Tandem CD20-CD19-Directed Non-Cryopreserved CAR T Cells - Zamtocabtagene Autoleucel (Zamto-Cel) in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma - Interim Results from a Phase 2 Pivotal Study (DALY II USA)

Abstract

Background

Zamto-cel is an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product for patients (pts) with relapsed/refractory diffuse large b cell lymphoma (r/r DLBCL) in the DALY II USA clinical trial (NCT04792489), a multicenter, open label, single-arm Phase 2 study. Here, we report efficacy and safety outcomes as part of a pre-planned interim analysis.

Methods

Eligible adults had r/r DLBCL after at least 2 prior lines of treatment and measurable disease per Lugano 2014 classification. Zamto-cel was manufactured utilizing CliniMACS Prodigy® (Miltenyi Biotec), a closed, automated system with a 14-day vein-to -vein time. The primary endpoint was overall response rate (ORR) defined as best overall response (BOR) of either complete response (CR) or partial response (PR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and CD19 and CD20 antigen expression at relapse.

Results

As of March 29, 2024, 69 pts received zamto-cel of which 59 were evaluable having received a fresh, conforming product and completed a minimum of 3 months follow-up. Median age was 63 years (range 25-85), 39 (66%) were male. The majority of pts presented with high risk factors including elevated LDH at study entry (53%), and 49% had ≥ 2 extranodal lesions. Successful manufacturing of a fresh, in specification product occurred in 91.3% out of 69 treated pts. No patient died or withdrew during the manufacturing process.

The ORR in the evaluable patient population (n=59) was 72.9% (95% CI, 59.7-83.6), with a CRR of 49.2% (95% CI,35.9-62.5). The 6 month and 12 month-PFS was 55% (95%CI, 41-67) and 42% (95%CI, 28-56), respectively; 12 month-OS was 72% (95%CI, 57-83) (Fig.1). The median DOR was 11.4 months (Fig. 2).

All 69 treated pts were assessed for safety outcomes. Thirty-two pts (46.4%) experienced cytokine release syndrome (CRS), all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12 pts (17.4%), grade 1-2 (9 pts; 13.1%); grade 3 (3 pts; 4.3%) (Fig.3). One patient experienced immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which resolved after 2 days.

Biopsies at progression were available in 24 pts. Only one patient experienced loss of both antigens compared to pre-treatment status, demonstrating maintenance of target antigen expression at relapse.

Conclusion

This pre-planned interim analysis represents the first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR-T cell product for patients with third-line r/r DLBCL. The results show encouraging activity and a favorable safety profile. Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time with a high manufacturing success rate.