Durable Remissions With Liso-Cel in High-Risk DLBCL in Updated Findings from TRANSCEND Study

Jeremy S. Abramson, MD, MMSc

Durable complete remissions (CRs) were seen in 46% of patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with the chimeric antigen receptor (CAR) T-cell therapy, lisocabtagene maraleucel (JCAR017; liso-cel), at 6 months. These results come from the updated findings from the phase I, multicenter TRANSCEND trial that were presented at the 2018 ASCO Annual Meeting.

The ongoing objective response rate (ORR) was 49% (95% CI, 32%-66%) at the 6-month assessment for the dose used in an ongoing pivotal cohort, with a CR rate of 46% (95% CI, 30%-63%). Durable responses were seen across poor-risk DLBCL subgroups, particularly those with double- or triple-hit lymphoma (n = 16), where there wqs ab ORR with liso-cel of 62.5%. Additionally, patients on chemotherapy who relapsed within 12 months on stem cell transplant had an ORR of 53.3% with liso-cel.

Patients achieving a CR with the pivotal dose had a 12-month overall survival (OS) rate of 89% (95% CI, 72%-96%), with a median OS that was not yet reached. In those with a PR, the median OS was 10.3 months (95% CI, 6.8-not evaluable) and the 1-year OS rate was 33% (95% CI, 9%-60%).

"Lisocabtagene maraleucel, a CD19-directed CAR T-cell product with defined composition, induced durable responses in high-risk patients with relapsed/refractory aggressive non-Hodgkin lymphoma," said lead investigator Jeremy S. Abramson, MD, MMSc, from the Massachusetts General Hospital Cancer Center. "The overall survival findings are far superior to what we might anticipate with traditional therapies in this relapsed/refractory DLBCL population."

In a dose findings portion of the TRANSCEND 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. Additionally, prior to CAR T cell infusion, patients received lymphodepleting fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) daily for 3 days.

Liso-cel was successfully manufactured for 99% of patients. There were 102 evaluable patients enrolled in the full study, with 73 assessable in the core group. Of the core population, there were 51 patients treated with the dose selected for the pivotal cohort. Eight patients were successfully treated in the outpatient setting.

The median age of patients in the core group was 60 years (range, 20-82), with 33% ≥65 years of age. Seventy-three percent had DLBCL and 27% had DLBCL transformed from follicular lymphoma. Twenty-two percent had double- or triple-hit lymphoma. Two-thirds of patients (67%) were chemorefractory, and patients had received a median of 3 prior therapies (range, 2-8), with 49% having never achieved a CR to prior therapy. Thirty-eight percent of patients had received a prior autologous stem cell transplant. "Ninety percent of treated patients have at least 1 poor-risk disease feature predictive of short median OS," Abramson noted.

In the core population, 88% of those in a CR at 3 months continued to have a CR at 6 months. After a median of 8 months of follow-up, 93% of patients with a CR at 6 months continued to have an ongoing response. The median duration of response in those achieving a CR was not yet reached (95% CI, 10.2-not evaluable [NE]). Those with a PR had a median duration of response of 2.1 months (95% CI, 1.0-5.0).

"The duration of response curves flatten out after the 3-month point, in both the full and the core datasets," said Abramson.

Across the full study population, the most frequently occurring treatment-emergent adverse events were neutropenia (63%), anemia (53%), fatigue (46%), thrombocytopenia (34%), decreased appetite (29%), nausea (28%), hypotension (26%), cough (26%), headache (25%), dizziness (25%), constipation (25%), and diarrhea (25%).

"The most common adverse events, which occurred in the majority of subjects, were cytopenias. This is expected after fludarabine and cyclophosphamide for lymphodepleting therapy. This was followed by fatigue," said Abramson. "All other toxicities occurred only in a minority of subjects and are low grade, including cytokine release syndrome."

In the full trial across all dose levels, 37% of patients had grade 1/2 cytokine release syndrome (CRS). There was 1 grade 3/4 event (1%). Neurotoxicity of any grade occurred in 23% of patients. Serious neurotoxicity was experienced by 13% of patients, the remainder had a grade 1/2 event. Overall, 43% of patients had either neurotoxicity or CRS.

"We saw a low overall use of rescue medications, including 17% use of tocilizumab and 21% use of corticosteroids," said Abramson. "We see no difference in neurotoxicity or CRS between DL1 and DL2, supporting our decision to explore DL2 in the pivotal cohort."

The pivotal cohort of the TRANSCEND trial exploring DL2 of liso-cel has fully enrolled participants, Abramson noted. "We will continue to evaluate this product in the outpatient setting, including in the pivotal cohort," he added. "We look forward to presenting this data at a future meeting."

Reference:

Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL.J Clin Oncol.2018;36 (suppl; abstr 7505)

If positive, Juno Therapeutics, the company developing liso-cel, 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.