The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ASH Annual Meeting 2024. Below is a recap of highlighted research presented from Dec. 7–9, 2024.
2024 Scientific Highlights
Safety and efficacy of Meta10-19, an IL-10 expressing CD19 CAR T-cell therapy for relapsed or refractory B-cell malignancies
92. IL-10 Expressing CD19 CAR-T Cells Induce Complete Remission and Improve Long-Term Protection in Relapsed or Refractory B-Cell Hematological Malignancies
Yongxian Hu (Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China) reported data on the first-in-human trial of Meta10-19, an IL-10 expressing CD19 CAR T-cell therapy for relapsed or refractory B-cell malignancies. This single-center, open label phase I trial (NCT06277011) enrolled 10 patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and 10 patients with r/r B-cell acute lymphoblastic leukemia (B-ALL). Primary outcomes were evaluation of safety and tumor response rate (ORR), while secondary outcomes were assessment of pharmacokinetic/pharmacodynamic (PK/PD) profile, and IL-10 levels. Patients with r/r DLBCL were dosed with 0.2 – 1.0 x 105 cells/kg and patients with r/r B-ALL were dosed with 1.0 – 2.0 x 105 cels/kg. Of patients with r/r DLBCL, 2 (20%) had central nervous system infiltration, and 9 patients (90%) had stage III or IV disease. In the r/r B-ALL population, 1 patient (10%) had prior allogenic stem cell transplantation, and 1 (10%) had extramedullary disease. At time of data cut-off (median follow-up of 7.65 months), all patients had achieved complete response (CR) with median time to best response of 0.9 months (range, 0.5–3). All patients experienced cytokine release syndrome (CRS), with most being grade 1–2 and only 1 patient with r/r B-ALL experiencing grade 3 CRS. There was no incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) in the r/r DLBCL population, and one patient with r/r B-ALL that exhibited grade 1 ICANS. Prolonged grade 3– 4 cytopenia was seen in 50%–70% of patients with r/r DLBCL and 30%–40% of patients with r/r B-ALL. The CAR T-cells expanded well in both patient populations, reaching the expansion peak about 12 days after infusion. Preliminary results of lower dosing (0.1% – 1% of commercial product) showed similar expansion and efficacy in a small number (n = 6) of patients with r/r DLBCL. These promising responses and manageable safety profile following treatment with Meta10-19 provide support for continued investigation of this IL-10 expressing CD19 CAR T therapy in larger cohorts of patients with B-cell malignancies.
Fresh, stem-like, early memory CD19 CAR T-cell therapy for relapsed/refractory non-Hodgkin lymphoma: updated analysis of the ATALANTA-1 trial
93. 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
Marie Jose Kersten (Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands) presented an updated analysis of ATALANTA-1 (CTIS: 2022-502661-23-00), a phase (Ph) 1/2 trial investigating safety and efficacy of GLPG5101, a fresh, stem-like, early memory phenotype CD19 CAR T-cell therapy with a 7-day vein-to-vein time, in patients with relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL). The study enrolled patients 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. The primary objectives of Ph1 were safety and determination of appropriate dose for Ph2, while the primary objective of Ph2 was efficacy, determined by overall response rate (ORR). Secondary objectives were safety, duration of response, minimal residual disease (MRD), pharmacokinetics, and feasibility of decentralized manufacturing. Of the 53 patients that had received leukapheresis, 49 were infused; two patients received a cryopreserved product, and 2 patients received less than the prespecified minimum dose so these patients were not included in the safety/efficacy analysis. A 7-day vein-to-vein time was achieved in 43/47 (91%) of the patients. Most patients had an intermediate or high international prognostic index score, 50%–100% of patients had stage III–IV disease across the dose level cohorts, and median number of prior therapies was 2–3. Cytokine release syndrome (CRS) occurred in 9/20 (45%) patients in Ph1 (grade ≤2 n=8; grade 3 n=1) and 10/25 (40%) patients in Ph2 (all grade ≤ 2). Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was experienced by 30% of patients in Ph1 and 12% of patients in Ph2, with 1 grade 3 event in Ph2. Prolonged cytopenias grade ≥ 3 were seen in 37% of patients in Ph1 and 36% of patients in Ph2. There were 3 adverse event-related deaths in Ph1 due to intra-abdominal hemorrhage, respiratory distress, or sepsis. At median follow-up of 13.0 months in Ph1 and 5.4 months in Ph2, pooled analysis of Ph1/2 revealed ORR of 100% for MCL, 95% for FL/MZL, and 69% in DLBCL. Of responding patients across Ph1/2, 32/37 (86%) had an ongoing response at the time of last assessment. In evaluable patients that achieved complete response, 12/15 (80%) were MRD-negative. Expansion of GLPG5101 in vivo was similar across all three dose levels in Ph1, with 15/18 (83%) patients having detectable GLPG5101 in peripheral blood at 6 months post-infusion. These results indicate robust clinical activity and a mild toxicity profile of a stem-like, early memory CD19 CAR T-cell therapy which can be manufactured reliably with a decentralized platform and 7-day vein-to-vein time, providing support for further clinical studies in the United States.
Safety and efficacy of a phase 1 study investigating a 4-1BB CAR T-cell product manufactured within 24 hours for the treatment of relapsed/refractory non-Hodgkin lymphoma
94. Phase I Study Results of UF-Kure19, a CAR-T Product Manufactured in Less Than 1 Day, in Patients with Relapsed/Refractory Non-Hodgkin’s Lymphoma
David Wald (Kure.ai and Case Western Reserve University, Cleaveland, OH, USA) highlighted data from a single-arm, multi-center phase 1 study (NCT05400109) evaluating the safety and efficacy of UF-Kure19, a second-generation 4-1BB CD19 CAR T-cell therapy for the treatment of relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL). This study implemented an ultra-fast CAR (UF-CAR) workflow that activated T-cells from a peripheral blood mononuclear cell (PBMC) sample and transferred the target gene into these T-cells directly, without the need for T cell isolation or ex vivo expansion, allowing for < 24 hour manufacturing of naïve, early memory T-cells. This study enrolled 10 patients with CD19+ r/r NHL with a primary objective of safety/tolerability and secondary objectives of efficacy (overall response rate [ORR], complete response [CR], and duration of response). Patients had a median age of 64.5 years and received a median of 1.5 prior lines of therapy. All patients received a single dose of UF-Kure19 (17.5 x 106 CAR T-cells) that was manufactured in less than one day, meeting all prespecified release criteria. At a median follow-up of 6 months, the ORR was 80% (8/10) with all 8 responders achieving CR. Complete remission was sustained in all responding patients by data cutoff. Cytokine release syndrome occurred in 20% (2/10) of patients (all grade ≤ 2), with one grade 3 neurotoxicity event that was resolved in 1 day. Delayed expansion and long-term persistence of the CAR T-cells was seen in many of the patients, with a peak expansion time of 21 days (range 6–30 days) and all responding patients exhibiting CAR T-cells that measured greater than 1% of all circulating T cells at a median of 90 days post-infusion. B-cell aplasia was reported in all samples tested at day 30 or longer post-infusion with a median sample measurement of 90 days post-infusion. These preliminary clinical data provide strong evidence for naïve/early memory CAR T-cells manufactured from a PBMC-based UF-CAR method to elicit deep responses in patients with r/r NHL, with a more manageable and mild safety profile than traditional CD19 CAR T-cell products.
2-year follow-up analysis of arm 2 of the EPCORE NHL-2 trial, evaluating fixed-duration epcoritamab + R2 in relapsed or refractory follicular lymphoma
342. Fixed-Duration Epcoritamab + R2 Drives Deep and Durable Responses in Patients with Relapsed or Refractory Follicular Lymphoma: 2-Year Follow-up from Arm 2 of the Epcore NHL-2 Trial
Lorenzo Falchi (Memorial Sloan Kettering Cancer Center, New York, NY, USA) reported 2-year follow-up data, including initial analysis of minimal residual disease (MRD) status, from arm 2 of the EPCORE NHL-2 trial (NCT04663347), a phase 1b/2 trial investigating the safety and efficacy of fixed-duration epcoritamab with rituximab + lenalidomide (R2) in patients with relapsed or refractory (r/r) CD20+ follicular lymphoma (FL). The primary endpoint was overall response rate (ORR) with secondary endpoints including other efficacy measurements, such as complete response (CR) rate, duration of response (DOR), and MRD analysis. A total of 111 patients with r/r FL were enrolled and received subcutaneous epcoritamab + R2 for 12 cycles (Cs; 28 d each). A total of 68/111 (61%) patients had stage IV disease, 65/111 (59%) had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3–5, 39/111 (35%) had primary refractory and/or double refractory disease, and median number of prior lines of therapy was 1. After a median follow-up of 25.3 months (range, 2.4+ to 34.1), 53/111 (48%) of patients discontinued treatment, with 14/111 (13%) attributed to COVID-19 infection. The ORR was 96% and CR rate was 87%, which was comparable across risk-status and refractoriness. Out of 75 patients that were MRD-evaluable, 66/75 (88%) were MRD-negative. At 21-month follow up, DOR was 78% and progression-free survival was 80%. In patients that were MRD-negative, PFS at 21-month follow-up was 86% relative to 44% in patients that were non-MRD-negative. Median overall survival (OS) was not reached for any risk category, with the overall population exhibiting a 90% OS rate at 25 months. No new safety signals were reported, with neutropenia as the most common treatment-related adverse event (62% of patients; 21% grade 3; 32% grade 4). A total of 47/111 (51%) of patients experienced cytokine release syndrome (CRS), mostly grade ≤ 2 with 2/111 (2%) of patients with grade 3. These results highlight deep and durable responses to epcoritamab + R2 in patients with r/r FL, which is bolstered by MRD-negativity in 88% of evaluable patients. With promising efficacy and no new safety concerns, these data support further investigation into the ongoing, randomized, phase 3 EPCORE FL-1 trial (NCT05409066).
Long-term follow-up and MRD analysis of arm 1 of the EPCORE NHL-2 study investigating safety and efficacy outcomes of epcoritamab + R-CHOP as first line treatment in DLBCL
581. Fixed-Duration Epcoritamab + R-CHOP Induces High Complete Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma With High-Risk Features: Long-Term Results from the Epcore NHL-2 Trial
Lorenzo Falchi (Memorial Sloan Kettering Cancer Center, New York, NY, USA) discussed long-term results from arm 1 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), evaluating the safety and efficacy of combining fixed-duration epcoritamab with standard treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first line treatment of patients with CD20+ diffuse large B-cell lymphoma (DLBCL) and International Prognostic Index (IPI) score of 3 or higher. The primary endpoint of this study was overall response rate (ORR) with secondary endpoints including other efficacy measurements, such as complete response (CR) rate, duration of response (DOR), and minimal residual disease (MRD) analysis. A total of 47 patients with CD20+ DLBCL were enrolled and received subcutaneous epcoritamab (QW in cycles 1–4; Q3W in cycles 5–6) + R-CHOP for 6 cycles (21 d each) followed by epcoritamab monotherapy Q4W in 28‑d cycles for up to 1 year. Of the patients with evaluable tissue (n=28), 6 (21%) had double-hit/triple-hit DLBCL and 16 (34%) had bulky disease. At median follow-up of 27.4 months, the ORR was 100% among evaluable patients (n=46), with a CR rate of 87%. Out of the patients that completed R-CHOP, ORR was 100% and 40/44 (91%) achieved CR. Sub-group analysis revealed similar response rates to the general population, regardless of IPI score, double-hit/triple-hit disease status, or bulky disease status. Among patients that completed treatment, 30/32 (94%) remained in CR as of last response assessment. In patients that were MRD-evaluable, 30/33 (91%) achieved MRD-negativity, with 25/30 achieving MRD-negativity by cycle 3. Estimates of 21-month duration of complete response and progression-free survival were 83% and 82% respectively. The 24-month estimated overall survival was 87%. No new safety signals were observed, with neutropenia being the most common treatment-emergent adverse event (TEAE) (70% of patients; 66% grade 3–4). Incidence of cytokine release syndrome was reported in 60% of patients, with 2 grade 3 cases (4%) and no grade 4 or 5. There were 2 grade 5 TEAEs attributed to COVID-19 infection and septic shock. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2/47 (4%) of patients, both grade ≤ 2 that resolved in a median time of 2.5 days. Fixed-duration epcoritamab + R-CHOP showed long-term response and high-rates of MRD clearance in the first-line treatment of patients with DLBCL, which compare favorably with R-CHOP alone, supporting the ongoing investigation of epcoritamab + R-CHOP in a phase 3 trial of first line DLBCL treatment (NCT05578976).
Addition of blinatumomab to standard chemotherapy significantly improves disease-free survival in pediatric patients with standard risk B-cell acute lymphoblastic leukemia
1. Blinatumomab Added to Chemotherapy Improves Disease-Free Survival in Newly Diagnosed NCI Standard Risk Pediatric B-Acute Lymphoblastic Leukemia: Results from the Randomized Children’s Oncology Group Study AALL1731
Rachel E. Rau (Seattle Children’s Hospital, University of Washington, Seattle, WA, USA) presented the first interim results from AALL1731 (NCT03914625), a phase 3 trial studying the addition of 2 non-sequential cycles of blinatumomab to chemotherapy in children with NCI standard risk (SR) B-cell acute lymphoblastic leukemia (B-ALL). After standard 3-drug induction, 4236 eligible patients (age 1–10, BCR::ABL1 negative, no testicular or CNS3 disease) were categorized to 3 risk groups (SR-Favorable, SR-Avg, and SR-High) based on tumor genetics, central nervous system (CNS) status, and minimal residual disease (MRD) at induction and end of induction (EOI). SR-Avg patients with undetectable EOI bone marrow MRD were assigned to standard-intensity chemotherapy alone; all other SR-Avg patients were included in randomization. SR-High patients received augmented BFM-based chemotherapy and only those with BM MRD < 0.1% at the end of consolidation were included in randomization. This study randomized (1:1) 1440 children with B-ALL and SR-Avg/SR-High disease to receive either chemotherapy alone or blinatumomab plus chemotherapy. The primary endpoint was disease-free survival (DFS). 722 patients were randomized to control Arms A (418 SR-Avg) and C (304 SR-High), and 718 to blinatumomab Arms B (417 SR-Avg) and D (301 SR-High). At median follow-up of 2.5 years, the estimated 3-year DFS was 96% for patients in the blinatumomab arms and 87.9% in the patients receiving chemotherapy alone (HR=0.39; 95%CI 0.24 to 0.64; 1-sided p<0.0001). Estimated 3-year DFS in SR-Avg patients was 97.5% for Arm B and 90.2% in Arm A (HR=0.33; 95%CI 0.15 to 0.69). Among SR-High patients, estimated 3-year DFS was 94.1% for Arm D and 84.8% for Arm C (HR=0.45, 95%CI 0.24-0.85). The risk of relapse was lower in the blinatumomab containing regimens relative to the standard chemotherapy arms in the overall cohort analysis (p<0.0001), and both the SR-Avg patients (p=0.002) and the SR-High patients (p=0.002). Post-hoc sub-group analysis indicated similar results across males/females, most racial/ethnic subsets, all cytogenetic risk groups, and EOI MRD status. There was low incidence of grade ≥ 3 cytokine release syndrome (CRS) (0.3% of patients) and seizure (0.7% of patients) in patients receiving blinatumomab. Grade ≥ 3 sepsis/catheter related infections in the SR-Avg group were significantly higher in the blinatumomab cohort with most events occurring in the chemotherapy portion of treatment. These data support the use of blinatumomab plus chemotherapy as the standard-of-care for pediatric patients with newly diagnosed SR-Avg/SR-High B-ALL, with implications for improved outcomes in NCI high risk patients as well.
β-Hydroxybutyrate, a key metabolite of a ketogenic diet, improves CAR T-cell function and tumor control in preclinical models
4. Ketogenic Diet Enhances CAR T Cell Antitumor Function Via β-Hydroxybutyrate
Shan Liu (Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA) leveraged various mouse models, in vitro cell culture, and metabolomics to show that a ketogenic diet improves CAR T-cell function and proliferation, driven by the metabolite β-hydroxybutyrate (BHB). In this study, immunocompetent mice (Balb/c) inoculated with diffuse large B-cell lymphoma (DLBCL) tumors were fed one of 5 experimental diets (ketogenic, high-fiber, high-fat, high-protein, Western) or a nutrient-matched control diet, followed by anti-CD19 CAR T-cell infusion. The ketogenic diet resulted in improved tumor control relative to all other diets. Incubation of serum from mice that were fed the ketogenic diet with CAR T-cells resulted in greater in vitro proliferation of CAR T-cells relative to serum from the control diet, with metabolomic analysis of the serum samples revealing significantly elevated levels of BHB in ketogenic-fed mice. Supplementation of BHB in vitro with CAR T-cells resulted in a similar increased proliferation seen with serum from mice fed the ketogenic diet. In a similar model, mice fed a control diet with BHB supplementation and mice fed a ketogenic diet saw similar improvements to tumor control and increases in cytokine secretion (IL-2, IFN-γ) relative to the control diet alone, however, these results were not seen in mice that did not receive CAR T-cell therapy. In a xenograft NSG mouse model inoculated with OCI-Ly18 cells, mice were randomized to receive CAR T-cell treatment or no treatment, both groups with or without BHB. BHB supplementation showed significant tumor control only when mice were treated with CAR T-cells, accompanied by significant CAR T-cell expansion and IFN-γ release relative to the other treatment groups. Using carbon-13 isotope labeling and analysis of cellular respiration, BHB was found to be preferentially metabolized into the citric acid cycle over glucose, with oxidative phosphorylation significantly increased in CAR T-cells treated with BHB. Mass spectrometric analysis of serum from patients (n=17) with large B-cell lymphoma treated with anti-CD19 CAR T-cells showed a positive correlation (R2=0.3272; p=0.0164) between BHB concentration and CAR T-cell expansion. These results highlight a key metabolite associated with a ketogenic diet, BHB, that induces potent CAR T-cell expansion and anti-tumor activity in preclinical models, with modified metabolic activity the likely driver of responses.
Response to blinatumomab in pediatric B-ALL is associated with elevated TCL1A before and during treatment
634. TCL1A Is Associated with Blinatumomab Response and Immune Activation in Pediatric B-ALL
Andrew Hughes (Children’s Hospital of Philadelphia, Philadelphia, PA, USA) uncovered a fascinating association between high T-cell leukemia/lymphoma protein 1A (TCL1A) protein expression before/during treatment and response to blinatumomab in pediatric patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) treated with blinatumomab and chemotherapy in the phase 3 AALL1331 trial. Proteomic analysis of pre-infusion bone marrow (BM) plasma in 16 responders (R) and 11 non-responders (NR) revealed an increase in TCL1A levels in R vs NR (p=0.023) which was more pronounced in patients entering the trial with a late marrow relapse (initial remission of ≥36 months) (p=3.4E-5). During treatment, peripheral blood (PB) plasma also showed higher TCL1A levels in R relative to NR that was most significant at 24-hours post-infusion (p<0.001). Protein and mRNA expression at 24 hours post-infusion in PB plasma showed significantly increased (p<0.01) levels of pro-inflammatory cytokines (CXCL9, IL-2, IL-2RA) and decreased expression of CTLA-4 in R compared to NR. There was also no correlation (R=0.16; p=0.24) between level of pre-infusion TCL1A and disease burden, indicating elevated levels of TCL1A were not due to increased B-ALL blasts. Preliminary single cell RNA sequencing with a few patients indicated that TCL1A was expressed in early B-cell clusters, but not B-cell blasts. These findings provide strong evidence in support of TCL1A as a predictive biomarker of response to blinatumomab, which may also be playing a role in the mechanism that drives blinatumomab activity.
Brexucabtagene autoleucel safety and efficacy in relapsed or refractory mantle cell lymphoma naïve to bruton tyrosine kinase inhibitors
748. Primary Analysis of ZUMA-2 Cohort 3: Brexucabtagene Autoleucel (Brexu-Cel) in Patients (Pts) with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Who Were Naive to Bruton Tyrosine Kinase Inhibitors (BTKi)
Tom van Meerten (Department of Hematology, University of Groningen, Groningen, Netherlands) presented the primary data analysis of cohort 3 from the ZUMA-2 trial (NCT02601313), a phase 2 study evaluating the safety and efficacy of brexucabtagene autoleucel (brexu-cel) in patients with Bruton tyrosine kinase inhibitor (BTKi)-naïve, relapsed or refractory (r/r) mantle cell lymphoma (MCL). The primary endpoint was overall response rate (ORR) with secondary endpoints of safety and additional efficacy signals, including progression-free survival (PFS), overall survival (OS), and duration of response (DOR). A total of 95 patients were enrolled in cohort 3, with 86 receiving an infusion of brexu-cel (2 x 106 cells/kg) representing the safety and efficacy analysis population. Of the 86 patients that received treatment, 73% had high or intermediate simplified MIPI (sMIPI) score, 52% had extranodal disease, 45% had a TP53 mutation, and 47% had Ki-67 ≥ 30%. All patients had received prior anti-CD20 therapy, 79% had previous anthracycline exposure, and 48% had prior autologous stem cell transplantation. At a median follow-up of 15.5 months, the ORR was 91% with 73% achieving complete response (CR). Similar ORR was seen across key sub-group analyses, including patients with TP53 mutations (100%), Ki67 scores ≥ 50% (94%), intermediate or high-risk sMIPI score (89%), and prior bendamustine treatment (83%). The median DOR and PFS were 26 months and 27.1 months respectively. The 12-month DOR, PFS, and OS rates were 80%, 75%, and 90% respectively. The most common grade ≥ 3 adverse event was neutropenia (43% of patients). Cytokine release syndrome (CRS) occurred in most patients (95%) with 6% experiencing grade ≥ 3. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade occurred in 66% of patients, with 21% of grade ≥ 3. At time of data cut-off, 13 patients (15%) had died, due to treatment related adverse events (n=4), non-treatment related adverse events (n=3), disease progression (n=5), and other causes (n=1). CAR T-cell expansion was not related to the severity of CRS (p=0.8649), but was greater in patients experiencing grade ≥ 3 ICANS (p=0.013). PFS was also improved in patients that had a greater than median percentage of naïve T-cells in the product prior to infusion (p=0.0031). These data indicate strong response and survival rates for patients with r/r MCL naïve to BTKi that was seen across many subgroup analyses, including TP53 mutation, supporting further investigation and longer follow-up.
Long-term follow-up of a phase 2 trial investigating fixed-duration glofitamab for relapsed or refractory large b-cell lymphoma
865. Fixed-Duration Glofitamab Monotherapy Continues to Demonstrate Durable Responses in Patients with Relapsed or Refractory Large B-Cell Lymphoma: 3-Year Follow-up from a Pivotal Phase II Study
Michael J. Dickinson (Royal Melbourne Hospital and The University of Melbourne, Melbourne, VIC, Australia) reported 3-year follow-up data from a pivotal phase 2 trial (NCT03075696) investigating fixed-duration glofitamab monotherapy for patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL). The primary endpoint was complete response (CR) rate with secondary endpoints including other efficacy signals such as progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and duration of response/complete response (DOR/DOCR). A total of 155 patients were enrolled with 154 receiving at least one dose of glofitamab. A total of 75.3% had stage III/IV disease, 89.6% were refractory to any prior therapy, 33.1% had prior CAR T-cell therapy with 29.9% refractory to prior CAR T-cell therapy, and the median number of prior lines of therapy was 3. With a median time on study of 41.0 months, the complete response (CR) rate was 40% and ORR was 52%. At a median follow-up of 37.7 months, the median DOCR was 29.8 months, and 56.4% of responders remained in remission at 24 months. Landmark analysis of patients with CR at cycle 3 revealed a median PFS of 31.1 months and median OS of 44.8 months. The 24-month PFS rate and OS rate were 57.3% and 77.2%, respectively, in the analysis of patients with CR at the end of treatment (EOT). The median PFS and OS were not reached in this EOT analysis. In patients that achieved CR at EOT and were evaluable for circulating tumor DNA (ctDNA), 55% had undetectable ctDNA at EOT and 72% were undetectable during follow-up after EOT. B-cell aplasia occurred in all patients during treatment that was recovered 12-18 months afterward. There were no new occurrences of cytokine release syndrome, infections, immune effector cell-associated neurotoxicity syndrome, or fatal adverse events that were reported since the last analysis. Two new grade ≥ 3 adverse events were reported, including neutropenia (grade 3) and adenocarcinoma of the pancreas (grade 4). The long-term responses of glofitamab monotherapy, supported by ctDNA analysis, and immune system recovery seen in this 3-year follow-up support the potential for long-lasting remission and survival for patients with r/r LBCL treated with fixed-duration glofitamab.
Primary analysis of odronextamab monotherapy in patients with diffuse large B-cell lymphoma after prior CAR T-cell therapy
866. Efficacy and Safety of Odronextamab Monotherapy in Patients (Pts) with Diffuse Large B-Cell Lymphoma (DLBCL) Progressing after CAR T-Cell Therapy: Primary Analysis from the ELM-1 Study
Matthew Matasar (Division of Blood Disorders, Rutgers Cancer Institute and RWJ Barnabas Health, New Brunswick, NJ, USA) highlighted the primary analysis from the phase 1 ELM-1 (NCT02290951) dose expansion cohort that assessed safety and efficacy of odronextamab monotherapy, a CD20xCD3 bispecific T-cell engager, in diffuse large B-cell lymphoma (DLBCL) progressing after prior CAR T-cell therapy. The primary endpoint was overall response rate (ORR) with secondary endpoints including duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. To note, no specific prior CAR T constructs warranted ineligibility for enrollment. A total of 60 patients were enrolled, with a median of 3 prior lines of therapy (LoT); 58.3% were primary refractory, 76.7% were refractory to most recent LoT, and 71.7% received CAR T-cell treatment as the most recent LoT. At a median follow-up of 16.2 months, the ORR was 48% and complete response (CR) rate was 32%. The median DOR was 14.8 months and median duration of complete response was not reached. Response rates (ORR) for patients that had relapsed more than 180 days after CAR T-cell therapy were above 80%, however the ORR was lower for those with relapse between 91–180 days (63.6%) and ≤ 90 days (20.7%). A similar trend was seen for CR rates. The median PFS and OS were 4.8 months and 10.2 months respectively, which were not reached for patients that achieved CR. A total of 51.7% of patients experienced a grade ≥ 3 treatment related adverse event (TRAE), though only 8.3% of patients discontinued treatment due to TRAEs. Two grade 5 events occurred due to COVID-19 pneumonia and a brain herniation associated with hyperammonemia. Cytokine release syndrome occurred in 48.3% of patients (all grade ≤ 2) and no cases of immune effector cell-associated neurotoxicity syndrome were observed. Infections were common, with 50% of patients experiencing an infection of any grade (20% grade ≥ 3). Rates of grade ≥ 3 infection within 90 days from the first dose were positively associated with CAR-HT score. Odronextamab showed a promising safety profile and good response in this early phase trial of patients with DLBCL progressing after prior CAR T-cell therapy, where outcomes remain poor.
Results from a first-in-human trial of a novel T-cell engager, AZD0486, for patients with relapsed or refractory diffuse large B-cell lymphoma
868. Evaluation of AZD0486, a Novel CD19xCD3 T-Cell Engager, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma in an Ongoing First-in-Human Phase 1 Study: High Complete Responses Seen in CAR-T–Naive and CAR-T–Exposed Patients
Sameh Gaballa (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA) discussed data from the ongoing first-in-human phase 1 dose-escalation trial (NCT04594642) of AZD0486 monotherapy, a novel CD19xCD3 bispecific T-cell engager, in patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). AZD0486 was designed with a low affinity CD3 binding domain and silenced Fc portion to limit toxicity and minimize immunologic reactions, respectively. Eligible patients had r/r CD19+ B-NHL that was r/r to ≥ 2 lines of therapy (LoT), with prior anti-CD19 treatment not exclusionary. Primary end-points included safety/tolerability, pharmacokinetics, maximum tolerable dose, and recommended phase 2 dose. Secondary endpoints included anti-tumor activity signals. Of the 58 patients enrolled, 52% had ≥ 4 prior lines of therapy, 34% were primary refractory, and 59% received prior CD19-directed CAR T treatment. In this analysis, 55/58 patients enrolled received AZD0486 at target doses of 2.4 mg (n=18), 7.2 mg (n=19), and 15 mg (n=18). Overall response rates (ORR) were dose-dependent in the overall population, with the highest response seen in the 15 mg group (50%) and lower responses in the 7.2 mg (47%) and 2.4 mg (39%) doses. A similar trend was seen with complete response (CR) rates: 39% for the 15 mg dose, 42% for the 7.2 mg dose, and 22% for the 2.4 mg dose. When stratified according to prior CAR T-cell therapy exposure (n=22 CAR T naïve; n=33 CAR T exposed), the CR rate in the 15 mg dose group was 38% for CAR T naïve and 40% for CAR T exposed. At a median study follow-up of 5 months, no patients who achieved CR had progressed and 92% of evaluable patients (11/12) were minimal residual disease (MRD)-negative. A total of 50% of patients discontinued treatment due to disease progression. The most common grade ≥ 3 treatment emergent adverse event was neutropenia (19%). Of the patients that received double-step-up dosing (n=42), cytokine release syndrome (CRS) occurred in 43% of patients (all grade 1), and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 19% of patients (14% grade ≤ 2; 5% grade 3), with most CRS and ICANS events occurring in cycle 1 of the step-up dosing. This first-in-human trial of a novel bispecific T-cell engager, AZD0486, revealed minimal toxicity early on in dosing, with higher response rates in higher dose cohorts. These data support further investigation of AZD0486 safety and efficacy in patients with r/r B-NHL
MRD-negativity associated with higher survival outcomes in patients with relapsed or refractory B-cell acute lymphoblastic leukemia receiving obecabtagene autoleucel in the FELIX trial
963. Obecabtagene autoleucel (obe-cel) for Adult Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL): Deep Molecular Remission May Predict Better Outcomes
Elias Jabbour (University of Texas MD Anderson Cancer Center, Houston, TX, USA) reported on the association between minimal residual disease (MRD)-negativity and response/survival outcomes in patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) receiving obecabtagene autoleucel (obe-cel) in the phase 1b/2 FELIX trial (NCT04404660). At median follow-up of 21.5 months, the 12-month event-free survival (EFS) and overall survival (OS) rates were 50% and 61% respectively. A total of 68/127 patients infused with obe-cel were evaluable for MRD status (MRD-negative threshold of < 10-6 leukemic cells) from bone marrow (BM) biopsy and represented the study population in this analysis. Of these patients, 57/68 (84%) were MRD-negative post-infusion. The proportions of patients with Philadelphia chromosome-positivity and prior allogenic stem cell transplantation were higher in patients that achieved MRD-negativity (33.3% and 49.1% respectively) than those that did not (18.2% and 9.1% respectively). Conversely, the proportion of patients with extramedullary disease and the median BM blast percentage at lymphodepletion was lower in patients with MRD-negativity (12.3% and 30% respectively) than those with detectable MRD (27.3% and 58% respectively). At median follow-up of 21.5 months, median EFS and OS were longer in patients that were MRD-negative (17.9 months and not estimable [NE], respectively) than those that were MRD-positive (4.5 months and 8.9 months, respectively). A total of 70% of patients that were MRD-negative are still alive at current follow-up. The proportion of patients achieving MRD-negativity to those who did not was higher at lower tumor burden (<5% BM blast percentage at lymphodepletion) than higher tumor burden (>75% BM blast percentage at lymphodepletion). A similar trend was seen with EFS and OS, with patients having lower tumor burden resulting in longer median EFS and OS than those with higher tumor burden (median EFS: NE vs. 11.9 months; median OS: NE vs. 17.1 months). This data highlights the potential for deep molecular remission to predict better outcomes for patients with r/r B-ALL receiving obe-cel.
Anitocabtagene autoleucel demonstrated manageable safety and promising outcomes in patients with triple- and penta-refractory multiple myeloma in the preliminary analysis of IMMagine-1
1031. Phase 2 Registrational Study of Anitocabtagene Autoleucel for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma: Preliminary Results from the IMMagine-1 Trial
Ciara Louise Freeman (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA) revealed preliminary data from the IMMagine-1 trial (NCT05396885), a single-arm, phase 2 study of anitocabtagene autoleucel (anito-cel) treatment, an anti-BCMA CAR T-cell with a novel D-domain binder, for patients with relapsed or refractory (r/r) multiple myeloma (MM). Eligible patients included those with triple-class-exposed r/r MM that had received ≥ 3 prior lines of therapy (LoT), and were refractory to the most recent LoT. The primary endpoint was overall response rate (ORR) with secondary endpoints of stringent complete response/complete response (sCR/CR) rate and ORR in patients limited to 3 prior LoT. Of the 117 patients that received an infusion of anito-cel, 98 were evaluable for safety (≥1 month of follow-up) and 86 were evaluable for efficacy (≥2 months follow-up) at data cutoff. Of the efficacy-evaluable population, 15% had extramedullary disease, 38% had high-risk cytogenics, 43% were penta-refractory, and 100% were refractory to the last LoT. At a median follow-up of 9.5 months, the ORR was 97% with sCR/CR rate of 62%. Of the 58 patients evaluable for minimal residual disease status (MRD), MRD-negativity was achieved in 93.1% of patients. The 12-month progression-free survival and overall survival estimates were 78.5% and 96.5%, respectively. In the safety-evaluable population, a total of 83% of patients experienced cytokine release syndrome (CRS) with most grade ≤ 2 (81%). There was one grade 5 CRS event, in a 76-year old patient who had rapidly progressive disease between screening and baseline and did not receive bridging therapy. The incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was 9% (8% grade ≤ 2; 1% grade 3). There were no reports of any non-ICANS delayed neurotoxicity, including cranial nerve palsies, Parkinsonism, polyneuropathy, or Guillain-Barré syndrome. The most common grade ≥ 3 treatment-emergent adverse event (TEAE) was cytopenia (54% neutropenia, 22% anemia, 20% thrombocytopenia). There were three deaths due to TEAEs attributed to CRS, fungal infection, and retroperitoneal hemorrhage secondary to biopsy complication. In this study, anito-cel demonstrated manageable safety and strong responses that led to promising survival rates in patients with high-risk r/r MM, including triple- and penta-refractory disease. These results support continued investigation of anito-cel in the global phase 3 randomized trial, IMMagine-3 (NCT06413498), enrolling patients with r/r MM after 1–3 LoT, including an anti-CD38 monoclonal antibody and an immunomodulatory drug.