Liso-Cel Demonstrates Safety, Efficacy in MCL Cohort

Michael Wang, MD

Michael Wang, MD

Lisocabtagene maraleucel (liso-cel; JCAR017) demonstrated a promising response rate and an acceptable toxicity profile in the TRANSCEND NHL 001 trial in a cohort of patients with relapsed or refractory mantle cell lymphoma (MCL).¹

According to results presented in a poster at the 2019 ASCO Annual Meeting, the objective response rate (ORR) in the MCL cohort was 71%, which consisted of a complete response (CR) rate of 53%. Seven of these 9 CRs were ongoing as of data cutoff.

“In the ongoing TRANSCEND NHL 001 study, treatment of patients with relapsed/refractory mantle cell lymphoma receiving both dose levels of liso-cel was associated with tolerable toxicity, including a low incidence of grade 3 or 4 cytokine release syndrome and neurotoxicity,” the study authors, led by Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, wrote in their poster. “Liso-cel showed promising clinical activity in patients with relapsed/refractory mantle cell lymphoma.”

The ongoing, open-label TRANSCEND NHL 001 trial (NCT02631044) is a phase I trial exploring the safety and efficacy of the anti-CD19, 4-1BB—containing chimeric antigen receptor (CAR) T-cell therapy in adult patients with relapsed/refractory B-cell non-Hodgkin lymphomas.

In the MCL cohort, patients were eligible to enroll in the trial if they had received ≥1 line of prior therapy, had an ECOG performance status of 0-2, and had confirmed cyclin D1 expression or evidence of transformation (11;14). Prior stem cell transplant was allowed and patients were eligible for enrollment even if they had secondary central nervous system (CNS) involvement.

Patients received lymphodepletion of 30 mg/m²of fludarabine and 300 mg/m²of cyclophosphamide for 3 days before receiving liso-cel. Twenty-five patients were enrolled and underwent leukapheresis for liso-cel manufacturing. Seventeen patients received the liso-cell product and were evaluable for safety. Liso-cel was given at one of 2 doses: 50 × 10⁶CAR-positive T cells (n = 6), or 100 × 10⁶CAR-positive T cells (n = 11).

Of note, 1 additional patient received a nonconforming liso-cel product with reduced CD8-positive CAR-positive T cell viability at the lower dose and was not included in the safety and efficacy analyses.

Across the 2 dose levels, the median age was 66 years (range, 53-80) and three-fourths of the patients were male. The patients had received a median of 4 prior lines of therapy (range, 1-8), which included prior ibrutinib (Imbruvica) in 94% of patients and venetoclax (Venclexta) in 12%.

The majority of patients had a poor risk factor, including blastoid variant in 4 patients,TP53mutation in 1, and a Ki-67 level >30% in 13 patients. Ten patients received a bridging chemotherapy while waiting for the liso-cel product.

In the patients who received the lower dose of liso-cel, the ORR was 67%, which consisted of 2 CRs (33%). The median time to CR was 3.6 months (range, 1-6.3). At a median follow-up for 18.0 months, the median progression-free survival (PFS) in patients receiving the lower dose was 2.6 months (range, 0.7-18.2+) and the median overall survival (OS) was 10.9 months (range, 1.2-18.2+).

Patients receiving the higher dose of liso-cel demonstrated an ORR of 73%, consisting of a CR rate of 64%. The median time to CR was 0.9 months (range, 0.9-4.9). The median PFS with the higher dose was 5.8 months (range, 0.4-6.0+) and the median OS was not reached (range, 0.4-9.2+) after a median follow-up of 6.2 months.

Overall, the median PFS was 5.8 months (range, 0.4-18.2+) and the median OS was 11.1 months (range, 0.4-18.2+).

The median duration of response has not yet been reached (range, 1.0-16.2+), but patients receiving the lower dose maintained their response through day 545, the time of data cutoff.

Of the 5 patients who did not respond to treatment with liso-cel, 1 had secondary CNS involvement but this patient had stable disease as of day 29.

Treatment-emergent adverse events (TEAEs) were observed in all 17 patients, and 13 patients experienced a grade 3/4 TEAE (76%). Serious TEAEs were observed in 10 patients (59%) and a grade 5 TEAE was observed in 1 patient, who had a dose-limiting toxicity of tumor lysis syndrome. This patient refused intubation and later died. One other patient experienced grade 5 diffuse alveolar damage, but the investigators did not consider this to be related to treatment with liso-cel.

The most common grade 3/4 TEAEs included thrombocytopenia in 6 patients at the higher dose and 1 at the lower dose (41% total), anemia in 4 patients at the higher dose and 2 at the lower (35% total), and neutropenia in 4 patients at the higher dose level and 2 at the lower dose level (35% total).

Cytokine release syndrome (CRS) occurred in 7 patients (41%), 6 of which were receiving the higher dose level of the CAR T-cell product, and 1 patient in the higher dose level had grade 3/4 CRS. The median time to onset of CRS was 7 days (range, 2-10) and the median time to resolution was 4 days (range, 2-8).

Neurotoxicity was observed in 3 patients (18%) receiving the higher dose level of liso-cel, and 2 of these events were grade 3/4. The median time to onset was 9 days (range, 7-25) and the median time to resolution was 3 days (range, 1-3). Three patients received tocilizumab (Actemra) and corticosteroids. The median maximum concentration (C_max) at the lower dose level was 9790 copies/µg and was 24,400 copies/µg at the higher dose level. Wang et al noted that the increased cell expansion at the higher dose level might have been associated with the increased CRS and neurotoxicity seen in the patients who received the higher dose, yet they stressed that this observation was based on a small number of patients.

Reference:

Wang M, Gordon LI, Palomba ML, et al. Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001.J Clin Oncol. 2019;37(suppl; abstr 7516). https://meetinglibrary.asco.org/record/174890/abstract.