In the phase 3 TRANSFORM study, lisocabtagene maraleucel bested standard of care as treatment of patients with high-risk relapsed/refractory large B-cell lymphoma.
Patients with high-risk relapsed/refractory large B-cell lymphoma (LBCL) receiving treatment in the second-line setting had a 64.4% reduction in the risk of an event with lisocabtagene maraleucel (liso-cel; Breyanzi) vs standard-of-care (SOC) chemoimmunotherapy induction and autologous stem cell transplantation (ASCT), according to findings from the phase 3 TRANSFORM study (NCT03575351) presented at the 2022 ASH Annual Meeting.1
After a median follow-up of 17.5 months in the open-label study, the median event-free survival (EFS) was not yet reached with liso-cel compared with 2.4 months for SOC (HR, 0.356; 95% CI, 0.243-0.522). The 18-month EFS rate was 52.6% with liso-cel (95% CI, 42.3%-62.9%) vs 20.8% with SOC (95% CI, 12.2%-29.5%). EFS findings were consistent across subgroups, with hazard ratios ranging from 0.10 to 0.46.
The median progression-free survival (PFS) was not yet reached with liso-cel (95% CI, 12.6-not reached) compared with 6.2 months with SOC (95% CI, 4.3-8.6), with a 60% reduction seen in the risk of progression or death with the CAR T-cell therapy (HR, 0.400; 95% CI, 0.261-0.615; P <.0001). The 18-month PFS rate was 58.2% with liso-cel (95% CI, 47.7%-68.7%) compared with 28.8% with SOC (95% CI, 17.7%-40.0%).
“The primary analysis of the TRANSFORM study confirms the superiority of liso-cel over SOC. Liso-cel resulted in significant improvements in event-free survival, complete response rates, and progression-free survival, with 18-month event-free and progression-free survival rates for liso-cel more than double those of standard of care,” lead study author Jeremy S. Abramson, MD, from the Massachusetts General Hospital Cancer Center, Harvard Medical School, in Boston. “Despite allowing for crossover, overall survival numerically favored liso-cel and a supportive overall survival adjusting for crossover showed an overall survival benefit in favor of liso-cel."
In the study, patients were randomized 1:1 to receive a conditioning regimen of fludarabine and cyclophosphamide followed by liso-cel at 100 x 106 CAR+ T cells (n = 92) or SOC, which consisted of 3 cycles of standard salvage immunochemotherapy followed by high-dose chemotherapy and ASCT (n = 92). In the liso-cel arm, 63% of patients received bridging therapy while the CAR T-cell therapy was manufactured. Patients were allowed to cross over from SOC to liso-cel, with 66% of patients (n = 61) discontinuing SOC for liso-cel and 57 receiving the treatment.
The patient characteristics were balanced between groups, with a median age of 60 and 58 years, in the liso-cel and SOC arms, respectively. More patients were male in the SOC arm (66%) than in the liso-cel group (48%). The most common LBCL subtype was diffuse large B-cell lymphoma not otherwise specified (58% in liso-cel arm vs 54% in SOC group). The ECOG performance status was either 0 (52% with liso-cel and 62% with SOC) or 1 (48% with liso-cel vs 38% with SOC). Most patients were refractory to their last therapy (73% with liso-cel vs 76% with SOC).
The objective response was 87% with liso-cel (95% CI, 78.3%-93.1%) compared with 49% with SOC (95% CI, 38.3%-59.6%). The complete response (CR) rate was 74% with liso-cel (95% CI, 63.7%-82.5%) compared with 43% with SOC (95% CI, 33.2%-54.2%), which was a statistically significant improvement with the CAR T-cell therapy (P <.0001). The duration of CR was not yet reached with liso-cel compared with 9.3 months with SOC (HR, 0.483; 95% CI, 0.262-0.890).
There were 26 patients with a partial response at the interim analysis. At the primary analysis that was presented at ASH, 9 of these responses deepened to a CR, with 6 of these being in the liso-cel group and 3 in the SOC arm. An analysis of liso-cel persistence found CAR T cells up to 23 months following induction in 5 of 15 evaluable patients. The median time to peak CAR T-cell expansion was 10 days.
The median overall survival (OS) was not yet reached in the liso-cel arm with 17.5 months of follow up. The median was 29.9 months in the SOC arm, with the bar for statistical superiority not yet reached between the arms (HR, 0.724; 95% CI, 0.443-1.183; P = .0987). The 18-month OS rate was 73.1% with liso-cel (95% CI, 63.9%-82.3%) compared with 60.6% with SOC (95% CI, 50.2%-71.1%).
A 2-stage accelerated failure time model was utilized to attempt to correct for the crossover seen between arms. In this assessment, the median OS was not reached in either arm with the 18-month OS rate in the SOC arm adjusted to 54.1% (95% CI, 43.1%-65.2%). The hazard ratio in this analysis was 0.415 in favor of liso-cel (95% CI, 0.251-0.686).
For the 61 patients who crossed over to liso-cel, the median follow up was 12.0 months and the median time from crossover to infusion of liso-cel was 15 days. At this assessment, the ORR was 61% with the CAR T-cell therapy, with a CR rate of 53%. The median EFS was 5.9 months (95% CI, 3.1-15.1) and the median PFS was 5.9 months (95% CI, 3.2-26.5). The median OS for this analysis was 15.8 months (95% CI, 11.8-not reached).
“Notably, the rates of complete response, event-free survival, and progression-free survival were lower in cross over patients than in patients on the liso-cel arm who received it in second-line, suggesting a benefit to earlier treatment,” said Abramson.
Cytokine release syndrome of any grade occurred in 49% of patients receiving liso-cel and was primarily grade 1/2 in severity, with 1 patient having a grade 3 event. The median onset to this event was 5.0 days following infusion and the median time to resolution was 4.0 days. Eleven percent of patients had a neurologic event (NE), with 4 having a grade 3 event, 2 with a grade 2, and 4 with a grade 1 NE. The median time to onset for NE was 11.0 days and the median time to resolution was 4.5 days.
Across both CRS and NE, tocilizumab monotherapy was utilized for 10% of patients, tocilizumab plus corticosteroids for 14% of patients, and corticosteroids alone for 2% of patients. No vasopressors or prophylactic steroids were administered. Other events of interest included prolonged cytopenias (43% with liso-cel vs 3% with SOC) and grade 3 or greater infection (15% with liso-cel and 21% with SOC).
“Although prolonged cytopenias were more common in the liso-cel arm vs the standard of care, it did not result in a higher rate of grade 3 or higher infection,” said Abramson. “The incidence of CAR T-cell associated adverse events was low and manageable, consistent with prior reports for this CAR T-cell product.”
Based on an earlier assessment of the TRANSFORM study, the FDA approved liso-cel as a second-line treatment for patients with LBCL in June 2022. This approval was specifically for those with refractory disease or relapse within 12 months of first-line chemoimmunotherapy. The agent was approved with a Risk Evaluation and Mitigation Strategy for CRS and NE.
Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel (liso-cel) versus standard of care (soc) with salvage chemotherapy followed by autologous stem cell transplantation (asct) as second-line (2L) treatment in patients with relapsed or refractory large B-cell lymphoma (LBCL): primary analysis of the randomized, phase 3 Transform study. Blood. 2022;140(suppl 1):1581-1583. doi:10.1182/blood-2022-159702