Zamto-Cel Induces Strong Responses in Relapsed or Refractory DLBCL

The tandem CD20/CD19-directed non-cryopreserved chimeric antigen receptor (CAR) T-cell product zamtocabtagene autoleucel (zamto-cel) induced a high rate of response in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to interim results from a pivotal, phase II study.

Results from DALY II USA (NCT04792489) were presented during the oral abstract session on myeloma and lymphoma at the Tandem Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR by Nirav N. Shah, MD, and showed that zamto-cel was well tolerated in patients.

“Dual targeting with CD20-CD19 may be a way to overcome one of the mechanisms of resistance we see with single targeted CD19 CAR T-cell therapy being antigen escape. Preclinical studies using this vector actually demonstrated, in high tumor–burden mice, that those treated with a dual CD20 CAR T-cell vector were able to clear the tumor without developing a relapsing population that was CD19 negative,” explained Dr. Shah, associate professor of Medicine at Medical College of Wisconsin, Division of Hematology and Oncology during his presentation.

The study evaluated 59 patients with relapsed or refractory DLBCL who made up the modified intention-to-treat population. Patients had a median age of 65 years (range, 25–85) and were predominantly male (68.1%), according to baseline characteristics. The majority of the population was White (82.6); 14.5% of patients identified as Asian, 1.4% identified as  Black, and 1.4% had an unknown racial identity.

Baseline disease characteristics showed that 55.1% of patients had elevated lactate dehydrogenase levels, 53.6% had two or more extranodal sites, and 75.4% had received at least two prior lines of therapy. In addition, 24.5% had received three or more prior lines of therapy. More than 24% of patients has previously undergone autologous stem cell transplantation. Bridging therapy consisted of a steroid for 4.3% of patients, and 1.4% had radiotherapy.

The objective response rate (ORR) to zamto-cel in the study was 72.8%, with 50.8% of patients having achieved a complete response and 22.0% having achieved a partial response; 5.1% of patients had stable disease. Progressive disease was observed in 20.3% of patients, and response was not evaluated in 1.7%. The median duration of response (DOR) was 11.4 months, and the median DOR among patients who achieved a complete response was not reached.

The median progression-free survival (PFS) observed was nine months with a 55% 6-month PFS. At the time of the interim analysis, the median overall survival was not reached.

In terms of safety, Shah and colleagues reported outcomes for the full analysis set of 69 patients. Results mainly revealed low-grade toxicity. Grade 1 cytokine release syndrome (CRS) occurred in 29.0% of patients, and grade 2 CRS was seen in 17.4%. Grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 7.2%, and grades 2 and 3 ICANS was observed in 5.8% and 4.3% of patients, respectively. Overall, 34 of the 69 patients required treatment for either CRS or ICANS.

“Importantly, we saw these variable outcomes without seeing any increase in toxicity compared to some of the CARs available now; with no grade 3 or higher cytokine release syndrome and grade 3 or higher ICANS in only 4% of patients,” said Shah, during his presentation.

DALY II USA investigators assessed the number of tumors with CD19, CD20, or both at the time of disease progression (n=27). Findings showed that 7% of patients had CD19 (<5%), 7% had CD20 (<5%), and 4% had CD19 and CD20 (<5%). Eighty-two percent of patients experienced no loss, and only one patient experienced dual antigen loss. These data suggest that antigen loss is not a driver of progression, according to Shah and colleagues.

 

Reference

Shah NN, Maziarz RT, Jacobson CA, et al. 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 # 43. Presented at Tandem Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 12-15, 2025; Honolulu, Hawai’i.