Liso-Cel Shows Potent, Durable Remissions in High-Risk DLBCL

Jeremy S. Abramson, MD, MMSc

Updated results from the TRANSCEND study demonstrated that liso-cel (lisocabtagene maraleucel), formally known as JCAR017, induced an 81% objective response rate (ORR) and a 63% complete remission (CR) rate in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

At the 3-month assessment for the dose being used in an ongoing pivotal trial for liso-cel, the ORR was 74% with a CR rate of 68% (95% CI, 43%-87%), according to the findings, which were presented at the 2017 ASH Annual Meeting. By month 6, the ORR and CR rates were both 50% in this group (95% CI, 23%-77%). There were comparatively low rates of severe cytokine release syndrome (CRS) and neurotoxicity in the trial, suggesting the potential for outpatient administration, according to lead investigator Jeremy S. Abramson, MD, MMSc.

"Lisocabtagene maraleucel, a CD19-directed CAR T cell product with a fixed defined composition, shows potent and durable remissions in high-risk diffuse large B-cell lymphoma," said Abramson, from the Massachusetts General Hospital Cancer Center. "The toxicity with liso-cell is overall manageable and low."

Liso-cel consists of a defined CD4 and CD8 composition and 4-1BB costimulatory domain. The defined composition allows administration of a precise dose, Abramson noted. At study entry, patients underwent leukapheresis followed by manufacturing of JCAR017. The expected time from apheresis to infusion was less than 3 weeks, he added, and the treatment was successfully manufactured for 98% of patients.

Prior to CAR T cell infusion, patients received lymphodepleting fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) daily for 3 days. In a dose findings portion of the study, 2 dose levels (DL) were utilized: 5 x 10⁷cells (DL1) as a single- or double-dose and liso-cel at 1 x 10⁸cells (DL2) as a single-dose. After the dose finding portion of the study, DL1 and DL2 as single infusions were further studied in a core assessment, with DL2 moving into the pivotal cohort focused on DLBCL.

Overall, 91 patients were enrolled in the full study, with 67 treated specifically in the core assessment. There were 40 patients treated with the dose selected for the pivotal cohort. Five patients were successfully treated in the outpatient setting.

In the core assessment, the median age of patients was 60 years (range, 20-82), with 36% ≥65 years of age. Two-thirds of patients (66%) were chemorefractory, and patients had received a median of 3 prior therapies (range, 1-8) with 51% having never achieved a CR to prior therapy. Forty-two percent of patients had received prior stem cell transplant. "Patients with prior allotransplant are not being included in the pivotal cohort," Abramson noted.

The most common B-cell subtype was DLBCL, NOS de novo (76%). The remainder of patients had DLBCL that was transformed from follicular lymphoma (tFL). Twenty-four percent of patients had double- or triple-hit lymphoma. The full study also included patients with marginal zone lymphoma (MZL), transformed chronic lymphocytic leukemia (tCLL), primary mediastinal B-cell lymphoma (PMBCL), and grade 3b follicular lymphoma (FL3B).

Efficacy data were available for 88 patients in the full trial. Across the full cohort, the ORR was 74% and the CR rate was 52%. At the 6-month analysis, the ORR was 35% and the CR rate was 31%. For those with DLBCL, NOS (n = 57), the ORR at 6 months was 35% and the CR rate was 32%. In the tFL group (n = 19), the 6-month ORR was 50% and the CR rate was 40%. In the non-core subgroup, those with tCLL and MZL (n = 10) did not respond to liso-cel.

In those with relapsed/refractory DLBCL regardless of B-cell subtype (n = 65), the best ORR was 80% and the CR rate was 55% across all doses. At 6 months, the ORR was 47% and the CR rate was 42%. In the DL1 group, the 6-month ORR and CR were 40% and 30%, respectively.

Responses to liso-cel were seen across all subgroups of DLBCL, particularly in those at high risk. Liso-cel elicited an ORR of 84.6% in those with double/triple hit lymphoma and an ORR of 84.6% in those who relapsed on stem cell transplant after <12 months. The ORR was 73.1% in patients who had never achieved a CR to prior therapy. Responses were similar between those who were chemosensitive and chemorefractory.

In the full cohort, the median duration of CR was 9.2 months and the median duration of ORR was 5.0 months. In the core study population, the median duration of CR was not yet reached. The median duration of ORR was 9.2 months. The duration of partial response was 2.1 months in each group.

"In those patients who were evaluable at 3 months in remission and then evaluable at 6 months we saw 80% of patients with a CR at 3 months continue to have a CR at 6 months," Abramson said. "In patients evaluable beyond 6 months, we see 92% of those patients in ongoing remission at the time of their last assessment."

For those achieving a CR, the median overall survival (OS) had not yet been reached. The 6-month OS rate in those achieving a CR was 92% in the full group and 94% in the core group. The 6-month OS rate in those with a partial remission (PR) was 75% and 81%, in the full and core groups, respectively. The median OS in those with a PR was 9 months.

"Overall survival compares favorably to historical controls for chemorefractory DLBCL," said Abramson. "In patients in the core group, at 1 year, overall survival was 73%."

Across the full study, 1 patient experienced severe CRS and 11 had severe neurotoxicity (12%). CRS of any grade was experienced by 35% of patients and 19% had neurotoxicity of any grade. Fifty-five patients (60%) did not experience CRS or neurotoxicity of any grade. The median time to onset of CRS was 5 days (range, 1-14) and for neurotoxicity it was 10 days (range, 3-23). Twelve percent of patients received tocilizumab and 16% received dexamethasone.

The 1 case of severe CRS was seen in the core study population at the DL1 dose. In this group, severe neurotoxicity was experienced by 15% of patients. In the DL2 group, the severe CRS and neurotoxicity rates were 0% and 7%. All-grade CRS and neurotoxicity was experienced by 36% and 21% of patients, respectively, in the core population. Overall, 58% of patients did not experience CRS or neurotoxicity.

Outside of CRS and neurotoxicity, the most common treatment-emergent adverse events (TEAEs) were neutropenia (49%), anemia (38%), fatigue (37%), thrombocytopenia (29%), nausea (27%), and diarrhea (25%).

"There were low rates of severe CRS and neurotoxicity, with only a single case of severe CRS," said Abramson. "Evaluation of outpatient administration is ongoing in the pivotal cohort."

The pivotal cohort of the TRANSCEND trial exploring DL2 of liso-cel is currently enrolling patients with DLBCL (NCT02631044). If positive, Juno Therapeutics, the company developing liso-cell plans to submit a biologics license application to the FDA. Based on earlier findings for the CAR T-cell therapy, liso-cel received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

Reference:

Abramson JS, Palomba ML, Gordon LI, et al. High Durable CR Rates in Relapsed/Refractory (R/R) Aggressive B-NHL Treated with the CD19-Directed CAR T Cell Product JCAR017 (TRANSCEND NHL 001): Defined Composition Allows for Dose-Finding and Definition of Pivotal Cohort. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 581.