Liso-cel Significantly Prolongs EFS Over SOC in Second-Line Relapsed/Refractory LBCL

Lisocabtagene maraleucel (Breyzani; liso-cel) significantly prolonged event-free survival (EFS) and progression-free survival and improved complete responses (CRs) compared with standard of care (SOC) when used in the second-line treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL), according to data from a prespecified interim analysis of the phase 3 TRANSFORM trial (NCT03575351).¹

Results, which will be presented at the 2021 ASH Annual Meeting, indicated that patients who received the CD19-directed CAR T-cell therapy (n = 92) experienced a median EFS of 10.1 months (95% CI, 6.1–not reached [NR]) vs 2.3 months (95% CI, 2.2-4.3) in those who received SOC treatment with salvage chemotherapy, followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT; n = 92; HR, 0.349; P < .0001).

Additionally, liso-cel resulted in a median PFS of 14.8 months (95% CI, 6.6–NR) vs 5.7 months (95% CI, 3.9-9.4) with SOC (HR, 0.406; P = .0001). The CAR T-cell therapy was also found to elicit a complete response (CR) rate of 66% (95% CI, 55.7%-75.8%) compared with 39% (95% CI, 29.1%-49.9%) with SOC (P < .0001).

“[We do not yet know what] this means for sequencing at this point in time; it is preliminary. We don't quite know what [comes] after CAR T-cell therapy,” lead study author Manali Kamdar, MD, clinical director of Lymphoma Services and associate professor in Medicine/Hematology at University of Colorado Medicine, told OncLive^®. “However, we do know that certain agents, other immunotherapy products, may come in handy and may be of value to patients who relapse after CAR T-cell therapy. [Regardless,] it is important to highlight that CAR T-cell therapy with liso-cel in the second-line setting really shows a paradigm shift compared [with] the SOC.”

Finding a second-line alternative to SOC for patients with relapsed/refractory LBCL is an unmet need for this patient population, according to Kamdar, as these patients may experience poor outcomes with standard practices. An autologous CD19-directed, defined composition, 4-1BB CAR T-cell product, liso-cel was designed to be administered at equal target doses of CD8- and CD4-positive CAR-positive T cells.

Previously, the agent was found to induce an objective response rate (ORR) of 73% in patients with relapsed/refractory LBCL who had received 2 or more prior lines of therapy, with a CR rate of 53%, according to data from the phase 1 TRANSCEND NHL 001 trial (NCT02631044).² In the global, multicenter phase 3 TRANSFORM trial, investigators sought to explore the efficacy of liso-cel vs SOC in patients with LBCL who relapsed within 12 months, or who were refractory to first-line treatment.

To be eligible for enrollment, patients needed to be 75 years or younger, have an ECOG performance status of 0 or 1, and acceptable organ function. Moreover, patients needed to be eligible for ASCT. Notably, patients with secondary central nervous system lymphoma were permitted. If patients previously received gene or anti-CD19–targeted therapy, or had an active infection, they were excluded.

A total of 184 patients underwent randomization and 92 patients were enrolled to each treatment arm. Patients in arm A, the control arm of the trial, received investigator’s choice of SOC, starting with R-DHAP (rituximab [Rituxan] plus dexamethasone, high-dose cytarabine, and cisplatin), R-ICE (rituximab, plus ifosfamide, carboplatin, and etoposide) or R-GDP (rituximab plus gemcitabine, dexamethasone, and cisplatin) for 3 cycles. Those who achieved a CR or partial response (PR) to treatment, then proceeded to receive BEAM (carmustine, etoposide, cytarabine, and melphalan) and undergo ASCT.

Those in arm B underwent lymphodepletion with fludarabine and cyclophosphamide; this was followed by liso-cel, which was administered at a target dose of 100 x 106 CAR-positive T cells. Patients in this arm were permitted to receive bridging therapy with an arm A chemotherapy regimen.

Notably, those in arm A who did not achieve a CR or PR following 3 cycles of chemotherapy, did not achieve a CR after ASCT, or who experienced disease progression, were permitted to crossover to receive the CAR T-cell therapy.

The primary end point of the trial is EFS per independent review committee and Lugano 2014 criteria. Key secondary end points comprised CR rate, PFS, and overall survival (OS). The P value significance threshold for end points to reject the null hypothesis was ≤ 0.012.

The median age of patients in arm A was 58 years (range, 26-75) vs 60 years (range, 20-74) in arm B. In the control arm, most patients were male (66%) and had an ECOG performance status of 0 (62%); in the investigative arm, 52% of patients were female and 52% had a status of 0. Across the arms, most patients had diffuse large B-cell lymphoma. In arm A, 74% had refractory disease and 26% had relapsed disease; in arm B, 73% had refractory disease and 27% had relapsed disease.

In arm A, 91 patients received treatment and 1 withdrew consent. After receiving SOC salvage chemotherapy, 43 patients went on to receive BEAM and ASCT; 28 of these patients achieved a CR to chemotherapy. A total of 50 patients in arm A crossed over to receive liso-cel. In arm B, 90 of 92 patients received liso-cel, and 58 patients received bridging therapy.

Additional data showed that patients who received liso-cel experienced a 6-month EFS rate of 63% (95% CI, 52.0%-74.7%) vs 33% (95% CI, 23.0%-43.8%) in those who received SOC. Moreover, the CAR T-cell product induced an ORR of 86% (95% CI, 77.0%-92.3%) vs 48% (95% CI, 37.3%-58.5%) with SOC.

The OS data are currently immature.

Treatment-emergent adverse effects (TEAEs) of any grade occurred in 100% of patients in the liso-cel group compared with 99% of those in the SOC group. Ninety-two percent of patients in the liso-cel arm experienced a TEAE that was grade 3 or higher vs 87% of those in the SOC arm. The most comment nonhematologic TEAEs reported in the liso-cel and SOC arms were nausea (53% and 57%, respectively), fatigue (39% and 38%), and diarrhea (25% and 42%).

Furthermore, the most common cytopenias experienced in the investigative and control arms were neutropenia (82% and 54%, respectively), anemia (63% and 64%), thrombocytopenia 58% and 68%), lymphopenia (27% and 11%), febrile neutropenia (15% and 24%), and leukopenia (15% and 14%). Additionally, 15% of patients who received liso-cel and 21% of those who were given SOC reported an infection that was grade 3 or higher.

Two percent of patients who received SOC treatment experienced tumor lysis syndrome vs no patients who were infused with liso-cel.

References

1. Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel, a CD19-directed chimeric antigen reception T cell therapy, versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma: results from the randomized phase 3 transform study. Paper presented at 63rd ASH Annual Meeting; December 11, 2021; Atlanta, GA. Accessed November 22, 2021. https://bit.ly/30KxmfW
2. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0