Lisocabtagene maraleucel (liso-cel, Breyanzi; Bristol Myers Squibb) approved for the second-line treatment of patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma grade 3B.
The FDA has approved lisocabtagene maraleucel (liso-cel, Breyanzi; Bristol Myers Squibb) for the second-line treatment of patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (such as DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma grade 3B.1
The approval is specific to patients with refractory disease to first-line chemoimmunotherapy or who relapse within 12 months of first-line chemoimmunotherapy; or refractory disease to first-line chemoimmunotherapy or relapse following first-line chemoimmunotherapy and who are not eligible for hematopoietic stem cell transplant (HSCT) because of comorbidities or age.
“As part of our commitment to developing innovative cancer treatments for patients with critical unmet need, [liso-cel] offers a potentially curative option for more patients,” said Ester Banque, senior vice president and general manager, US Hematology, Bristol Myers Squibb, in a press release. “Based on the demonstrated clinical benefit, this approval of [liso-cel] underscores the significant advances we are making to deliver on the promise of cell therapy.”
The approval was based on findings from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 PILOT trial (NCT03483103). The TRANSFORM trial was a global, randomized, multicenter study, the results of which were assessed through a pre-specified interim analysis conducted by an independent review committee.
The study met its primary endpoint of demonstrating a clinically meaningful and highly statistically significant improvement in event-free survival (EFS), complete responses (CRs), and progression-free survival (PFS) vs standard salvage chemotherapy followed by high-dose chemotherapy plus autologous HSCT. It also met the key secondary endpoints of complete response rate and progression-free survival (PFS) compared to standard of care.
The results of the trial allowed researchers to look outside the current gold standard treatment of high-dose chemotherapy and stem cell transplant for patients with relapsed or refractory LBCL, because this is the first time a therapy has shown a benefit over this standard of care, according to the study authors. Additionally, the results are the first time a CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown potential as a second-line therapy in this patient population as well.
In PILOT, liso-cel produced a high rate of durable overall and CRs as second-line therapy in frail patients with relapsed/refractory LBCL for whom HCST was not intended.
TRANSFORM enrolled patients between 18 and 75 years of age with aggressive non-Hodgkin lymphoma, including DLBCL not otherwise specified, high-grade B-cell lymphoma with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histiocyte-rich LBCL.
Patients needed to be refractory or relapsed for a maximum of 1 year after frontline treatment with an anthracycline and a CD20-targeted agent. The maximum ECOG performance status permitted was 1. Patients also must have been candidates for HSCT.
After screening plus leukapheresis, patients randomized to the investigative cohort were administered 100 x 106 CAR T cells and patients in the control group were administered 3 cycles of salvage chemotherapy followed by high-dose chemotherapy plus autologous SCT (ASCT).
Patients in the placebo cohort were permitted to crossover to the liso-cel cohort if they did not respond by 9 weeks following randomization, if they experienced disease progression at any time, or if they started a new antineoplastic therapy after ASCT.
At a median follow-up of 6.2 months across both cohorts, the median EFS in patients administered liso-cel (n = 92) was 10.1 months (95% CI, 6.1–not reached [NR]) compared with 2.3 months (95% CI, 2.2-4.3) in patients administered standard-of-care (SOC) treatment (n = 92; HR, 0.349; 95% CI, 0.229-0.530; P < .0001).2 The 6-month EFS rates in the investigative cohort was 63.3% (95% CI, 52.0%-74.7%) compared with 33.4% (95% CI, 23.0%-43.8%) in the control group. At 12 months, EFS rates in the investigative cohort was 44.5% (95% CI, 29.4%-59.6%) vs 23.7% (95% CI, 13.4%-34.1%) in the control cohort.
Median PFS in the liso-cel arm was 14.8 months (95% CI, 6.6-NR) compared with 5.7 months (95% CI, 3.9-9.4) in the SOC group (HR, 0.406; 95% CI, 0.250-0.659; P = .0001). The 6-month PFS rate with liso-cel was 69.4% (95% CI, 58.1%-80.6%) compared with 47.8% (95% CI, 35.0%-60.6%) with SOC. The 12-month PFS rates were 52.3% (95% CI, 36.7%-67.9%) in the liso-cel cohort vs 33.9% (95% CI, 20.1%-47.7%) in the control arm.
Liso-cel produced a CR rate of 66% (95% CI, 55.7%-75.8%) compared with 39% (95% CI, 29.1%-49.9%) in the SOC (P < .0001) group. ORRs in the investigative cohort were 86% (95% CI, 77.0%-92.3%) compared with 48% (95% CI, 27.3%-58.5%) in the control arm.
OS data were immature at the time of data cutoff; however, researchers found a numerical trend favoring liso-cel. The median OS in the liso-cel arm had not yet been reached (95% CI, 15.8-NR) compared with 16.4 months (95% CI, 11.0-NR) in the SOC arm (HR, 0.509; 95% CI, 0.258-1.004; P = .0257). The estimated OS rate at 6 months was 91.8% (95% CI, 85.4%-98.2%) in the investigative cohort compared with 89.4% (95% CI, 82.9%-96.0%) in the control group. At 12 months, the estimated rates were 79.1% (95% CI, 67.1%-91.1%) in the investigative cohort vs 64.2% (95% CI, 50.5%-77.9%) in the control group.
“[Liso-cel] represents a remarkable advance over a nearly 30-year standard of care, providing significantly improved efficacy with a well-established safety profile,” TRANSFORM study lead investigator Manali Kamdar, MD, associate professor, clinical director of Lymphoma Services, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, said 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.”
All patients administered liso-cel reported treatment-emergent adverse effects (TEAEs) compared with 99% in the SOC arm. The most frequently reported TEAEs with liso-cel were neutropenia (82%), anemia (63%), and thrombocytopenia (58%).
Further, 92% of patients administered liso-cel had grade 3 or higher TEAEs compared with 87% of patients in the SOC group. Common grade 3 or higher TEAEs in patients administered liso-cel included neutropenia (80%), anemia (49%), thrombocytopenia (49%), and lymphopenia (25%). Any-grade serious TEAEs were reported in 48% of patients across both cohorts
“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,” Lee Greenberger, PhD, chief scientific officer of the Leukemia & Lymphoma Society (LLS), said in a press release. “As one of the earliest supporters of CAR T since the 1990s, 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.”