Liso-Cel Elicits ORR of 97% in Relapsed/Refractory Follicular Lymphoma

A single administration of lisocabtagene maraleucel (Breyanzi; liso-cel) provided deep and durable remissions when used as third-line treatment in patients with relapsed or refractory follicular lymphoma, including those with high-risk features, according to data from the primary analysis of the phase 2 TRANSCEND FL trial (NCT04245839).¹

Data presented at the 17th International Conference on Malignant Lymphoma (ICML) showed that the CAR T-cell therapy elicited an objective response rate (ORR) of 97% (95% CI, 91.6%-99.4%) by independent review committee (IRC) with a complete response (CR) rate of 94% (95% CI, 87.5%-97.8%) in this population (n = 101), meeting the primary and key secondary end points of the trial. Notably, all patients who responded to treatment experienced a CR except for 3 patients, and ORRs were consistently high spanning the subgroups analyzed.

At a median follow-up of 16.6 months, the median duration of response (DOR) was not yet reached (NR; 95% CI, 18.0-NR) and the 12-month DOR rate 81.9% (standard error [SE], 3.99). At a median follow-up of 17.5 months, the median progression-free survival (PFS) with liso-cel was also NR (95% CI, 19.0-NR), with a 12-month PFS rate of 80.7% (SE, 3.99).

“Liso-cel demonstrated clinically meaningful benefit in patients with relapsed or refractory follicular lymphoma, supporting [the CAR T-cell therapy] as a potential new treatment option for these patients,” said Franck Morschhauser, MD, PhD, lead study author and professor of hematology at Hospital Claude Huriez, in Lille, France, said in a late-breaking presentation on the data.

Patients with relapsed or refractory follicular lymphoma who have previously received at least 2 lines of systemic therapy or those with high-risk disease who received 1 prior line of systemic treatment do not have a definitive standard of care available to them and thus, are known to have poor outcomes. Novel options such as liso-cel, an autologous, CD19-targeted, 4-1BB CAR T-cell therapy, are under exploration to address this unmet need.

The open-label, single-arm, multicohort, multicenter TRANSCEND trial enrolled patients with relapsed or refractory follicular lymphoma who were at least 18 years of age, who had an ECOG performance status of 0 or 1, and who had previously received an anti-CD20 antibody and alkylator combination. They also needed to have acceptable bone marrow, kidney, liver, and cardiac function. Notably, patients were divided into 3 cohorts: those in the second line (POD24 and/or GELF; 2L), those in the third line (3L), and those in the fourth or later line (4L+).

After the screening period, patients were enrolled to the trial and received leukapheresis. Bridging therapy was permitted while the CAR T-cell product was manufactured. Following reconfirmation of PET-positive disease, participants received a lymphodepletion regimen comprised of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 3 days. Two to 7 days following chemotherapy, liso-cel was administered at a target dose of 100 x 106 CAR+ T cells.

The primary end point of the trial was ORR with a best overall response of a CR or a partial response per IRC and by PET/CT leveraging Lugano 2014 criteria. Important secondary end points comprised CR rate, DOR, DOR if BOR is CR, and PFS by IRC and PET/CT using Lugano criteria, as well as overall survival, safety, cellular kinetics, and health-related quality of life. B-cell aplasia served as a key exploratory end point.

The study end points of ORR and CR rate were evaluated hierarchically with null hypotheses at 1-sided α = .025 significance: an ORR of up to 60% and a CR rate of up to 30% in the 3L cohort, as well as an ORR of up to 50% and a CR rate of up to 20% in the 4L+ cohort.

At the 2023 ICML, Morschhauser shared data specifically from the 3L cohort, which was referred to as the focused efficacy subset. A total of 114 of these patients underwent leukapheresis, and 107 received the CAR T-cell therapy. However, 6 patients were not evaluable for efficacy, and so 101 patients comprised the focused efficacy set.

The median age of the 107 patients in the 3L cohort who received liso-cel was 62 years (range, 23-80) and the majority were male (62%). “We had up to [25] patients with grade 3A follicular lymphoma, [88%] with advanced stage disease according to Ann Arbor, and in terms of prior lines [of therapy,] a median of 3 and up to 10,” Morschhauser noted. “The most salient high-risk feature was the [Met modified] GELF criteria [at most recent relapse] in 53% of patients. Sixty-four percent of patients had double-refractory disease and 54% had POD24.”

Additional data showed that in terms of cellular kinetics, liso-cel showcased rapid expansion, with median time to meet the maximum transgene level of around 10 days, Morschhauser said. Notably, persistence of liso-cel was observed up to 18 months after infusion in the 22 of 49 evaluable patients. Follow-up is ongoing, according to Morschhauser.

Seventy-six percent of patients had B-cell aplasia, defined as less than 3% CD19-positive B cells in the peripheral blood by flow cytometry, at baseline due to prior therapies. Morschhauser noted an increase in those with B-cell aplasia following the administration of liso-cel. “This reached 100% after liso-cel infusion, was maintained above 90% through month 3, then decreased at month 6, but remained constant through month 18, at around 63%,” he said.

Regarding safety, the most common treatment-emergent adverse effects (TEAEs) reported in at least 10% of patients in the 2L cohort who received liso cel (n = 130) were neutropenia (all grade, 65%; grade ≥3, 58%), cytokine release syndrome (CRS; 58%; 1%), anemia (38%; 10%), headache (29%; 0%), thrombocytopenia (25%; 10%), constipation (20%; 0%), pyrexia (18%; 0%), diarrhea (17%; 0%), lymphopenia (15%; 13%), fatigue (15%; 0%), tremor (14%; 0%), leukopenia (14%; 12%), and asthenia (12%; 0%).

Febrile neutropenia was observed in 6% of patients, and 25% of patients experienced serious TEAEs.

Of the 58% of patients who experienced CRS with the CAR T-cell therapy, 42% had a grade 1 event, 15% had a grade 2 event, and 1% had a grade 3 event. The median time to onset was 6 days (range, 1-17) and the median time to resolution was 3 days (range, 1-10). Fourteen percent of patients with CRS received tocilizumab (Actemra) and 12% received tocilizumab and corticosteroids.

Neurological events served as another toxicity of special interest. Of the 15% of patients who experienced this toxicity, 12% had a grade 1 event, 2% had a grade 2 event, and 2% had a grade 3 event. The median time to onset was 8.5 days (range, 4-16) and the median time to resolution was 3.5 days (range, 1-17). Six percent of patients with this toxicity received corticosteroids.

Prolonged cytopenia that was grade 3 or higher at day 29 was observed in 22% of patients; 90% of patients had recovery to grade 2 or lower neutropenia, 83% had recovery to grade 2 or lower anemia, and 58% had recovery to grade 2 or lower thrombocytopenia at day 90. Five percent of patients had grade 3 or higher infections, and 1 patient had macrophage activation syndrome (MAS). Moreover, 5% of patients had hypogammaglobulinemia and 3% had second primary malignancy in the form of acute myeloid leukemia (n = 2), rectal cancer (n = 1), and colon adenocarcinoma (n = 1).

One patient who underwent leukapheresis died before CAR T infusion due to respiratory failure; this was not determined to be related to study treatment. Twelve deaths occurred after infusion; 4 were due to disease progression, 1 due to grade 5 MAS, 1 due to progressive multifocal leukoencephalopathy (PML) which occurred after the 90-day treatment-emergent period, and 2 due to a new malignancy of AML after the 90-day period. The remaining 4 deaths were due to heart failure (n = 1), COVID-19 (n = 2), and erythema multiforme (n = 1).

Only 2 deaths were considered to potentially be related to liso-cel: the grade 5 MAS and the PML that occurred following the 90-day treatment-emergent period, according to Morschhauser.

Editor’s Note: Morschhauser disclosed consultancy fees received from AbbVie, Bristol Myers Squibb, Genmad, Gilead, Norvartis, and Roche. He served on the Data and Safety Monitoring Board or advisory board for AbbVie, AstraZeneca, Gilead, and Roche, and he received honoraria from Chugai and Roche.

Reference

Morschhauser F, Dahita S, Palomba ML, et al. TRANSCEND FL: Phase 2 study results of lisocabtagene maraleucel (liso-cel) in patietns (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). Hematol Oncol. 2023;41(suppl 2):877-880. doi:10.1002/hon.3196_LBA4