Zamtocabtagene autoleucel in relapsed/refractory B-NHL: 5-year follow-up of a CD20/19 tandem CAR T-cell phase 1 trial

Clinical Snapshot

Key Findings

• P Value: Not reported for primary outcomes

• Effect Size: Best overall response rate 75% (9/12 patients); complete remission rate 42% (5/12 patients)

• Primary Outcome: Maximum tolerated dose not reached; no dose-limiting toxicities observed

• Nnt Or Sensitivity: Complete remission rate 42% with durable responses up to 5 years; no relapses in CR patients during follow-up period

• Confidence Interval: Not reported

Clinical Application

Requires specialized CAR-T manufacturing and administration infrastructure; noncryopreserved approach may improve accessibility Relevant to Australian haematology-oncology practice; CAR-T therapies available through PBS for eligible patients; would require TGA approval and specialized treatment centers Highly selected patients with relapsed/refractory B-cell NHL who have failed standard therapies and are eligible for CAR-T cell therapy

Abstract

Emerging long-term data indicate relapse rates of >50% after CD19-redirected chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen, we conducted a first-in-human phase 1 clinical trial of zamtocabtagene autoleucel (zamto-cel), a noncryopreserved tandem CD20-CD19-directed CAR T-cell therapy. Two predefined dose levels (dose level 1 [DL1], 1 × 106 and DL2, 2.5 × 106 CAR+ T cells per kg bodyweight) were applied. The primary end point (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events, best overall response (BOR), and biomarker assessments. A total of 12 patients, 6 patients per DL, were treated. No dose-limiting toxicity and no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome of grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75%, with 5 of 12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with a higher mean maximum observed concentration of zamto-cel and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ central memory T cells in patients with CR, facilitating persistence and improved outcomes in R/R B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal phase 2 clinical trials for patients with R/R aggressive B-NHL. This trial was registered at www.ClinicalTrials.gov as NCT03870945.

References

1. 1.Balke-Want, H., Hyatt, G., Gödel, P., Schmid, C., Ayuk, F., Friedrichs, B., van Heteren, P., Holtkamp, S., Zadoyan, G., Brillant, C., Costa, J., Hanssens, L., Holzer, T., Wöhle, C., Biedermann, S., Bürger, I., Orentas, R., Overstijns, T., Scheid, C., Holtick, U., Miltenyi, S., Hallek, M., Borchmann, P., & Kutsch, N. (2026). Zamtocabtagene autoleucel in relapsed/refractory B-NHL: 5-year follow-up of a CD20/19 tandem CAR T-cell phase 1 trial. Blood Advances. https://doi.org/10.1182/bloodadvances.2025018073