (100% in phase 1; 82% in phase 2). Grade 3 or higher hematologic TEAEs included neutropenia (94%; 71%), anemia (38%; 6%), lymphopenia (31%; 18%), thrombocytopenia (25%; 24%), and leukopenia (38%; 29%). Other notable grade 3 or higher TEAEs that occurred in at least 2 patients were pyrexia (13%; 6%) and pleural effusion (13%; 0%).

All patients in phase 1 experienced a treatment-related AE vs 82% in phase 2. Serious TEAEs were experienced by 31% and 18% of patients in phase 1 and 2, respectively. No patients in phase 2 experienced a TEAE leading to death vs 6% of patients in phase 1.

“If you look at the AEs of specific interest, we mostly had only low-grade CRS…and overall, the risk of ICANS was very low.” Kersten added. The incidence of any-grade CRS was 44% in phase 1 and 29% in phase 2. ICANS was observed in 38% of patients in phase 1 and 6% of patients in phase 2.

Two cases of grade 3 CRS were observed in phase 1, and no cases were reported in phase 2. No cases of grade 3 ICANS were reported in phase 1, and 1 case of grade 3 ICANS was reported in phase 2. Regarding other AEs of special interest, both grade 3 or higher infections and any-grade hemophagocytic lymphohistiocytosis occurred in 6% of patients in phase 1, respectively, and no patients in phase 2. Most patients with prolonged cytopenia that was grade 3 or higher developed this AE 30 days after infusions (47% in phase 1; 36% in phase 2) vs 60 days after infusion (27%; 27%). Deaths during the phase 1 treatment period were caused by intra-abdominal hemorrhage (n = 1, dose level 2) or respiratory distress (n = 1, < dose level 1). Deaths after the phase 1 treatment period were caused by Escherichia sepsis (n = 1, dose level 2).

“At the moment, we are still enrolling in this study for the indolent lymphomas and MCL at dose level 2. We’re still 1 patient short for dose level 3 for the DLBCL cohort, but once the DLBCL [RP2D] is defined, we will also open cohorts for Burkitt lymphoma and PCNSL,” Kersten concluded.

References

1. Kersten, MJ, Saevels K, Servais S, et al. Seven-day vein-to-vein point-of-care manufactured CD19 CAR T cells (GLPG5101) in relapsed/refractory non-Hodgkin lymphoma: Results from the phase 1/2 Atalanta-1 trial. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S243.
2. Galapagos presents encouraging new data for CD19 CAR-T candidate GLPG5101 in non-Hodgkin lymphoma at EHA 2024. News release. Galápagos. June 14, 2024. Accessed July 3, 2024. https://www.glpg.com/press-releases/galapagos-presents-encouraging-new-data-for-cd19-car-t-candidate-glpg5101-in-non-hodgkin-lymphoma-at-eha-2024/