Updated phase 2 data presented at the 2024 ASH Annual Meeting highlight the promise of rapcabtagene autoleucel (YTB323), a CD19-directed CAR T-cell therapy, for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The study (NCT03960840) demonstrated high rates of complete remission and a favorable safety profile, offering a potential new treatment option for this challenging patient population.
High Response Rates and Durability
In the phase 2 study, 60 patients with DLBCL received rapcabtagene autoleucel at a dose of 12.5 x 106 CAR+ cells. The overall response rate (ORR) was 88.3% (95% CI, 77.4%-95.2%), with a complete remission (CR) rate of 65% (95% CI, 51.6%-76.9%). These responses proved durable, with 53.9% of patients continuing to respond at 12 months. Among those who achieved a CR, the 12-month duration of response rate was 69.1%.
"Rapcabtagene autoleucel was associated with responses including a CR in 65% at a median follow-up of 16 months. These responses are durable with 54% of responders still in response at the 12-month mark," said lead investigator Peter A. Riedell, MD, from the David and Etta Jonas Center for Cellular Therapy, University of Chicago.
Manufacturing and Patient Characteristics
Rapcabtagene autoleucel is manufactured using the T-Charge platform from Novartis, which allows for rapid cell manufacturing in less than 2 days. The median vein-to-door time was 13 days globally and 9 days within the United States. Prior to infusion, patients underwent lymphodepletion for 3 days using either a lower dose (25/250 mg/m2) or a higher dose (30/500 mg/m2) of fludarabine/cyclophosphamide. The median age of patients was 64 years, and 54% had an IPI score less than 3. A quarter of patients (25.4%) had double or triple hit mutations, and 58.7% were refractory to their last therapy.
Progression-Free and Overall Survival
At a median follow-up of 16 months, the median progression-free survival (PFS) was 11.9 months across all treated patients. For those who achieved a CR at month 3, the median PFS was not yet reached, and the 12-month PFS rate was 79.3%. The 12-month overall survival (OS) rate was 83.0% across all evaluable patients and 100% in those who achieved a CR at month 3.
Safety Profile
While 98.4% of patients experienced an adverse event (AE) of any grade, 84.1% experienced a grade 3 or higher event. Serious AEs were seen in 52.4% of patients. The rates of traditional CAR T AEs were low, with any-grade cytokine release syndrome (CRS) seen in 44.4% and grade 3 or 4 CRS in 6.4%. Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon, with 3.2% of patients having a grade 1/2 event and 4.8% experiencing a grade 3 or 4 event.
Lymphodepletion Dosage
Interestingly, lower incidences of CRS were observed in the low-dose lymphodepletion group compared to the higher-dose arm (39.3% vs 48.5%). However, ICANS was more common in the low-dose group (14.3% vs 3.0%). "Collectively, the risk analysis supports the use of lower dose of lymphodepletion therapy prior to infusion," Riedell noted.
Future Directions
This trial is ongoing to further evaluate the efficacy and safety of rapcabtagene autoleucel. Additionally, the therapy is being investigated in earlier lines of treatment, including a cohort of patients in the frontline setting who did not achieve a CR after two cycles of chemotherapy and rituximab-based treatment.
