A Phase 1 study of KITE-753 or KITE-363 in patients with relapsed/refractory B-cell lymphoma: Initial safety and preliminary efficacy of KITE-753 and updated results of KITE-363
Year: 2025
Type: conference-abstract
Abstract: Introduction: KITE-363 and KITE-753 are dual-targeting, autologous chimeric antigen receptor (CAR) T-cell therapies designed to overcome heterogeneity in CD19/CD20 tumor antigen expression and potentially prevent relapses due to antigen loss. They use the same bicistronic construct comprised of an anti-CD19 CAR with a CD28 co-stimulatory domain and an anti-CD20 CAR with a 4-1BB co-stimulatory domain. KITE-753 uses a rapid manufacturing process that reduces turnaround time and preserves a greater proportion of juvenile (naive and early memory) T cells in the product than KITE-363, which was associated preclinically with antitumor activity at a >25-fold lower dose (Murakami JL, et al. ASH 2024. Abstract 3481). Here we report the results from an open-label, multicenter, umbrella Phase 1 study of KITE-753 or KITE-363 in patients with relapsed/refractory (R/R) B-cell lymphoma. Initial safety and preliminary efficacy of KITE-753 and updated results of KITE-363 are described. Methods: Eligible adults with B-cell lymphoma R/R after ≥2 lines of therapy (patients with large B-cell lymphoma [LBCL] could have second-line primary refractory disease) were enrolled in dose escalation (1A) and expansion (1B; LBCL only) cohorts. Following leukapheresis and lymphodepletion, patients received dose level (DL) 1, 2, or 3 of KITE-753 (3.0×104, 1.0×105, or 2.0×105 CAR T cells/kg, respectively) or KITE-363 (0.5×106, 1×106, or 2×106 CAR T cells/kg, respectively). Primary endpoints were incidence of dose-limiting toxicities (DLTs; Phase 1A) and investigator-assessed objective response rate (ORR; per Lugano; Phase 1B). Results: As of 03/18/25, 59 patients were enrolled; 14 received KITE-753 (3 in DL1, 8 in DL2, 3 in DL3), and 37 received KITE-363 (3 in DL1, 8 in DL2, 26 in DL3). Median age of patients treated with KITE-753 at the time of analysis was 58.5 years (range, 25-84), 71% had LBCL and 29% had indolent non-Hodgkin lymphoma, 86% had Stage III/IV disease, 14% had bulky disease, 14% were primary refractory (20% in LBCL), and 43% had prior CAR T-cell exposure. Baseline characteristics of patients treated with KITE-363 were previously reported. No DLTs occurred with KITE-753 in dose escalation. Grade ≥3 adverse events (AEs) occurred in 79% of patients (100% in DL3), primarily cytopenias. Serious AEs occurred in 36% of patients (DL3, 0%). Grade 1/2 cytokine release syndrome (CRS) occurred in 3 patients. One Grade 3 CRS (LBCL; DL2) and no Grade 4/5 CRS occurred. Median onset of CRS was 9.5 days with median duration of 6.5 days. Two Grade 1/2 immune effector cell-associated neurotoxicity syndrome (ICANS; DL2) and no Grade ≥3 ICANS occurred. Median onset of ICANS was 12.5 days with median duration of 6.5 days. Three patients died (DL2; 2 due to infections determined by the investigator to be unrelated to KITE-753 [1 respiratory syncytial virus and 1 aspergillus, on days 213 and 23, respectively] and 1 due to progression). At 4.4-months median follow-up with KITE-753, all patients in DL3 had a complete response (CR; 2 CAR naive, 1 CAR exposed). In DL1/2 (n=11), ORR was 64% and CR rate was 45% (CAR naive [n=6]: ORR, 67%; CR rate, 67%). No DLTs or pausing criteria occurred with KITE-363 on study. Grade 3 CRS occurred in 1 patient; Grade 3 ICANS occurred in 3 patients; no Grade ≥4 CRS/ICANS occurred. At 11.1-months median follow-up with KITE-363 in DL3, ORR among CAR-naive patients (n=23) was 87% and CR rate was 78%; median duration of CR (DOCR) was not reached (95% CI, 5.2-not estimable) and the 6-month DOCR rate was 71.4%. Among all treated patients (N=37), 9 died (8 due to progression). Lymphodepletion was reduced and immune reconstitution was improved with KITE-363 compared to axicabtagene ciloleucel (axi-cel; Locke FL, et al. N Engl J Med. 2022). B-cell aplasia and recovery was comparable to axi-cel despite more pronounced CAR T-cell expansion. CAR T-cell expansion with KITE-753 was comparable to axi-cel even at a 10-fold lower dose. Conclusions: KITE-363 results showed high response rates with encouraging durability in DL3 and a manageable safety profile. KITE-753's rapid manufacturing process preserving a juvenile product phenotype, in addition to its bicistronic CAR design with dual co-stimulation, was associated with low incidence of CRS and ICANS, mostly Grade 1/2. The preliminary efficacy and safety profiles of KITE-753 DL3 appeared promising; the expansion phase with DL3 in LBCL (n=17) is ongoing and will be presented.
Source: Blood
Authors: Saurabh Dahiya, Matthew Ulrickson, Jean Yared, Patrick Reagan, Timothy Voorhees, Ran Reshef, Cameron Turtle, Lizamarie Bachier-Rodriguez, Marie José Kersten, Prof. Dr. Max S Topp, Gary Simmons, Robin Sanderson, Loretta Nastoupil, Scott Jung, Enrique Granados, Jinghui Dong, Joshua Winters, Rhine Shen, Justyna Kanska, Myrna Nahas, Sairah Ahmed
Institutions: Stanford Medicine, Stanford University, Banner MD Anderson Cancer Center, University of Maryland, Baltimore, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Rochester Medicine, University of Rochester, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbia University Irving Medical Center, Columbia University, The University of Sydney, Royal North Shore Hospital, Northside Hospital, Amsterdam University Medical Centers, Cancer Center Amsterdam, University of Amsterdam, Universitätsklinikum Würzburg, Virginia Oncology Associates, King's College Hospital, The University of Texas MD Anderson Cancer Center
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417011001