Liso-cel Shows Improved EFS, PFS, and Durable Responses in Second-line LBCL at 3 Years

Lisocabtagene maraleucel (liso-cel; Breyanzi) continued to demonstrate improved disease control and event-free and progression-free survival (PFS) compared with standard of care (SOC) therapy in the second-line setting of patients with large B-cell lymphoma (LBCL), according to a 3-year update from the phase 3 TRANSFORM trial (NCT03575351) that was presented during the 2024 ASCO Annual Meeting¹ and 2024 EHA Congress.²

Results showed that at a median follow-up of 33.9 months, the median event-free survival (EFS) was 29.5 months (95% CI, 9.5-not reached [NR]) with liso-cel compared with 2.4 months (95% CI, 2.2-4.9) with SOC (censored stratified HR, 0.375; 95% CI, 0.259-0.542). The 3-year EFS rates were 45.8% (95% CI, 35.2%-56.5%) and 19.1% (95% CI, 11.0%-27.3%), respectively. The EFS benefit with liso-cel was observed across all prespecified subgroups.

Additionally, the overall response rate (ORR) with liso-cel was 87% (n = 80/92; 95% CI, 78.3%-93.1%) and the complete response (CR) rate was 74% (n = 68/92; 95% CI, 63.7%-82.5%). In the SOC arm, these rates were 49% (n = 45/92; 95% CI, 38.3%-59.6%) and 43% (n = 40/92; 95% CI, 33.2%-54.2%), respectively.

The median duration of response (DOR) was NR (95% CI, 16.9-NR) with liso-cel vs 9.1 months (95% CI, 5.1-NR) with SOC (censored stratified HR, 0.603; 95% CI, 0.364-1.000). The 2-year DOR rates were 60.5% (95% CI, 49.7%-71.4%) and 43.5% (95% CI, 28.8%-58.1%), respectively. Also, the median duration of CR was NR (95% CI, 28.65-NR) with liso-celand 9.3 months (95% CI, 5.06-NR) with SOC (censored stratified HR, 0.503; 95% CI, 0.283-0.894). The 2-year duration of CR rates were 67.0% (95% CI, 55.65%-78.3%) and 46.4% (95% CI, 30.7%-62.0%), respectively.

“The TRANSFORM trial, now, after median follow-up of 34 months, continues to show an ongoing improvement in EFS, PFS, CR rate and ORR favoring liso-cel over standard of care [SOC], [which is] consistent with the primary analysis,” Jeremy Abramson, MD, lead study author, director of the Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital, and associate professor of medicine at Harvard Medical School, said in an oral presentation during the meeting. “Liso-cel as second-line therapy is superior to SOC, warranting liso-cel continuing to be considered as the new SOC along with other approved CAR T-cell products in this space for patients with primary refractory or relapsed LBCL.”

In June 2022, the FDA approved liso-cel as a second-line treatment for adult patients with LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS; including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma (HGBCL), primary mediastinal LBCL (PMBCL), and follicular lymphoma grade 3B (FL3B).³ The decision was partly based on earlier findings from TRANSFORM.

In TRANSFORM, all patients underwent leukapheresis following screening. They were then randomized 1:1 to have optimal bridging therapy with PET (if bridging therapy was given), lymphodepletion with fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 for 3 days, then liso-cel at 100 x 106 CAR T-cells for 2 to 7 days after fludarabine plus cyclophosphamide (n = 92) or standard therapy with 3 cycles of salvage chemoimmunotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplant (HSCT; n = 92). Disease assessments took place in both arms up to 36 months after randomization.

To be eligible for enrollment, patients had to be aged between 18 and 75 years and have aggressive non-Hodgkin lymphoma (NHL) that comprised DLBCL NOS, transformed DLBCL (tDLBCL) from indolent NHL, HGBCL that is double or triple hit, FL3B, PMBCL, and T-cell/histiocyte-rich large B-cell lymphoma (THRBCL). Patients also had to have disease that was refractory to relapsed within 12 months after frontline treatment that contained an anthracycline and a CD20-targeted agent, an ECOG performance status of 0 to 1, and be transplant eligible.

In the SOC arm, crossover to liso-cel was permitted if SOC therapy failed based on an independent review committee (IRC)-confirmed EFS event. Crossover occurred in 62% of patients (n = 57) on the SOC arm to liso-cel.

In the liso-cel arm, 97% (n = 89) of patients received treatment and 1 patient received a nonconforming product; 99% of patients on the SOC arm (n = 91) started SOC; 47% (n = 43) received HDCT/HSCT. Forty-seven percent (n = 43) and 27% (n = 25) of patients continued to long-term follow-up on the liso-cel and SOC arms, respectively.

Also in the SOC arm, 66% of patients (n = 61) were approved for crossover, 58 of whom received CAR T-cell therapy that was liso-cel (n = 57) or a nonconforming product (n = 1). Twenty-five patients (27%) continued through to long-term follow-up.

The primary end point was EFS per IRC assessment via Lugano 2014 criteria; key secondary end points were CR rate, PFS, and overall survival (OS).

Previous findings from TRANSFORM showed that, at a median follow-up of 6.2 months, the median EFS was was 10.1 months (95% CI, 6.1–NR) with liso-cel compared with 2.3 months (95% CI, 2.2-4.3) in those who received SOC treatment (HR, 0.349; 95% CI, 0.229-0.530; P < .0001).⁴

At the 2024 ASCO Annual Meeting and 2024 EHA Congress, longer follow-up data of TRANSFORM were presented.

Regarding baseline characteristics in the intention-to-treat (ITT) population, the median age was 59 years (range, 20-75) and 57% of patients overall were male. LBCL subtypes were comprised of DLBCL NOS (56%), HGBCL with rearrangements in MYC and BCL2, BCL6, or both (23.5%), PMBCL (9.5%), tDLBCL from any indolent lymphoma (8.5%), THRBCL (2.5%), FL3B (0.5%). Forty-six percent of patients had germinal center B-cell disease, 57% had an ECOG performance status of 0, and 60.5% of patients had a secondary age-adjusted International Prognostic Index of 0 or 1. A total 74.5% of patients had refractory disease vs 25.5% of those who had relapsed disease as their prior response status.

Further findings showed that, in the ITT population, the median PFS based on IRC assessment was NR (95% CI, 12.6-NR) with liso-cel compared with 6.2 months (95% CI, 4.3-8.6) with SOC (censored stratified HR, 0.422; 95% CI, 0.279-0.639). The 3-year PFS rates were 50.9% (95% CI, 39.9%-62.0%) and 26.5% (95% CI, 15.9%-37.1%), respectively.

OS was evaluated in ITT set as well as in in a sensitivity analysis with a 2-stage accelerated failure time model. The median OS was NR in both the liso-cel (95% CI, 42.8-NR) and SOC arms (95% CI, 18.2-NR), translating to an estimated 25% reduction in the risk of disease progression or death (censored stratified HR, 0.757; 95% CI, 0.481-1.191). Three-year OS rates were 62.8% (95% CI, 52.7%-72.9%) with liso-cel and 51.8% (95% CI, 41.2%-62.4%) with SOC, respectively.

“However, this separation is not statistically significant, likely owing in large part to the built-in cross over on this study,” Abramson said, noting that two-thirds of patients on SOC immediately crossed over to receive liso-cel in the third-line setting, with a median time to approval of crossover and receipt of liso-cel of 2 weeks. “Because this built-in crossover likely confounded the overall survival analysis, we did perform a sensitivity analysis adjusting for the effect of cross over.”

In the 2-stage accelerated failure time model, the median OS was still NR in both the liso-cel (95% CI, 42.8-NR) and SOC arms (95% CI, 10.0-NR; censored stratified HR, 0.566; 95% CI, 0.359-0.895), which Abramson said was found to be significant.

Regarding safety, nearly all patients in the safety set in both arms experienced any treatment-emergent adverse effect (TEAE). Any-grade adverse effects (AEs) that occurred in more than 40% of patients on liso-cel were neutropenia (liso-cel, 83% vs SOC, 55%), anemia (67% vs 68%), thrombocytopenia (60% vs 73%), nausea (53% vs 58%), cytokine release syndrome (CRS; 49% vs 0%), and headache (43% vs 23%).

Grade 3/4 AEs occurred in 92% and 89% of liso-cel– and SOC-treated patients, respectively; grade 3/4 AEs that occurred in at least 15% of patients on liso-cel were neutropenia (liso-cel, 82% vs SOC, 52%), anemia (52% vs 56%), thrombocytopenia (50% vs 68%), lymphopenia (26% vs 10%), and leukopenia (16% vs 13%).

In the post–treatment-emergent period, any AEs occurred in 16% and 14% of patients on liso-cel and SOC. AEs occurring in at least 40% of patients on liso-cel was neutropenia (liso-cel, 4% vs SOC, 2%), anemia (0% vs 1%), thrombocytopenia (1% vs 0%), nausea (0% vs 1%), and headache (0% vs 1%).

Any 3/4 AEs in this period was 9% vs 5%, respectively. Grade 3/4 AEs in at least 15% of patients on liso-cel were neutropenia (liso-cel, 3% vs SOC, 2%) and thrombocytopenia (1% vs 0%).

The rate of secondary primary malignancies (SPMs) was 3% in each treatment arm (SOC, excluding crossover); when including post-crossover, the SPM rate was 4% for the SOC arm. No reported SPMs were T-cell malignancies.

There were 34 deaths (37%) on the liso-cel arm compared with 9 (10%) on the SOC arm (excluding crossover). When crossover was included, there were 42 deaths (46%) on the SOC arm.

Regarding TEAEs of special interest in the safety set, CRS in the liso-cel arm was any grade in 49% of patients (n = 45); this was broken down by grade 1 (37%; n = 34), grade 2 (11%; n = 10), grade 3 (1%; n = 1). There were no reports of grade 4/5 CRS. The median time to CRS onset was 5 days; the median time to resolution was 4 days.

Any-grade neurological events occurred in 11% (n = 10) of patients and was grade 1 (4%; n = 4), grade 2 (2%; n = 2), and grade 3 (4%; n = 4). There were no grade 4 or 5 neurologic events, with a median time to onset of 11 days and a median time to resolution of 4.5 days.

Treatment for CRS and/or neurologic events consisted of corticosteroids only (2%), tocilizumab (Actemra) alone (10%), or both (14%). CRS events were treated with tocilizumab alone (11%) or tocilizumab and corticosteroids (12%). Neurologic events were treated with corticosteroids online (7%) and tocilizumab and corticosteroids (1%).

Prolonged cytopenias were managed with 43% and 3% of patients on liso-cel and SOC; grade 3 or higher infections occurred in 15% and 21% of patients, respectively.

Additionally, persistence of liso-cel in the blood via droplet digital polymerase chain reaction was seen in 26% of patients on the liso-cel arm (n = 9/34) at month 35, measuring the time from liso-cel infusion, in the cellular kinetic analysis set. B-cell aplasia via T-cell, B-cell, natural killer cell assay was observed in 31% of patients on liso-cel (n = 11/36) in the safety set at month 36 of study visits.

References

1. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study. J Clin Oncol. 2024;42(suppl 16):7013. doi:10.1200/JCO.2024.42.16_suppl.7013
2. Abramson J, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by ASCT as second-line treatment in patients with r/r large B-cell lymphoma: 3-year follow-up of TRANSFORM. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract 272.
3. US FDA approves Bristol Myers Squibb’s CAR T cell therapy breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb. June 24, 2022. Accessed June 24, 2022. https://news.bms.com/news/details/2022/US-FDA-Approves-Bristol-Myers-Squibbs-CAR-T-Cell-Therapy-Breyanzifor-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx
4. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, versus standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (Pts) with relapsed or refractory (R/R) large B lymphoma (LBCL): results from the randomized phase 3 TRANSFORM study. Blood. 2021;138(suppl 1):91. doi:10.1182/blood-2021-147913