Lisocabtagene maraleucel demonstrated statistically and clinically meaningful improvement in event-free survival compared with the standard of care as a second-line therapy in patients with relapsed or refractory large B-cell lymphoma.
Lisocabtagene maraleucel (liso-cel) demonstrated a statistically and clinically meaningful improvement in event-free survival (EFS) compared with the standard of care (SOC) as a second-line therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to results of a prespecified interim analysis of the phase 3 TRANSFORM study (NCT03575351) presented at the 2021 American Society of Hematology Annual Meeting & Exposition.
“Liso-cel is an autologous CD19-directed, defined composition, 4-1BB chimeric antigen receptor [CAR] T-cell product administered at equal target doses of CD8-positive and CD4-positive CAR T cells,” said Manali Kamdar, MD, clinical director of Lymphoma Services at the University of Colorado Hospital in Aurora. “Liso-cel has [previously] demonstrated efficacy and a manageable safety profile in patients with relapsed/refractory LBCL after at least 2 prior lines of therapy in the TRANSCEND NHL 001 study [NCT02631044].”
The median follow-up in both arms was 6.2 months.
The median EFS in the 92-patient liso-cel arm was 10.1 months (95% CI, 6.1 to not reached [NR]) vs 2.3 months (95% CI, 2.2-4.3) among the 92 patients treated with SOC (HR, 0.349; 95% CI, 0.2290.530; P < .0001). The 6-month EFS rate was 63.3% (95% CI, 52.0%-74.7%) in the liso-cel group compared with 33.4% (95% CI, 23.0%-43.8%) in the SOC group. Patients in the liso-cel arm achieved a 12-month EFS rate of 44.5% (95% CI, 29.4%-59.6%) vs 23.7% (95% CI, 13.4%-34.1%) in the SOC arm.
EFS results also favored liso-cel across all of the subgroups examined in the analysis. Refractory patients in the liso-cel group (n = 67) experienced an EFS event at a rate of 44.8% vs 76.5% in the SOC arm (n = 68; HR, 0.350; 95% CI). Among the relapsed patients treated with liso-cel (n = 25), 5 had an event compared with 11 of the 24 patients treated with SOC (HR, 0.343; 95% CI). Male patients in the liso-cel arm (n = 44) experienced an event at a rate of 43.2% vs 72.1% in the 61-patient SOC subgroup (HR, 0.331; 95% CI).
To be eligible for the 1:1 randomized trial, patients had to be aged between 18 and 75 years and have aggressive non-Hodgkin lymphoma, including diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high-grade B-cell lymphoma (HGBCL) with DLBCL histology, follicular lymphoma grade 3B, primary mediastinal large B-cell lymphoma, or T-cell/histiocyte-rich large B-cell lymphoma. Patients needed to be refractory or relapsed for a maximum of 12 months after a first-line treatment containing an anthracycline and a CD20-targeted agent. The maximum ECOG performance status allowed was 1 and patients needed to be eligible for hematopoietic stem cell transplantation (SCT).
After screening plus leukapheresis and randomization, patients in the liso-cel arm received 100 x 106 CAR T cells and patients in the SOC arm received 3 cycles of salvage chemotherapy followed by high-dose chemotherapy plus autologous SCT (ASCT). Crossover to the liso-cel arm was allowed if patients failed to respond by 9 weeks post randomization, experienced disease progression (PD) at any time, or started a new antineoplastic therapy after ASCT. Investigators assessed response at weeks 9 and 18, as well as at months 6, 9, 12, 18, 24, and 36.
The primary end point of the trial was EFS, defined as time from randomization to death due to any cause, PD, failure to achieve complete response (CR) or partial response by 9 weeks post randomization, or the start of a new antineoplastic therapy, whichever occurs first. The key secondary end points were CR rate, progressionfree survival (PFS), and overall survival (OS). Additional secondary end points included duration of response, objective response rate (ORR), and safety. The exploratory end points consisted of cellular kinetics and B-cell aplasia.
A total of 232 patients were screened; 184 received leukapheresis and were randomized into the trial. At the time of reporting, the liso-cel arm had 78 ongoing patients and the SOC arm had 32. Fifty patients in the SOC group were approved for crossover and 46 of these patients received CAR T-cell therapy as a third-line treatment.
The median age in the liso-cel cohort was 60 years (range, 53.5-67.5) vs 58 (range, 42-65) in the SOC arm. The most common LBCL subtype in both groups was DLBCL NOS (58% vs 53%, respectively) followed by HGBCL with DLBCL histology (24% vs 23%, respectively). Most patients in both arms had an ECOG performance status of 0 (52% vs 62%, respectively) and had refractory disease (73% vs 74%, respectively).
The CR rate among patients treated with liso-cel was 66% (95% CI, 55.7%-75.8%; P < .0001) compared with 39% (95% CI, 29.1%-49.9%) in the SOC arm. Patients in the liso-cel arm achieved an ORR of 86% (95% CI, 77.0%-92.3%) vs 48% (95% CI, 37.3%-58.5%) in the SOC arm.
The median PFS in the liso-cel cohort was 14.8 months (95% CI, 6.6-NR) vs 5.7 months (95% CI, 3.9-9.4) in the SOC cohort (HR, 0.406; 95% CI, 0.250-0.659; P = .0001). The 6-month PFS rates were 69.4% (95% CI, 58.1%-80.6%) and 47.8% (95% CI, 35.0%-60.6%), respectively. The 12-month PFS rates were 52.3% (95% CI, 36.7%-67.9%) and 33.9% (95% CI, 20.1%-47.7%), respectively.
Although OS data were immature at this data cutoff, investigators observed a numerical trend favoring liso-cel. The median OS in the liso-cel cohort was NR (95% CI, 15.8-NR) vs 16.4 months (95% 11.0-NR) in the SOC group (HR, 0.509; 95% CI, 0.258-1.004; P = .0257). The 6-month OS rates were 91.8% (95% CI, 85.4%-98.2%) and 89.4% (95% CI, 82.9%-96.0%), respectively. The 12-month OS rates were 79.1% (95% CI, 67.1%-91.1%) and 64.2% (95% CI, 50.5%-77.9%), respectively.
In terms of safety, 100% of patients treated with liso-cel experienced a treatment-emergent adverse effect (TEAE) compared with 99% of patients treated with SOC. The most common TEAEs of any grade in the liso-cel cohort were neutropenia (82%), anemia (63%), and thrombocytopenia (58%).
Grade 3 or higher TEAEs were present at a rate of 92% and 87% in the liso-cel and SOC arms, respectively. Common grade 3 or higher TEAES among patients receiving liso-cel included neutropenia (80%), anemia and thrombocytopenia (both 49%), and lymphopenia (25%). Serious TEAEs of any grade were present in 48% of patients in both arms.
Cytokine release syndrome (CRS) and neurological events (NEs) were TEAEs of special interest in the liso-cel arm. Forty-nine percent of patients experienced 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).
Twelve percent of patients experienced NEs of any grade. The median time to onset was 11 days (range, 7-25) and the median time to resolution was 6 days (range, 1-30).
Regarding cellular kinetics, persistence of liso-cel was observed 11 months after infusion with follow-up ongoing. Among 83 evaluable patients in the liso-cel arm, the median cmax was 33,349 copies/μg (range, 13,873-95,618), the median tmax was 10 days (range, 9-11), and the median area under the curve 0-28 day x copies/μg was 270,345 (range, 111,550-793,716).
“[These results] provide support for liso-cel as a potential new standard of care for the second-line treatment of patients with relapsed/refractory LBCL,” concluded Kamdar.