Treatment with JCAR017 demonstrated a complete response rate of 59% and an objective response rate of 86% for patients with relapsed or refractory diffuse large B-cell lymphoma.
Jeremy S. Abramson, MD
Treatment with JCAR017 demonstrated a complete response (CR) rate of 59% and an objective response rate (ORR) of 86% for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to updated findings from the core group of the phase I TRANSCEND study presented at the 2017 International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland.
In the study, the CD19-targeted CAR T-cell therapy JCAR017, which consists of a defined cell composition and 4-1BB costimulatory domain, was administered to 67 total patients at the May 4, 2017, data cutoff. The core group presented at ICML included those with de novo and transformed DLBCL and an ECOG performance status of 0 or 1 (n = 44). The core population is the focus of future pivotal studies for JCAR017.
In the core group, after 3 months of follow-up, the CR rate with JCAR017 was 50% (95% CI, 32%-68%) and the ORR was 66% (95% CI, 47%-81%). Ninety percent of those responding at 3 months continued to response at 6 months (9 of 10). Of those with any level of response (n = 38), 97% remained alive after a median follow up of 3.2 months. The median overall survival in the full population (which included those with ECOG 2 status) was 4.2 months.
"This is the first multicenter trial of a CD19-directed CAR T cell product with defined composition to deliver potent and durable responses in poor-prognosis subgroups of relapsed/refractory aggressive non-Hodgkin lymphoma," said lead investigator Jeremy S. Abramson, MD, from Massachusetts General Hospital Cancer Center. "A DLBCL pivotal cohort is planned to open later this year for the core patient population."
In the TRANSCEND study, patients underwent leukapheresis at study entry followed by manufacturing of JCAR017. Efforts are under way to bring the total manufacturing time from apheresis to delivery for JCAR017 to below 21 days, Abramson noted.
Across all evaluable patients (n = 55), the median age was 61 years, with 40% ≥65 years of age. Overall, 40 patients had de novo DLBCL (73%), 14 had transformed DLBCL (26%), and 1 patient had grade 3B follicular lymphoma (2%). Two patients had central nervous system (CNS) involvement. Seventy-six percent of patients were chemorefractory, and 27% had double or triple hit lymphoma. The median number of prior therapies was 3 (range, 1-11) and 49% of patients had received a prior stem cell transplant (allogeneic, 7%; autologous, 44%).
Across all doses in 54 evaluable patients, the ORR was 76%, with a CR rate of 52%. After 3 months of follow-up, the ORR was 51% (95% CI, 35%-67%) and the CR rate was 39% (95% CI, 24%-56%). In the 3-month assessment, ORRs were highest in poor risk subgroups, including patients with double/triple hit lymphoma, wherein the ORR was 81.8% (95% CI, 48.2%-97.7%). Those who relapsed less than 12 months after transplant had an ORR of 90.9% with JCAR017 (95% CI, 58.7%-99.8%).
In those evaluable in the DL2S group (n = 18), the ORR was 72% and the CR was 50%. After 3 months (n = 11), the ORR was 64% (95% CI, 31%-89%) and the CR rate was 46% (95% CI, 17%-77%). In the DL1S group (n = 30), the ORR was 80% and the CR was 53%. At 3 months (n = 24), the ORR was 46% (95% CI, 26%-67%) and the CR rate was 33% (95% CI, 16%-55%). In the DL1D group (n = 6), the ORR was 67% and the CR rate was 50%. After 3 months (n = 6), the ORR and CR rate were both 50% (95% CI, 12%-88%).
"Both patients with CNS involvement by lymphoma who were treated on study had complete resolution of their CNS disease," said Abramson. "One patient with progression after CR re-expanded CAR T cells following incisional biopsy and achieved a second CR without intervening therapy."
In the core assessment, the ORRs were 84%, 87%, and 100% and the CR rates were 59%, 56%, and 60% in the DL1S, DL2S, and DL1D groups, respectively. With ≥3 months of follow-up, the ORRs were 58%, 78%, and 75% and the CR rates were 42%, 56%, and 75%, in the DL1S, DL2S, and DL1D groups, respectively. "These early data suggest a dose-response relationship," noted Abramson.
All-grade treatment-emergent adverse events (TEAEs) were experienced by approximately 90% of patient. There were 2 deaths related to TEAEs in the study: one due to lymphoma progression and the other related to chemotherapy and JCAR017 on day 23 for a patient who refused mechanical ventilation for progressive respiratory failure.
Cytokine release syndrome (CRS) was primarily grade 1/2 (33%), with just 1 grade 3/4 event that occurred in the DL1S group. The median time to the onset of CRS was 5 days (range, 1-23). Neurotoxicity was grade 3/4 (16%) and grade 1/2 (6%) in severity, and the median time to onset was 11 days (range, 5-23). Overall, 40% of patients experienced CRS or neurotoxicity, of which 16% was severe. To treat these AEs, 11% of patients received tocilizumab and 24% received dexamethasone.
In the core population, 33% of patients had CRS or neurotoxicity. Grade 1/2 CRS was experienced by 27% of patients and the 1 grade 3/4 event fell within this group. Neurotoxicity in the core group was grade 1/2 (5%) and grade 3/4 (18%) in severity.
"JCAR017 toxicities have been manageable at all dose levels tested with a favorable safety profile that may enable outpatient administration," said Abramson. "Evaluation of outpatient administration is ongoing and planned in pivotal cohort."
The TRANSCEND trial continues to recruit patients with non-Hodgkin lymphoma, with a target enrollment of 274. Juno Therapeutics, the company developing JCAR017, expects the pivotal arm of the trial to open later this year. This portion with exclude those with ECOG performance status 2 and those with DLBCL transformed from chronic lymphocytic leukemia or marginal zone lymphoma. Those with primary mediastinal B-cell lymphoma will also be excluded from the pivotal study (NCT02631044).
Abramson JS, Palomba ML, Gordon LI, et al. High CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001). Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. Abstract 128. DOI: 10.1002/hon.2437_127.
Prior to CAR T cell infusion, patients received lymphodepleting fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days. A modified continual reassessment method was utilized to determine CAR T cell dose level (DL), to avoid potential adverse events (AEs). Two DLs were utilized: 5 x 107 cells (DL1) and 1 x 108 cells (DL2) either as a single-dose or double-dose. Thirty patients got single DL1 (DL1S), 6 got double DL1 (DL1D), and 19 patients received DL2 as a single dose (DL2S).