The FDA has approved lisocabtagene maraleucel as second-line therapy for adult patients with large B-cell lymphoma, including diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.
The FDA has approved lisocabtagene maraleucel (liso-cel; Breyanzi) as second-line therapy for 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 LBCL, and follicular lymphoma grade 3B.1
The indication is specific to patients who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or 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.
The approval is based on findings from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 PILOT trial (NCT03483103).
In TRANSFORM, liso-cel significantly improved event-free survival (EFS), complete responses (CRs), and progression-free survival (PFS) vs standard salvage chemotherapy followed by high-dose chemotherapy plus autologous HSCT in this patient population. In PILOT, liso-cel resulted in a high rate of durable overall and complete responses as second-line therapy in frail patients with relapsed/refractory LBCL for whom HCST was not intended.
“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,” Ester Banque, senior vice president and general manager, US Hematology, Bristol Myers Squibb, stated 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.”
TRANSFORM enrolled patients between the ages of 18 years and 75 years 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 following frontline treatment containing an anthracycline and a CD20-targeted agent. The maximum ECOG performance status permitted was 1. Patients needed to be candidates for HSCT.
Following screening plus leukapheresis and randomization, those in the investigative arm were administered 100 x 106 CAR T cells and those in the control arm were given 3 cycles of salvage chemotherapy followed by high-dose chemotherapy plus autologous SCT (ASCT).
Patients on the placebo arm were allowed to crossover to receive liso-cel if they did not respond by 9 weeks after randomization, experienced progressive disease at any time, or began a new antineoplastic therapy following ASCT.
The primary end point of the trial was EFS, and key secondary end points included CR rate, PFS, and overall survival (OS). Other end points of interest included duration of response (DOR), objective response rate (ORR), and safety.
At a median follow-up of 6.2 months in both treatment arms, the median EFS in those who received liso-cel (n = 92) was 10.1 months (95% CI, 6.1–not reached [NR]) vs 2.3 months (95% CI, 2.2-4.3) in those who received 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 and control arms were 63.3% (95% CI, 52.0%-74.7%) and 33.4% (95% CI, 23.0%-43.8%), respectively; at 12 months, these rates were 44.5% (95% CI, 29.4%-59.6%) and 23.7% (95% CI, 13.4%-34.1%), respectively.
The median PFS in the liso-cel arm was 14.8 months (95% CI, 6.6-NR) vs 5.7 months (95% CI, 3.9-9.4) in the SOC arm (HR, 0.406; 95% CI, 0.250-0.659; P = .0001). The 6-month PFS rate with the CAR T-cell therapy was 69.4% (95% CI, 58.1%-80.6%) vs 47.8% (95% CI, 35.0%-60.6%) with SOC; the 12-month PFS rates were 52.3% (95% CI, 36.7%-67.9%) and 33.9% (95% CI, 20.1%-47.7%), respectively.
Moreover, liso-cel elicited a CR rate of 66% (95% CI, 55.7%-75.8%) vs 39% (95% CI, 29.1%-49.9%) with SOC (P < .0001). The ORRs achieved in the investigative and control arms were 86% (95% CI, 77.0%-92.3%) and 48% (95% CI, 27.3%-58.5%), respectively.
OS data were immature at the time of data cutoff, but a numerical trend favoring the CAR T-cell therapy was observed. The median OS in the liso-cel arm had not yet been reached (95% CI, 15.8-NR) vs 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 in the investigative and control arms were 91.8% (95% CI, 85.4%-98.2%) and 89.4% (95% CI, 82.9%-96.0%), respectively; these estimated rates were 79.1% (95% CI, 67.1%-91.1%) and 64.2% (95% CI, 50.5%-77.9%), respectively, at 12 months.
“[Liso-cel] represents a remarkable advance over a nearly 30-year standard of care, providing significantly improved efficacy with a well-established safety profile,” Manali Kamdar, MD, lead investigator of the TRANSFORM study and associate professor, Clinical Director of Lymphoma Services, Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado Cancer Center, stated 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.”
In terms of safety, all patients who received liso-cel reported treatment-emergent adverse effects (TEAEs) vs 99% in the SOC arm. The TEAEs that were most frequently experienced with the CAR T-cell therapy included neutropenia (82%), anemia (63%), and thrombocytopenia (58%).
Ninety-two percent of patients who received liso-cel experienced grade 3 or higher TEAEs vs 87% of those who were given SOC. Common grade 3 or higher TEAEs reported in those who received the CAR T-cell therapy comprised neutropenia (80%), anemia (49%), thrombocytopenia (49%), and lymphopenia (25%). Any-grade serious TEAEs occurred in 48% of those in both treatment arms.
Investigators identified cytokine release syndrome (CRS) and neurological events (NEs) as TEAEs of special interest with liso-cel, and 49% of patients reported any-grade CRS. The median time to onset was 5 days (range, 1-63), and the median time to resolution was 4 days (range, 1-16). Moreover, 12% of patients experienced any-grade NEs. The median time to onset of this effect was 11 days (range, 7-25), and the median time to resolution was 6 days (range, 1-30).
In the efficacy analysis set of all 61 patients treated with liso-cel in PILOT, 80% of patients achieved an objective response (95% CI, 68.2%-89.4%; P < .0001).3 Among 27 patients with a hematopoietic cell transplantation comorbidity index (HCT-CI) score of 3 or more, the ORR was 81% (95% CI, 61.9%-93.7%), and patients with an HCT-CI score less than 3 had an ORR of 79% (95% CI, 62.1%-91.3%).
At a median follow-up of 12.3 months (range, 1.2-26.5), the CR rate was 54% (95% CI, 40.8%-66.9%), with a median DOR of 21.7 months (95% CI, 12.1-NR).
Moreover, median PFS was 9 months (95% CI, 4.2-NR) after a median follow-up of 13 months (range, 12-18.1), while median OS was NR (95% CI, 17.3-NR) after a median follow-up of 17.6 months (range, 12.4-18.6).
Notably, there were no significant differences among the efficacy or safety outcomes depending on HCT-CI score.
Eligible patients had received 1 prior line of treatment that included an anthracycline and a CD20-targeted agent, an ECOG performance score of 2, and adequate organ function. Moreover, eligible patients had to have diffusing capacity of the lungs for carbon monoxide at 60% or less, left ventricular ejection fraction less than 50%, a creatine clearance less than 60 mL/min, and/or alanine aminotransferase or aspartate aminotransferase greater than double the upper limit of normal as reasons for not undergoing HSCT.
Liso-cel was given at 100 x 106 CAR T cells for 2 to 7 days after fludarabine and cyclophosphamide lymphodepletion at doses of 30 mg/m2 and 300 mg/m2, respectively.
The safety profile was consistent with prior reports, and no new or increased safety profiles were reported. 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, with 2 having grade 5 COVID-19–related TEAEs.
CRS or neurotoxicity incidence was low with no grade 4 or 5 events and was managed with tocilizumab and/or corticosteroids in 26% and 13%, respectively. Overall, 23 patients had CRS of any grade with 11 patients having grade 1 CRS and 11 having grade 2 CRS. Nineteen patients had neurotoxicity of any grade, with 11 patients experiencing grade 1 neurotoxicity, 5 having grade 2 neurotoxicity, and 3 patients had grade 3 neurotoxicity.
The median time to resolution for patients experiencing neurotoxicity was 6 days (range, 1-89) compared with a median onset of 4 days (range, 1-12) for patients that experienced CRS and a median of 4 days (range, 1-12) to resolution.
“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), stated in a press release. “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.”
Previously, in February 2021, the FDA approved liso-cel for the treatment of adult patients with certain types of LBCL who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.4