Paper Details

ABSTRACT

Introduction:

Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive B-cell non-Hodgkin lymphoma. Although commercially available CD19-directed CAR T-cell therapies have improved outcomes for relapsed/refractory (r/r) DLBCL, prolonged manufacturing times in the context of rapidly progressive disease and target antigen loss remain ongoing challenges. Zamtocabtagene autoleucel (zamto-cel; MB-CART2019.1) is a tandem CD20/CD19-directed fresh CAR T-cell therapy designed to mitigate antigen escape while enabling rapid treatment through fresh product delivery and automated manufacturing. Zamto-cel is currently being evaluated in DALY II USA (NCT04792489), a multicenter, open-label, single-arm phase 2 study. Here, we report the primary efficacy and safety for patients (pts) with r/r DLBCL, including secondary central nervous system lymphoma (SCNSL).

Methods:

Adult pts with r/r DLBCL after ≥2 prior lines of therapy or SCNSL after ≥1 prior line of therapy, were eligible. Enrolled pts received a single dose of zamto-cel at 2.5 × 10⁶ CAR T cells/kg manufactured using the CliniMACS Prodigy® (Miltenyi Biotec) closed, automated platform with a 14-day vein-to-vein time. Unique to this product, lymphodepletion is initiated during manufacturing to facilitate the fresh infusion. The primary objective was objective response rate (ORR) based on best overall response; secondary objectives included safety and additional efficacy measures. Responses were assessed by an independent review committee (IRC) per Lugano 2014 classification.

Results:

As of the data cutoff, 110 pts had received a fresh, conforming dose of zamto-cel (104 DLBCL; 6 SCNSL). Among the total 134 leukapheresed pts, only 5 (3.7%) did not receive an infusion. Seven pts received out-of-specification product and 9 received cryopreserved product to allow for comorbidity management. All pts had at least 9 months of follow-up from CAR T-cell infusion, with a median follow-up of approximately 24 months.

The median age was 64.5 years (range, 25-85), and 37 pts (33.6%) were female.  Most pts received zamto-cel as 3L (74.5%), 18.2% as 4L, and 7.3% as >5L (ASCT not counted as a separate line of therapy); 26.4% of pts received prior ASCT. The study enrolled a high-risk population: 71.8% of pts were refractory to their most recent therapy, 53.6% had LDH >1x ULN, and 52% had ≥2 extranodal lesions. Bridging chemotherapy was not permitted on study. Consistent with the rapid 14-day vein-to-vein manufacturing time, only 15 pts (13.6%) required bridging treatment with corticosteroids and/or radiotherapy.

The ORR by IRC per Lugano 2014 criteria was 80.0% (88/110; 95% CI, 71-87), including a CR rate of 63.6% (70/110; 95% CI, 54-73); 16.4% of pts achieved a best response of PR and 14.5% had PD. Responses were durable, with median DOR not reached with an estimated 1-year DOR of 57%. Median PFS was 12.2 months (95% CI, 6-NE), with an estimated 1-year PFS of 52%; median OS was not reached, with an estimated 1-year OS 79%. Efficacy results were similar in all leukapheresed pts.

Overall, 45/110 pts (40.9%) had a serious adverse event (SAE), including 28 pts (25.5%) with a treatment-related SAE. There were no infusion-related reactions or T-cell malignancies. CRS occurred in 61 pts (55.5%), with only 1 gr ≥3 event (0.9%), and ICANS occurred in 18 pts (16.4%), including 2 gr ≥3 events (1.8%). Gr ≥3 infections occurred in 16.4% of pts, and gr ≥3 MAS/IEC-HS/HLH in 1.8%.

Among 42 pts with tumor biopsies available at disease progression, the majority maintained CD19 and CD20 expression relative to baseline. Loss of both CD19 and CD20 was observed in 2 tumors, while isolated loss of CD19 and CD20 occurred in 2 and 1 tumors, respectively. All others retained baseline target antigens.

Conclusion:

This primary analysis of the pivotal DALY II USA study represents the first completed phase 2 study of a tandem CD20/CD19-directed CAR T-cell therapy in aggressive B-cell lymphoma. With a median of 2 years of follow-up, we demonstrated that zamto-cel provides durable clinical benefit with a favorable safety profile in pts with r/r DLBCL and SCNSL who had received ≥2 prior lines of treatment. As a fresh infused CAR T-cell therapy, zamto-cel was administered with a short vein-to-vein time with a low leukapheresis-to-infusion attrition rate. The low frequency of dual CD19/CD20 antigen loss at relapse demonstrates a key advantage of dual-antigen targeting in an era of sequential targeted therapies.