Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma

Rationale

Axicabtagene ciloleucel (axi-cel, KTE-C19) is made from the patient's own T cells, transduced with a retroviral vector that encodes a chimeric antigen receptor (CAR) against CD19, and given as one intravenous infusion of 2×10^6 CAR T cells/kg after three days of fludarabine and cyclophosphamide lymphodepletion. CD19 is expressed on normal and malignant B cells, including most large B-cell lymphomas. The CAR lets T cells recognize CD19 without HLA restriction, expand and kill lymphoma cells. Chemotherapy-refractory large B-cell lymphoma responds poorly to further chemotherapy, so a cytotoxic mechanism that does not depend on chemosensitivity was expected to produce responses.

Results

In the pivotal phase 2 cohorts of ZUMA-1 (refractory DLBCL, primary mediastinal B-cell lymphoma or transformed follicular lymphoma; 101 treated), axicabtagene ciloleucel produced an investigator-assessed objective response in 82% with 54% complete responses at the primary analysis, and in 84 of 101 (83%) with 59 (58%) complete responses at the 5-year analysis (data cut 11 August 2021, median follow-up 63.1 months). At 5 years, 31 of 101 patients had an ongoing response, median overall survival was 25.8 months and estimated 5-year overall survival was 42.6%. In these 101 patients, cytokine release syndrome (CRS) occurred in 93% (grade 3 or higher 11%) and neurologic events in 64% (grade 3 or higher 30%); 4 died of adverse events, 2 related to axi-cel. In phase 1, 1 of 6 DLT-evaluable patients had a dose-limiting toxicity. In the exploratory safety management cohorts 3 to 6 (posted results, final data cut), grade 3 or higher CRS occurred in 0% to 3% of patients and objective responses in 63% to 95%. No replication-competent retrovirus was detected in any of 277 treated participants.

• In adults with chemotherapy-refractory large B-cell lymphoma (diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma), a single infusion of axicabtagene ciloleucel (target 2×10^6 anti-CD19 CAR T cells/kg after fludarabine and cyclophosphamide) produced an investigator-assessed objective response in 84 of 101 treated patients (83%; 95% CI 74–90), including complete response in 59 (58%), in ZUMA-1 phase 2 cohorts 1 and 2 at both the 2-year (11 August 2018) and 5-year (11 August 2021) data cuts. (Locke 2018; Neelapu 2023)
• In 101 patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel in ZUMA-1 phase 2, with a median follow-up of 63.1 months, median overall survival was 25.8 months (95% CI 12.8–not estimable), estimated 5-year overall survival was 42.6% (64.4% among complete responders), estimated 5-year disease-specific survival was 51.0%, and 31 of 101 patients (31%) had an ongoing response at the data cut. (Neelapu 2023)
• In refractory large B-cell lymphoma treated with axicabtagene ciloleucel in ZUMA-1 phase 2 (n=101, median follow-up 63.1 months), the median duration of complete response was 62.2 months (59 complete responders), whereas the median duration of partial response was 1.9 months (25 partial responders). (Neelapu 2023)
• In 101 patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel in ZUMA-1 phase 2 cohorts 1 and 2, cytokine release syndrome occurred in 94 (93%), grade 3 or higher in 11 (11%), and neurologic events occurred in 65 (64%), grade 3 or higher in 30 (30%), at the 5-year analysis; 4 patients died of adverse events, 2 of them related to axi-cel (haemophagocytic lymphohistiocytosis and cardiac arrest, reported at the 2-year analysis). (Neelapu 2023; Locke 2018)
• In the ZUMA-1 phase 1 cohort of refractory large B-cell lymphoma, 1 of 6 DLT-evaluable patients given axicabtagene ciloleucel (target 2×10^6 anti-CD19 CAR T cells/kg after fludarabine and cyclophosphamide) had a dose-limiting toxicity within 30 days of infusion (ClinicalTrials.gov posted results). (Registry results)
• In 40 patients with relapsed or refractory large B-cell lymphoma in ZUMA-1 cohort 6 who received axicabtagene ciloleucel with prophylactic oral dexamethasone (10 mg on days 0–2), levetiracetam prophylaxis and earlier corticosteroid and tocilizumab intervention, cytokine release syndrome occurred in 80% with no grade 3 or higher events, neurologic events occurred in 58% (grade 3 or higher in 13%), and the objective and complete response rates were 95% and 80% at a median follow-up of 8.9 months (data cut 16 June 2020). In the ClinicalTrials.gov posted results at the final data cut (up to 4.1 years), grade 3 or higher neurologic toxicity in cohort 6 was 18%, including grade 5 in 5%. (Oluwole 2021)
• In 38 patients with relapsed or refractory large B-cell lymphoma in ZUMA-1 cohort 3 who received axicabtagene ciloleucel with prophylactic tocilizumab and levetiracetam, grade 3 or higher cytokine release syndrome occurred in 3% but grade 3 or higher neurologic toxicity occurred in 42%, compared with 11% and 30% in the 101 patients of pivotal cohorts 1 and 2 who did not receive prophylaxis (cohort 3 from ClinicalTrials.gov posted results at the final data cut; cohorts 1 and 2 from the 5-year analysis). (Neelapu 2023)
• In ZUMA-1 safety management cohorts of relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel, grade 3 or higher cytokine release syndrome and neurologic toxicity occurred in 2% and 17% of 41 patients in cohort 4 (levetiracetam prophylaxis with earlier corticosteroid and tocilizumab intervention) and in 2% and 12% of 50 patients in cohort 5 (debulking chemoimmunotherapy before axi-cel); investigator-assessed objective response rates were 76% and 72% (ClinicalTrials.gov posted results, final data cut). (Registry results)
• In 97 evaluable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel in ZUMA-1 phase 2, median peak blood CAR T-cell levels were 65.76 cells/µL in patients with an ongoing response at 60 months, 35.27 cells/µL in those who relapsed after responding and 12.08 cells/µL in non-responders; 21 of 23 evaluable patients in ongoing response at 3 years showed polyclonal B-cell recovery. (Neelapu 2023)
• No replication-competent retrovirus was detected in blood samples from any of 277 participants with refractory or relapsed large B-cell lymphoma treated with the retrovirally transduced CAR T-cell product axicabtagene ciloleucel across ZUMA-1 phase 1 and phase 2 cohorts 1 to 6, with follow-up of up to 7.7 years (ClinicalTrials.gov posted results). (Registry results)

Design implications

A single dose of autologous anti-CD19 CAR T cells after fludarabine-cyclophosphamide lymphodepletion can induce remissions lasting more than 5 years in chemotherapy-refractory large B-cell lymphoma. Complete responses were durable (median 62.2 months) while partial responses were brief (median 1.9 months), so depth of response is the efficacy signal to optimize. Durable remission did not require lasting B-cell aplasia: most patients in long-term response recovered polyclonal B cells. Patients with ongoing responses had higher early CAR T-cell expansion, which makes product fitness and expansion relative to tumor burden levers for improvement. CRS and neurologic toxicity are the main liabilities of this CD19 CAR T-cell product: prophylactic tocilizumab lowered severe CRS but not severe neurologic toxicity, while prophylactic dexamethasone with earlier corticosteroid and tocilizumab use removed grade 3 or higher CRS without an apparent loss of response.

Limitations

ZUMA-1 was single-arm and open-label with no concurrent control. The pivotal cohorts treated 101 patients; safety management cohorts 3 to 6 (38 to 50 each) were exploratory and not designed for comparison. No success criterion for the primary response endpoint was found in the sources read (the primary-analysis paper was available as abstract only). Disease assessments after 24 months followed institutional practice.