Liso-Cel Elicits Rapid, Durable Responses in Relapsed/Refractory Mantle Cell Lymphoma

The CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) produced rapid and durable responses in heavily pretreated patients with relapsed/refractory mantle cell lymphoma (MCL), according to data from the primary analysis of the MCL cohort of the phase 1 TRANSCEND-NHL-001 trial (NCT02631044) presented at the 17th Annual International Conference on Malignant Lymphoma.¹

Findings showed that patients in the primary analysis set (n = 74) experienced an overall response rate (ORR) of 86.5% (95% CI, 76.5%-93.3%; P < .0001) per independent review committee (IRC) assessment, including a complete response (CR) rate of 74.3% (95% CI, 62.8%-83.8%; P < .0001) and a partial response (PR) rate of 12.2%. Additionally, 6.8% of patients had stable disease, no patients had progressive disease, and 6.8% of patients were not evaluable.

Among the efficacy analysis set (n = 83), the IRC-assessed ORR was 83.1% (95% CI, 73.3%-90.5%), including a CR rate of 72.3% (95% CI, 61.4%-81.6%). The median time to first response was 0.95 months (range, 0.7-3.0).

“The ORR was consistent in patients, [irrespective of] whether they were 75 years [of age] or younger, had a [prior] stem cell transplant, central nervous system [CNS] lymphoma, [were] refractory to last [line of] therapy, Ki67 [level], blastoid variant, TP53 mutation [status], or whether they had bridging therapy,” lead study author Michael Wang, MD, a professor in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said in a presentation of the data.

The multicenter TRANSCEND NHL 001 study evaluated liso-cel in patients with B-cell non-Hodgkin lymphoma. Previous data from the trial supported the February 2021 FDA approval of liso-cel for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.²

The MCL cohort enrolled patients at least 18 years of age with PET-positive MCL that was confirmed with a tissue diagnosis. At least 2 prior lines of therapy were required, including a BTK inhibitor, an alkylator, and a CD20-targeted agent. Other key inclusion criteria included an ECOG performance status of 0 or 1, and adequate bone marrow, organ, and cardiac function. Patients with secondary CNS lymphoma or who underwent prior autologous or allogeneic hematopoietic stem cell transplant (HSCT) were allowed to enroll.¹

After leukapheresis, enrolled patients were allowed to receive bridging therapy consisting of standard-of-care regimens without limitation. PET-positive disease was reconfirmed following bridging therapy. Following 3 days of lymphodepletion consisting of 30 mg/m² of fludarabine and 300 mg/m² of cyclophosphamide per day, patients received a single infusion of liso-cel between 2 and 7 days later. Liso-cel was given at a target dose of 50 x 10⁶ CAR+ T cells (dose level 1) or 100 x 10⁶ CAR+ T cells (dose level 2).

Safety and ORR served as the co-primary end points. CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), cellular kinetics, and health-related quality of life comprised secondary end points.

Of the 104 patients to undergo leukapheresis, 12 patients did not receive CAR T cells due to death (n = 9) or no longer meeting eligibility criteria (n = 3). Additionally, 4 patients received a nonconforming product. In the liso-cel–treated population, 6 patients received dose level 1, and 82 patients were given dose level 2. Five patients from this group were not included in the efficacy analysis population due to lack of PET-positive disease at baseline (n = 3) or lack of repeated PET scan following bridging therapy (n = 2).

In the efficacy analysis population, 6 patients received dose level 1, and 77 were given dose level 2. The primary analysis set was comprised of patients treated at dose level 2 who had received at least 2 prior lines of therapy, including a BTK inhibitor, an alkylator, and a CD20-targeted agent.

At data cutoff, 30 patients had completed the study, and 10 patients were ongoing. Forty-eight patients (55%) discontinued the study due to death (n = 44) or withdrawal of consent (n = 4). Causes of death included disease progression (n = 28), adverse effects (AEs; n = 9), other (n = 6), and unknown (n = 1). Notably, 7 patients died due to COVID-19.

The median age of the liso-cel–treated population was 68.5 years (range, 36-86), and patients received a median of 3 (range, 1-11) prior lines of therapy. Thirty percent of patients received at least 5 prior lines of therapy. Thirty-three percent of patients underwent prior HSCT, 94% were treated with a prior BTK inhibitor, and 74% received ibrutinib (Imbruvica). Additionally, 69% of patients had refractory disease, and 53% were refractory to a BTK inhibitor.

Seventy-five percent of patients had a Ki67 proliferation fraction of at least 30%, 23% of patients had a TP53 mutation, and 31% had blastoid morphology. Notably, 11% of patients had a lactate dehydrogenase level of at least 500 u/L before lymphodepletion, and 9% had a sum of the product of perpendicular diameters of at least 50 cm² before lymphodepletion.

Eight percent of patients had secondary CNS lymphoma at the time of liso-cel infusion. Sixty-six percent of patients underwent bridging therapy.

Additional data showed that at a median follow-up of 22.8 months (95% CI, 16.7-23.0), the median DOR for all patients in the efficacy analysis set was 15.7 months (95% CI, 6.2-24.0). The 12- and 18-month continued response rates were 52.9% (95% CI, 40.1%-64.2%) and 42.7% (95% CI, 29.9%-54.9%), respectively.

Patients who experienced a CR had a median DOR of 16.8 months (95% CI, 7.5-24.0). The 12- and 18-month continued response rates for complete responders were 57.8% (95% CI, 44.2%-69.2%) and 46.7% (95% CI, 32.8%-59.4%), respectively. The median DOR for partial responders was 2.2 months (95% CI, 1.5-2.4).

At a median follow-up of 23.5 months (95% CI, 17.7-23.8), the median PFS for the overall efficacy analysis set was 15.3 months (95% CI, 6.6-24.9). The median PFS among complete responders, partial responders, and non-responders was 17.8 months (95% CI, 8.3-24.9), 3.2 months (95% CI, 2.5-not reached [NR]), and 1.6 months (95% CI, 0.4-24.0), respectively.

The 12- and 18-month PFS rates for the overall efficacy analysis set were 52.8% (95% CI, 40.6%-63.6%) and 43.9% (95% CI, 31.8%-55.4%), respectively. Those rates were 59.8% (95% CI, 46.3%-71.0%) and 49.4% (95% CI, 35.7%-61.8%) among complete responders, respectively.

The median OS among the overall efficacy analysis set population was 18.2 months (95% CI, 12.9-36.3). The median OS for complete responders, partial responders, and non-responders was 36.3 months (95% CI, 15.7-NR), 17.1 months (95% CI, 2.6-NR), and 3.1 months (95% CI, 0.9-10.6), respectively.

The 12- and 18-month OS rates for the overall efficacy analysis population were 61.8% (95% CI, 50.2%-71.4%) and 50.8% (95% CI, 39.2%-61.2%), respectively. Among complete responders, those rates were 72.9% (95% CI, 59.6%-82.5%) and 59.8% (95% CI, 45.9%-71.3%), respectively.

When censoring for 6 patients in the efficacy analysis set who were in ongoing CR and died due to COVID-19, the median PFS was 17.8 months (95% CI, 7.6-24.9), and the median OS was 24.8 months (95% CI, 15.7-NR).

Regarding safety, the most common treatment-emergent AEs (TEAEs) were cytokine release syndrome (CRS; any-grade, 61%; grade ≥3, 1%), neutropenia (59%; 56%), anemia (44%; 37.5%), fatigue (35%; 2%), thrombocytopenia (30%; 25%), hypokalemia (24%; 8%), headache (23%; 0%), decreased appetite (20%; 5%), nausea (18%; 2%), diarrhea (17%; 0%), hypophosphatemia (17%; 9%), peripheral edema (17%; 1%), pyrexia (17%; 0%), and confused state (16%; 2%).

The maximum-tolerated dose of liso-cel was NR, and dose-limiting toxicities were reported in 2 patients among 31 evaluable who were treated at dose level 2: grade 5 tumor lysis syndrome in a patient with high tumor burden, and grade 3 neutropenia and grade 4 thrombocytopenia in another patient.

Grade 5 TEAEs occurred in 4.5% of patients, and 3 were considered related to liso-cel: cryptococcal meningoencephalitis, lung infection (COVID-19 pneumonia), and tumor lysis syndrome. One patient experienced cardiopulmonary arrest that was considered unrelated to liso-cel.

Among the 54 patients to experience CRS, it was reported as grade 1/2 in 53 patients. One patient had grade 4 CRS. The median time to onset of CRS was 4.0 days (range, 1-10), and the median time to resolution was 4.0 days (range, 1-14).

Any-grade neurological events were reported in 27 patients (31%), including grade 1/2 events (n = 19; 22%), grade 3 events (n = 7; 8%), and grade 4 events (n = 1; 1%). The median time to onset of neurological events was 8.0 days (range, 1-25), and the median time to resolution was 5.0 days (range, 1-45). Other AEs of special interest included prolonged cytopenias (40%), grade 3 or higher infections (15%), and hypogammaglobulinemia (7%).

Cellular kinetic parameters evaluated in 79 patients showed the t_max was 10 days (interquartile range [IQR], 9-14), the c_max was 29,335 copies/µg (IQR, 9255-136,684), and the AUC_(0-28d) was 288,557 days x copies/µg (range, 91,759-900,208).

Notably, 58% of patients had B-cell aplasia at baseline, and after liso-cel infusion, the frequency of B-cell aplasia increased to 98% by month 2, then decreased to 73% by month 12.

Disclosures: Dr Wang reported consultancy fees from AbbVie, Acerta Pharma, ADC Therapeutics America, Amphista Therapeutics Limited, AstraZeneca, Be Biopharma, BeiGene, BioInvent, Deciphera Pharmaceuticals, DTRM BioPharma (Cayman) Limited, Genentech, InnoCare, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Lilly, Merck, Miltenyi Biomedicine, Milken Institute, Oncternal Therapeutics, Parexel, PeproMene Bio, Pharmacyclics, and VelosBio.

He also reported receiving honoraria from AbbVie, Acerta Pharma, AstraZeneca, Bantam Pharmaceutical, BeiGene, BioInvent, Bristol Myers Squibb, Chinese American Hematologist and Oncologist Network, DAVA Oncology, Eastern Virginia Medical School, Genmab, i3 Health, IDEOlogy Health, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Medscape, Meeting Minds Experts, MD Education, MJH Life Sciences, Merck, Moffitt Cancer Center, Nurix Therapeutics, Oncology Specialty Group, OncLive, Pharamcyclics, Physicians’ Education Resource, Practice Point Communications, Scripps, Studio ER Congressi, and WebMD.

He also received research grants from Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, InnoCare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal Therapeutics, Pharamcyclics, VelosBio, and Vincerx Pharma; and serving as a committee for the board of the Leukemia & Lymphoma Society.

References

1. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in R/R MCL: primary analysis results from the MCL cohort of the single-arm, multicenter, seamless design TRANSCEND NHL 001 study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract LBA3.
2. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. News release. FDA. February 5, 2021. Accessed June 19, 2023.