FDA Approves Liso-Cel for Second-Line Treatment of R/R LBCL


The FDA has granted approval lisocabtagene maraleucel for the treatment of adult patients with large B-cell lymphoma, with specific indications for patients with relapsed or refractory disease.

The FDA has granted approval of the CD19-directed chimeric antigen receptor (CAR) T cell therapy, lisocabtagene maraleucel (liso-cel; Breyanzi), for the treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.1

The indication includes patients with refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy. The indication also includes patients with refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant (HSCT) due to comorbidities or age.

Approval of liso-cel for the treatment for second-line treatment of relapsed/refractory LBCL is supported by findings from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 PILOT trial (NCT03483103).

“Breyanzi represents a remarkable advance over a nearly 30-year standard of care, providing significantly improved efficacy with a well-established safety profile,” said Manali Kamdar, MD, lead investigator of the TRANSFORM study and associate professor, clinical cirector of Lymphoma Services, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, in a press release. “This important milestone reinforces the benefit of offering a CAR T-cell therapy option to patients earlier in their treatment journey, and it’s critical that we begin the work to implement this therapy into standard practice as a second-line treatment in order to help improve outcomes for more patients.”

Liso-cel in the TRANSFORM study

In TRANSFORM, liso-cel treatment was compared with standard of care (SOC) therapy consisting of 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 in 184 patients between the ages of 18 and 75 year old. At the prespecified interim analysis of the study, patients who were treated with 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 SOC therapy (HR, 0.349; 95% CI, 0.229-0.530; P < .0001).2

In addition to the improved median EFS, the EFS rate at 6 months per independent review committee was 63.3% (95% CI, 52.0-74.7) in the liso-cel arm compared with 33.4% (95% CI, 23.0-43.8). At 12 months, the EFS rate was 44.5% (95% CI, 29.4-59.6) with liso-cel vs 23.7% (95% CI, 13.4-34.1) with SOC. EFS outcomes were consistent across subgroups.

In terms of the key secondary end points including, the 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% vs 39.1%. The median PFS was also significantly higher in liso-cel arm at 14.8 months (95% CI, 6.6 to not reached [NR]) vs 5.7 months (95% CI, 3.9-9.4) with SOC (HR, 0.406; 0.250-0.659; P = .0001). OS data were immature at the time of the interim analysis, but the median OS observed with liso-cel was NR (95% CI, 15.8-NR), while the median OS for SOC was 16.4 (11.0-NR), showing a stratified hazard ratio of 0.509 (95% CI, 0.258-1.004; P = .02570.

The safety findings from TRANSFORM showed that treatment-emergent adverse events (TEAEs) were very common in both treatment arms with comparable rates of grade 3 or higher TEAEs. The liso-cel arm had a slightly lower rate (15%) of grade 3 or higher infections versus SOC (21%).

Cases of cytokine release syndrome (CRS) was reported in 49% of patients in the liso-cel arm, and 1 had grade 3 CRS. Tocilizumab (Actemra) was adminstered to 24% of patients to treat CRS and neurological events. Grade 3 neutropenia was more common in the liso-cel arm (80%) compared with the SOC arm (51%). Lymphopenia was also more common with liso-cel (25%) compared with SOC (9%). Also, prolonged cytopenias were reported in 43% of the liso-cel arm vs only 3% in the SOC arm.

There was 1 death reported in the liso-cel arm that was attributed to failure to thrive in the context of disease progression. In the SOC arm, 2 deaths were attributed to sepsis and acute respiratory distress syndrome.

Liso-cel in the PILOT study

In the PILOT study, second-line treatment with liso-cel achieved to durable responses in patients with relapsed/refractory LBCL who were not intended to undergo hematopoietic stem cell transplantation (HCST). Results from the primary analysis were presented during the 2022 American Society of Clinical Oncology Annual Meeting.3

In a total of 61 patients, liso-cel showed an overall response rate (ORR) of 80% (95% CI, 68.2%-89.4%, P < .0001). Among the 27 patients with a hematopoietic cell transplantation specific comorbidity index (HCT-CI) score of 3 or more, the ORR was 81% (95% CI, 61.9%-93.7%). Moreover, in patients with an HCT-CI score less than 3, the ORR was 79% (95% CI, 62.1%-91.3%).

The study also demonstrated that liso-cel achieved CRs in 54% (95% CI, 40.8%-66.9%) of the population, which was achieved after a median follow-up of 12.3 months (range, 1.2-26.5). The CRs were durable with a median duration of response (DOR) of 21.7 months (95% CI, 12.1-not reached [NR]), according to the investigators.

In terms of survival, the median progression-free survival (PFS) in the entire efficacy analysis group was 9 months (95% CI, 4.2-NR) after a median follow-up of 13 months (range, 12-18.1). The median OS was NR (95% CI, 17.3-NR) after a median follow-up of 17.6 months (range, 12.4-18.6).

Among patients with an HCT-CI score of 3 or greater, the median PFS was NR, but was 7.4 months (95% CI, 2.9-13) in the patient group with an HCT-CI score lower than 3. The same differences were observed when assessing EFS with patients with a score lower then 3 having a longer EFS at 7.4 months (95% CI, 2.9-13) versus 7.2 months (95% CI, 3-NR) in those with a score of 3 or higher. In both cohorts, median OS was NR.

The safety profile of liso-cel in PILOT was consistent with previous reports. The most common grade 3 or greater TEAEs were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Grade 3 or greater infections were reported in 4 patients, including grade 5 COVID-19–related TEAEs in 2 patients.

Rates of cytokine release syndrome (CRS) or neurotoxicity was low with no grade 4 or 5 events observed. The events were managed with tocilizumab and/or corticosteroids in 26% and 13%, respectively. Overall, 23 patients had any-grade CRS, 11 patients had grade 1 CRS, and 11 had grade 2 CRS. Nineteen patients had any-grade neurotoxicity. Of those with neurotoxicity, 11 patients had grade 1 neurotoxicity, 5 hade grade 2 neurotoxicity, and 3 patients had grade 3 neurotoxicity.

According to the developer, liso-cel now has the most broad eligibility for CAR T-cell therapy in relapsed/refractory LBCL.

“Patients with large B-cell lymphoma whose disease does not respond to or relapses after first-line therapy often face lengthy and intensive cycles of chemotherapy with the goal of proceeding to stem cell transplant,” said Lee Greenberger, PhD, chief ccientific officer of the Leukemia & Lymphoma Society, in a statement.1 “As one of the earliest supporters of CAR T since the 1990’s, LLS is excited to see the FDA approval of a CD19 CAR T-cell therapy that has moved from later lines of therapy to a second-line option, which offers patients with relapsed or refractory large B-cell lymphoma the potential for long-term remission and the hope of a cure.”


1. U.S. 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. June 24, 2022. Accessed June 25, 2022. https://bit.ly/3HPA7O3

2. 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

3. Sehgal A, Hoda D, Riedell P, et al. Lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for HSCT: Primary analysis from the phase 2 PILOT study. J Clin Oncol. 2022;40(suppl 16):7062. doi:10.1200/JCO.2022.40.16_suppl.7062

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