Background: Single-antigen CD19-targeting chimeric antigen receptor (CAR) T-cell therapies have become a standard of care for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL), yet opportunity remains to improve outcomes. Rondecabtagene autoleucel (ronde-cel, LYL314) is an autologous, dual-targeting CD19/CD20 CAR T-cell product candidate manufactured from CD62L+ enriched naïve and central memory T cells. Ronde-cel is designed to maximize response regardless of baseline antigen heterogeneity, while reducing CAR T-cell exhaustion, enhancing T-cell persistence, and mitigating antigen loss. Here, we present updated data from the ongoing Phase 1/2 multi-center trial (NCT05826535) with a focus on patients with high-risk second-line (2L) LBCL, as well as extended follow up of patients treated in the third- or later-line (3L+) setting. Enrollment is ongoing and additional data will be available at the time of the conference.

Methods: Patients with R/R disease that was measurable prior to lymphodepletion (LD) were enrolled, patients treated in a 2L setting were required to have relapsed within 12 months of first-line therapy or had primary refractory disease. No baseline CD19 or CD20 antigen testing was required for enrollment and there was no upper age limit. Following a standard 3-day LD regimen of fludarabine and cyclophosphamide, patients received a single dose of ronde-cel, in the outpatient or inpatient setting, at the recommended Phase 2 dose (RP2D) of 100 x 106 CAR cells. The primary endpoint is overall response rate, and key secondary endpoints include CR rate, progression free survival and pharmacokinetics.

Results: As of June 27, 2025, 60 patients had received ronde-cel (23 2L; 37 3L+). Median age was 65 years (range 21-87), 65% (39/60) had ECOG status of 1, 40% (24/60) had an International Prognostic Index of ≥ 3 at time of enrollment, 55% (33/60) had Stage IV disease, 42% (25/60) had elevated lactate dehydrogenase (LDH) at baseline, and 55% (33/60) received bridging therapy. Median (IQR) baseline tumor burden (sum of target lesion product diameters) was 18.2 cm2 (6 - 42). In the 2L setting, 70% (16/23) of patients had primary refractory disease. Forty-six patients were response evaluable: 15 and 31 in the 2L and 3L+ settings, with median follow up of 7 and 10 months, respectively. Among patients in the 2L, the overall response rate was 87% (13/15) including a complete response rate of 60% (9/15), with 100% (7/7) of patients with complete response remaining in complete response at ≥ 6 months. Among the patients in 3L+, the overall response rate was 90% (28/31) and the complete response rate was 71% (22/31). Grade 1 or 2 cytokine release syndrome (CRS) was reported in 62% (37/60) patients, with no ≥ Grade 3 CRS, and 42% (25/60) of all patients receiving tocilizumab. Grade 1 or 2 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12% (7/60) of patients. Grade ≥ 3 ICANS was reported in 13% (8/60) of patients, including 7% (1/15) of patients after the introduction of routine dexamethasone prophylaxis, and resolved promptly with standard therapy (median time to < Grade 3 was 2.5 days). Grade 3 infections were reported in 13% (8/60) patients. There were no deaths on study related to ronde-cel.

Conclusions: Ronde-cel achieved high overall response and complete response rates with an encouraging safety profile in high-risk patients with LBCL in a Phase 1/2 multi-center trial. Complete responses were durable, including 100% CR at ≥ 6 months among patients treated in the 2L setting. A single-arm pivotal trial of ronde-cel is ongoing in patients treated in the 3L+ setting (PiNACLE), and a Phase 3 head-to-head, randomized controlled trial of ronde-cel versus investigator's choice of approved CD19 CAR T-cell therapy (lisocabtagene maraleucel or axicabtagene ciloautoleucel) has been initiated (PiNACLE-H2H).

This content is only available as a PDF.
2025
Sign in via your Institution