CAR T-cell therapies, axicabtagene ciloleucel (axi-cel; Yescarta) and lisocabtagene maraleucel (liso-cel; Breyanzi), are demonstrating significant promise in treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients, including those both eligible and ineligible for autologous stem cell transplant (ASCT). These therapies offer new hope for patients with limited treatment options.
ZUMA-7 Trial: Axicabtagene Ciloleucel (Axi-Cel) in ASCT-Eligible Patients
The phase 3 ZUMA-7 trial (NCT03391466) evaluated axi-cel in patients with relapsed or refractory DLBCL within one year of primary therapy completion who were also intending to proceed to ASCT. The study's updated outcomes with four years of follow-up continue to show statistically significant progression-free survival (PFS), with a hazard ratio (HR) of 0.51 (95% CI, 0.38-0.67). The primary endpoint of event-free survival (EFS) was also met, demonstrating a statistically significant advantage for the axi-cel arm with an HR of 0.42 (95% CI, 0.33-0.55).
Initially, there was no overall survival (OS) benefit, but further follow-up revealed an OS benefit in the axi-cel arm compared to the standard-of-care arm, with a hazard ratio of 0.73 (95% CI, 0.54-0.98; stratified P = .03). These results, with almost four years' median follow-up, highlight the long-term efficacy of axi-cel.
In the ZUMA-7 trial, cytokine release syndrome (CRS) of any grade was observed in 92% of patients, with only 6% experiencing grade 3 or higher CRS. Neurologic events of any grade occurred in 61% of patients, with 21% experiencing grade 3 or higher events. Comparatively, in the ASCT arm, neurologic events of any grade occurred in approximately 20% of patients, with grade 3 or higher events in only 1%.
ALYCANTE Study: Axicabtagene Ciloleucel (Axi-Cel) in ASCT-Ineligible Patients
Axi-cel was also investigated as a second-line therapy for relapsed/refractory large B-cell lymphoma patients deemed ineligible for ASCT. The phase 2 ALYCANTE study (NCT04531046) focused on complete response rate as its primary endpoint, revealing a 71% complete response rate and a 75% objective response rate (ORR).
In this population, 86% experienced grade 1/2 CRS, with 94% experiencing CRS of any grade. Any-grade immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in approximately 50% of patients, with 37% experiencing grade 1/2 ICANS and 15% experiencing grade 3/4 ICANS. The median onset of CRS was 1.5 days, while the median onset of ICANS was 6 days. Some patients experienced prolonged grade 3 or higher cytopenias, and approximately one-fourth of the patient population required intensive care unit transfers due to CAR T-cell therapy.
TRANSFORM Trial: Lisocabtagene Maraleucel (Liso-Cel) in ASCT-Eligible Patients
The TRANSFORM trial evaluated liso-cel, which has a 4-1BB costimulation domain, in contrast to axi-cel's CD28 costimulation. Liso-cel also has a 1:1 ratio of CD8 and CD4 components. Patients in this trial had either primary refractory disease or relapsed within 12 months of completing anthracycline-based therapy and were eligible for a transplant. The primary endpoint was EFS. Patients randomized to the liso-cel arm were allowed bridging therapy with one cycle of platinum-based therapy.
The primary endpoint of EFS, as well as PFS, were both positive with an HR of 0.356 (95% CI, 0.243-0.522) and 0.4 (95% CI, 0.261-0.615), respectively, demonstrating a statistically significant advantage for liso-cel in both EFS and PFS.
While the TRANSFORM trial did not show a statistically significant OS advantage (HR, 0.724; 95% CI, 0.443-1.183; P = .0987), a statistical analysis adjusting for crossover showed a statistically significant HR in favor of liso-cel compared with standard of care at 0.415 (95% CI, 0.251-0.686).
The percentage of complete response in the liso-cel arm was 74% vs 43% with standard of care, which was statistically significant.
The all-grade CRS was noted at 49%, with the vast majority being grade 1 or grade 2 (48%), with only 1 event of grade 3 or higher CRS. Regarding neurologic events, any grade was at 11%, with 8% grade 1/grade 2, and only 4 individuals having grade 3, with no grade 4 or 5 events. The median onset of CRS was 5 days and 11 days for ICANS. Grade 3 or higher neutropenia at study day 64 was seen in 37% of the liso-cel arm vs 2% of the standard-of-care arm.
PILOT Study: Lisocabtagene Maraleucel (Liso-Cel) in ASCT-Ineligible Patients
The PILOT study (NCT03483103) investigated liso-cel for patients not eligible for transplant based on age, ECOG performance status, or impaired organ function. Approximately half of the patients had primary refractory disease, 21% had relapsed within one year of therapy, and 25% had relapsed greater than 12 months post-first-line therapy.
With a short follow-up of 12 months, the ORR was 80%. Neutropenia was seen in approximately half of the patients and thrombocytopenia in approximately 20% of the patients. CRS occurred in 38% with only 1 case of grade 3 or higher CRS, and neurologic events occurred in 31% of all grades with 3 AEs that were grade 3. There were no grade 4 AEs or deaths.
