Liso-Cel Elicits Clinically Meaningful Activity in Heavily Pretreated, Relapsed/Refractory MCL

In a post-hoc subgroup analysis that looked at the number of previous lines of systemic therapy and response to prior BTK inhibitors, treatment with lisocabtagene maraleucel (liso-cel; Breyanzi) demonstrated clinically meaningful activity across all subgroups of patients with heavily pretreated, relapsed/refractory mantle cell lymphoma (MCL), according to data from the MCL cohort of the phase 1 TRANSCEND NHL 001 trial (NCT02631044) presented at the 2024 ASCO Annual Meeting.

Within the efficacy-analysis set (n = 83), the overall response rates (ORR) were 83% (95% CI, 72.7%-90.2%), 86% (95% CI, 68.3%-96.1%), and 81% (95% CI, 60.6%-93.4%) in patients treated with 2 or more prior lines (n = 81), 3 to 4 prior lines (n = 29), and 5 to 11 prior lines (n = 26), respectively. Regarding complete response (CR), the respective rates were 72% (95% CI, 60.5%-81.1%), 72% (95% CI, 52.8%-87.3%), and 65% (95% CI, 44.3%-82.8%).

Regarding those evaluated for response to prior BTK inhibitors (n = 80), the ORR was 91% (95% CI, 76.9%-98.2%) in those who were not refractory (n = 35) and 76% (95% CI, 60.5%-87.1%) in those who were refractory (n = 45). The respective CR rates were 80% (95% CI, 63.1%-91.6%) and 64% (48.8%-78.1%).

In a presentation of the data, it was noted that 2 patients were efficacy-evaluable among the 3 patients who had received 1 prior line of therapy; both patients achieved CR with a duration of response (DOR) of 16.8 and more than 23.3 months, the latter of which was ongoing at the time of study completion, respectively.

“Longer median DOR, progression-free survival [PFS], and overall survival [OS] were observed in patients with relapsed/refractory MCL who received [less than] 5 prior lines of therapy and those with disease not refractory to prior BTKi, supporting the use of liso-cel in earlier lines of therapy,” M. Lia Palomba, MD, a hematologist-oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, stated in the presentation.

To enroll in the MCL cohort of TRANSEND NHL 001, participants at least 18 years or older had to have PET-positive MCL with a confirmed tissue diagnosis; have undergone at least 2 prior lines of systemic therapy, including a BTK inhibitor, an alkylating agent, and a CD20-targeted agent; have an ECOG performance status of 0 or 1; and have adequate bone marrow, organ, and cardiac function. Secondary central nervous system lymphoma or prior autologous or allogeneic hematopoietic stem cell transplant was permitted.

Following leukapheresis and optional bridging therapy liso-cel was manufactured after which PET-positive disease was reconfirmed. Following this, patients underwent lymphodepletion during which they received fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) for 3 days. Liso-cel was then administered 2 to 7 days after fludarabine and cyclophosphamide, on day 1, followed by the first disease assessment on day 29. Patients were followed for 24 months on study as well as in a separate long-term follow-up study (NCT03435796) lasting up to 15 years after the last liso-cel infusion.

Two doses of liso-cel were initially evaluated: 50 x 106 CAR+ T cells and 100 x 106 CAR+ T cells, the latter of which was determined to be the recommended dose for dose expansion.

The primary end points of the study were safety and ORR as evaluated by an independent review committee. Secondary end points included CR, DOR, PFS, OS, and cellular kinetics.

Within the overall patient population (n = 88) 69% of patients had refractory disease, 28% had chemotherapy-refractory disease, and 53% were refractory to any BTK inhibitor. The best response to any prior therapy in this group included an 81% CR rate, 14% partial response (PR) rate, 2% stable disease (SD) rate, and 3% progressive disease (PD) rate. The median time from diagnosis to liso-cel infusion was 63.75 months (range, 3.9-299.5).

For the present analysis patients in the efficacy-analysis set were split into groups by number of prior lines of therapy (≥ 2; 3-4; and 5-11) and response to prior BTK inhibitors (not refractory to any BTK inhibitor vs refractory to any BTK inhibitor).

Palomba reported that although the median DOR, PFS, and OS were consistent with the overall population across most subgroups they were numerically lower in patients with 5 or more prior lines of systemic therapy and those refractory to prior BTK inhibitors.

In the overall population, the median DOR, PFS, and OS were 15.7 months (95% CI, 6.2-24.0), 15.3 months (95% CI, 6.6-24.9), and 18.2 months (95% CI, 12.9-36.3), respectively. When evaluating by number of prior lines of therapies, these numbers were 14.5 months (95% CI, 5.7-not reached [NR]), 12.3 months (95% CI, 12.3-NR), and 17.1 months (95% CI, 11.1-36.3) in the 2 or more prior therapies group; 17.5 months (95% CI, 3.3-NR), 16.6 months (95% CI, 2.6-NR), and 18.4 months (95% CI, 6.7-NR) in the 3 to 4 prior therapies group; and 6.7 months (95% CI, 2.4-15.8), 7.4 (95% CI, 3.3-12.3), and 13.5 months (95% CI, 9.5-17.1) in the 5 to 11 prior therapies group.

Regarding patients who were not refractory to prior BTK inhibition, the median DOR, PFS, and OS were 24.0 months (95% CI, 7.6-NR), 24.0 months (95% CI, 8.6-NR), and 36.3 months (95% CI, 15.3-NR), respectively. Among patients who were refractory to prior BTK inhibition, the respective median DOR, PFS, and OS were 5.3 months (95% CI, 2.3-15.8), 6.1 months (95% CI, 3.1-16.5), and 11.1 months (95% CI, 6.1-17.1).

Regarding safety, the incidences of grade 3 or higher treatment-emergent adverse effects (TEAEs) across subgroups were generally consistent with the overall population; however, there were numerically higher incidences of some cytopenias in patients with 5 or more prior lines of systemic therapy.

In the overall population, 86% of patients experienced grade 3 or greater TEAEs. When evaluating by number of prior lines of therapy, 87% of patients with 2 or more prior lines, 84% of patients with 3 to 4 prior lines, and 96% of patients with 5 to 11 prior lines experienced grade 3 or greater TEAEs. Regarding the response to prior BTK inhibitors, 83% of patients who were not refractory and 89% of those who were refractory experienced grade 3 or greater TEAEs.

The most common grade 3 or higher TEAEs included neutropenia (overall population, 56%; ≥ 2 lines, 56%; 3-4 lines, 45%; 5-11 lines, 58%; not refractory, 53%; refractory, 57%), anemia (37.5%; 39%; 29%; 65%; 33%; 45%), thrombocytopenia (25%; 26%; 16%; 42%; 22%; 28%), hypophosphatemia (9%; 9%; 6%; 15; 3%; 15%), hypokalemia (8%; 8%; 10%; 12%; 6%; 11%), leukopenia (7%; 7%; 6%; 8%; 8%; 6%), and lymphopenia (6%; 6%; 3%; 0%; 8%; 4%).

Additionally, the incidence of TEAEs of special interest (cytokine release syndrome [CRS] and neurological events) were similar across subgroups and similar to the overall population, and no grade 5 CRS or neurological events were reported.

Among patients who received 2 or more, 3 to 4, or 5 to 11 prior therapies and those who were vs were not refractory to prior BTK inhibition, the incidence of CRS was 61%, 62%, 68%, 69%, 58%, and 64%, respectively. This included grade 1/2 (61%; 65%; 69%; 56%; 64%) and grade 3/4 (1%; 3%; 0%; 3%; 0%) events in these groups, respectively.

Among patients who received 2 or more, 3 to 4, or 5 to 11 prior therapies and those who were vs were not refractory to prior BTK inhibition, the incidence of neurological events was 31%, 32%, 27%, 22%, and 36%, respectively. The respective rates of grade 1/2 events were 22%, 23%, 19%, 17%, and 26%; the rates of grade 3/4 events were 8%, 10%, 8%, 6%, and 11% in these respective patient subgroups.

Prolonged cytopenia, grade 3 or higher infections, and tumor lysis syndrome was seen in 40%, 15%, and 2% of patients in the overall population; 41%, 15%, and 2% in the 2 or more prior therapies group; 32%, 13%, and 3% in the 3 to 4 prior therapies group; 50%, 19%, and 4% in the 5 to 11 prior therapies group; 33%, 11%, and 3% of the non–BTK refractory group; and 45%, 19%, and 2% in the refractory group.

Additional findings also showed that liso-cel expansion and peak transgene levels were consistent between the overall population and most subgroups. However, numerically lower median Cmax and AUC0-28d levels were seen in patients with 5 or more prior lines of systemic therapy and those refractory to prior BTK inhibitors.

“The better efficacy outcomes and safety profile observed in patients with R/R MCL who received [less than] 5 prior lines of therapy and those with disease not refractory to prior BTKi support the use of liso-cel in earlier lines of therapy,” Palomba concluded.

Reference

1. Palomba ML, Siddiqi T, Gordon, LI, et al. Lisocabtagene maraleucel (liso-cel) in patients (pt) with R/R mantle cell lymphoma (MCL): subgroup analyses by number of prior systemic lines of therapy (LOT) and by response to prior Bruton tyrosine kinase inhibitor (BTKi) from the TRANSCEND NHL 001 MCL cohort (TRANSCEND-MCL). J Clin Oncol. 2024;42(suppl 16):7016. doi:10.1200/JCO.2024.42.16_suppl.7016