Second-Line Liso-Cel CAR T-Cell Therapy Shows EFS Benefit for R/R LBCL

Lisocabtagene maraleucel (liso-cel, Breyanzi), a chimeric antigen receptor (CAR) T-cell therapy, demonstrated benefit to event-free survival (EFS) for patients with relapsed/refractory large B-cell lymphoma (R/R LBCL), according to data presented by Jeremy Abramson, MD, at the European Society for Blood and Marrow Transplantation Annual Meeting.¹

At the prespecified interim analysis from the phase 3 TRANSFORM study (NCT03575351), patients receiving liso-cel had a median EFS of 10.1 months (95% CI, 6.1-not reached [NR]) versus 2.3 (95% CI, 2.2-4.3) with standard-of-care (SOC) therapy (HR, 0.349; 95% CI, 0.229-0.530; P < .0001).

“Patients with primary refractory or early relapse of LBCL have poor outcomes with the SOC of salvage chemotherapy and autologous [stem cell] transplant,” Abramson, director of the Jon and Jo Ann Hagler Center for Lymphoma and associate professor of medicine at Harvard Medical School, said in his presentation.

Liso-cel is a CD19-targeted CAR T-cell therapy that is currently approved for R/R LBCL after 2 or more lines of systemic therapy.² Axicabtagene ciloleucel (Yescarta), another CD19-targeted CAR T-cell therapy, demonstrated efficacy in the ZUMA-7 trial (NCT03391466), while tisagenlecleucel (Kymriah) did not show benefit over SOC in the BELINDA trial (NCT03570892).^3,4

The TRANSFORM study evaluated its efficacy as second-line therapy versus SOC in 184 patients aged 18 to 75 with primary refractory or relapsed disease at 12 months or less after first-line therapy who were eligible for hematopoietic stem cell transplant and had not received prior anti-CD19–targeted therapy.1 Patients were stratified by refractory versus relapsed disease and patients’ second-line age-adjusted International Prognostic Index scores of 0/1 versus 2/3.

Patients were randomized 1:1 to receive either lymphodepletion followed by liso-cel infusion of 100 × 106 CAR+ T cells or SOC, which consisted of R-DHAP (rituximab [Rituxan], dexamethasone, high-dose cytarabine, and cisplatin), R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin), followed by BEAM (carmustine [BCNU], etoposide, cytarabine and melphalan) high-dose chemotherapy plus autologous stem cell transplant.

Bridging therapy with SOC chemotherapy was allowed for the liso-cel arm, and 58 out of 92 patients (63%) received bridging therapy. Patients were allowed to cross over to the liso-cel arm upon confirmation of an EFS event. Of 50 who applied to cross over, 46 were able to receive liso-cel. Only 32 patients of the 91 who started SOC are continuing on SOC, while 78 of 90 who originally received liso-cel are still receiving therapy.

In addition to the improved median EFS, the EFS rate at 6 months as assessed by independent review committee was 63.3% (95% CI, 52.0-74.7) in the liso-cel arm versus 33.4% (95% CI, 23.0-43.8). At 12 months, the EFS rate was 44.5% (95% CI, 29.4-59.6) for liso-cel versus 23.7% (95% CI, 13.4-34.1). EFS was consistent across subgroups. Key secondary end points included rate of complete response (CR), progression-free survival (PFS), and overall survival (OS).

The overall response rate was 86.0% versus 47.8%, while the CR rate was 66.3% versus 39.1%. The median PFS was also significantly higher with liso-cel: 14.8 months (95% CI, 6.6-NR) versus 5.7 months (95% CI, 3.9-9.4) with SOC (HR, 0.406; 0.250-0.659; P = .0001). While OS data were immature, the median OS for the liso-cel arm was NR (95% CI, 15.8-NR), while the median OS for SOC was 16.4 (11.0-NR) with a stratified hazard ratio of 0.509 (95% CI, 0.258-1.004; P = .0257.

“We did see improvement in quality of life [QOL] based on patient-reported outcomes [PRO] favoring liso-cel over SOC, specifically with improvements in fatigue and global health and quality of life domains,” Abramson said. “We see more improvement and less deterioration in these PRO measures in liso-cel compared [with] SOC, so this was associated with improved QOL as well as improved efficacy outcomes.”

In terms of safety, treatment-emergent adverse events (TEAEs) were extremely common in both arms, and grade 3 or higher TEAEs were comparable at 92% in the liso-cel arm and 87% in the comparator arm. The liso-cel arm had a slightly lower rate (15%) of grade 3 or higher infections versus SOC (21%).

Cytokine release syndrome (CRS) was reported in 49% of patients receiving liso-cel, but only 1 had grade 3 CRS. Tocilizumab (Actemra) was given to 24% of patients to treat CRS and neurological events. Grade 3 neutropenia was more common in the liso-cel arm (80% versus 51%), as was lymphopenia (25% versus 9%), but no other types of cytopenias were significantly higher in the liso-cel arm. However, prolonged cytopenias were reported in 43% of the liso-cel arm versus only 3% in the SOC arm.

One death reported in the liso-cel arm was attributed to failure to thrive in the context of disease progression, while 2 deaths in the SOC arm were attributed to sepsis and acute respiratory distress syndrome, respectively.

“In conclusion, liso-cel demonstrated superiority over the standard of care with significant improvement in EFS, CR rate, and PFS as a second-line therapy in patients with LBCL which was primary refractory or relapsed within 1 year of first-line therapy,” Abramson said. “…These data support liso-cel as a new SOC for second-line treatment in patients with R/R LBCL.”

_References:

_{1. Kamdar M, Solomon SR, Arnason J, et al. GS2-02 lisocabtagene maraleucel versus standard of care (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation) as second-line therapy in relapsed/refractory LBCL: TRANSFORM results. Paper presented by Jeremy Abramson at: 48th European Society for Blood and Marrow Transplantation Annual Meeting; March 19-23, 2022; virtual. Accessed March 21, 2022. https://bit.ly/36vjLv7}

_{2. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. FDA. Published February 5, 2021. Accessed March 21, 2022. https://bit.ly/3ud3DHa}

_{3. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133}

_{4. Bishop MR, Dickinson M, Purtill D, et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med. 2022;386(7):629-639. doi:10.1056/NEJMoa2116596}