Axi-cel and Tisa-Cel Demonstrate Comparable Efficacy in Follicular Lymphoma

Michael Dickinson, MD

According to the primary and sensitivity analysis findings from a match-adjusted analysis, treatment with axicabtagene ciloleucel (Yescarta; axi-cel) in the ZUMA-5 trial (NCT03105336) compared with tisagenlecleucel (Kymriah; tisa-cel) in the ELARA trial (NCT03568461), showed similar efficacy profiles in patients with follicular lymphoma.¹

The analysis also showed that the safety profile among those treated with tisa-cel in both the primary and sensitivity analyses were more favorable compared with the axi-cel-treated population, according to a presentation given during the 2022 Transplantation & Cellular Therapy Meetings.

“Tisa-cel and axi-cel have both been evaluated in pivotal phase 2 clinical trials with registrational intent—ELARA and ZUMA-5, respectively—which included patients with greater than or equal to 2 prior lines of therapy and both trials demonstrated high overall response rates [ORRs] and complete responses [CRs],” Michael Dickinson, MD, said during a presentation of the data. Dickinson is lead of the aggressive lymphoma disease group within Clinical Hematology at Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia.

“Given this clinical context, as well as promising 12-month progression-free and overall survival [OS] data, and because head-to-head comparisons between CAR T-cell products are unlikely to occur, we performed an indirect comparison of these 2 clinical trials and their CAR T interventions. The objectives of this study were to indirectly compare efficacy and safety outcomes between tisa-cel and axi-cel in relapsed or refractory follicular lymphoma using matching adjusted, indirect comparison.”

To conduct the analysis, investigators adjusted the population using individual patient-level data, using what Dickinson described as factors of convenience. “[Investigators of] both ZUMA-5 and ELARA have reported clinically relevant factors…these factors were reasonably reflective [of real-world] patients in that they were in both primary analyses and how clinicians think about prognostic factors for real-world refractory lymphoma.”

The weighting and match analysis included the following factors: age, sex, ECOG performance status, Ann Arbor tumor staging, follicular lymphoma international prognostic index score, tumor burden, number of prior lines of therapy, prior autologous stem cell transplant (ASCT), and progression of disease in 24 months. Patients treated with tisa-cel in ELARA were matched to the average baseline characteristics from aggregated summary data of those who received axi-cel in ZUMA-5.

Two analyses were performed. The primary analysis compared included patients from ELARA who received infusion and did not have exposure to bridging chemotherapy with comparable patients from ZUMA-5. The sensitivity analysis compared those in ELARA with and without exposure to bridging chemotherapy with patients from ZUMA-5.

“ELARA differed from ZUMA-5 in that it allowed bridging chemotherapy prior to CAR T-cell therapy,” Dickinson said. “We know from other studies, particularly in the large cell lymphoma setting, this may select for patients with poorer prognosis disease.”

Of note, Dickinson said investigators used a data cutoff of March 20, 2020, for ZUMA-5 and a March 29, 2021, data cutoff for ELARA. Efficacy-evaluable patients were defined as those with at least 12 months of follow-up.

Once balanced populations were achieved, investigators compared binary outcomes including ORR, CR, and safety, as well as an analysis of progression-free survival (PFS) and OS using weighted Cox proportional hazards model for hazard ratio estimation.

Results from the Primary Analysis

The primary analysis included 50 patients from ELARA and 84 patients from ZUMA-5. The ORRs after weighting were 92.59% vs 94.05% (P < .05) and the CRs were 77.45% vs 79.76%, respectively. Dickinson noted that these results were comparable to the results observed before weighting which showed ORRs of 90% vs 94.05% and CRs of 70% vs 79.76%, among those treated with tisa-cel and axi-cel respectively.

The PFS was also comparable between the 2 agents. After weighting, the median PFS for those who received tisa-cel was not reached (NR; 95% CI, NR-NR) vs not reached (95% CI, 23.54-NR) with axi-cel (HR, 0.90; 95% CI, 0.39-2.06; P = .81). Prior to weighting investigators noted a hazard ratio of 1.02 (95% CI, 0.52-1.99).

OS analyses were also similar in the primary analysis with a hazard ratio of 0.33 (95% CI, 0.07-1.57) after weighting compared with 0.45 (95% CI, 0.13-1.59) prior to weighting.

The safety analysis was conducted among 53 patients from ELARA and 124 patients from ZUMA-5. Those who received tisa-cel had lower rates of cytokine release syndrome (CRS), corticosteroid and tocilizumab use for CRS, and overall incidence of neurologic events compared with those who received axi-cel.

Specifically, the rate of any-grade CRS, corticosteroid use, tocilizumab use, and any-grade neurological events among those who received tisa-cel were 45.52%, 2.63%, 9.59%, and 8.75%, respectively. Among patients treated with axi-cel these rates were 78.23%, 15.32%, 45.16%, and 56.45%, respectively. In terms of grade 3 events, no patients who received tisa-cel experienced grade 3 CRS compared with 6.45% of patients who received axi-cel. Further, only 0.29% of patients who received tisa-cel had a grade 3 neurologic event compared with 15.32% of patients who received axi-cel.

Results from the Sensitivity Analysis

In an efficacy evaluation which included patients who received bridging therapy in ELARA (n = 90), results were also comparable in terms of efficacy to patients who received axi-cel in ZUMA-5 (n = 124). After weighting the ORR was 89.77% among those who received tisa-cel vs 94.05% among those who received axi-cel. The CR rates were 75.05% and 79.76%, respectively.

In terms of survival data, the median PFS for those who received tisa-cel was not reached (95% CI, 19.45-NR) vs not reached (95% CI, 23.53-NR) for those who received axi-cel (HR, 1.13; 95% CI, 0.60-2.15). These results were comparable to those observed prior to weighting in which the hazard ratio was 1.35 (95% CI, 0.79-2.32).

The weight-adjusted OS analysis showed that tisa-cel was significantly better than axi-cel with an HR of 0.23 (95% CI, 0.07-0.70) compared with 0.56 (95% CI, 0.21-1.52) prior to weighting.

“We’d like to be cautious of this result, given the short follow-up of ELARA and the earlier data cutoff from ZUMA-5,” Dickinson noted.

In terms of safety, 97 patients from ELARA were compared with 124 patients from ZUMA-5. Results were similar to those reported in the primary analysis. The median follow-up for safety was 17 months in ELARA and 15 months in ZUMA-5.

The rate of any-grade CRS, corticosteroid use, tocilizumab use, and any-grade neurological events among those who received tisa-cel were 47.01%, 4.89%, 13.71%, and 7.96%, respectively. Among patients treated with axi-cel these rates were 78.23%, 15.32%, 45.16%, and 56.45%, respectively. In terms of grade 3 events, CRS was reported among 0.06% of patients in ELARA compared with 6.45% in ZUMA-5 and 0.97% of patients who received tisa-cel had a grade 3 neurologic event compared with 15.32% of patients who received axi-cel.

“Future studies using long term follow-up data from both trials or real-world data will be important for comparisons of the efficacy and safety of tisa-cel and axi-cel for the treatment of relapsed or refractory follicular lymphoma,” Dickinson said.

_Reference

_{Dickinson M, Martinez-Lopez J, Jousseaume E, at al. Comparative efficacy and safety of tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) in relapsed/refractory follicular lymphoma (FL). Presented at: 2022 Transplantation & Cellular Therapy Meetings; April 23-26, 2022. Abstract 77.}