Axi-Cel Retains Its Benefit in a Real-World Setting in Large B-Cell Lymphomas

Caron A. Jacobson, MD

Axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated a similar overall response rate (ORR) and toxicity rates among patients with relapsed or refractory large B-cell lymphoma treated with the chimeric antigen receptor (CAR) T-cell therapy in both a trial and non-trial setting, according to the results of a study of post-commercial experience with the CAR product that was recently published in the Journal of Clinical Oncology.1

However, statistically significant improvements were seen in terms of complete response (CR) rates and the durations of response (DOR) for patients who were treated in the ZUMA-1 clinical trial.

“Axi-cel in the nontrial setting retains its efficacy, with a similar safety profile. Patients eligible for ZUMA-1 do better than do ineligible patients, but CAR T cells do yield durable responses in this latter group as well ,” the study authors, led by Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute, wrote in the published report. “This then is not a group to exclude from CAR T-cell therapy, but rather, defines a group for whom there is an unmet need with our currently available treatments.”

Axi-cel was approved by the FDA in October 2017 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma based on findings from the ZUMA-1 trial. In the trial, which included 101 evaluable patients with relapsed/refractory large B-cell lymphoma, the ORR was 83% and CRs were seen in 58% of patients with a median overall DOR of 11.1 months. The median progression-free survival (PFS) was 5.9 months, and the median overall survival (OS) was not reached.2

However, researchers wondered whether the benefit of therapy would be restricted to a subset of patients with fewer comorbidities and complicated tumor characteristics in line with the parameters of the trial enrollment criteria and if a more “real-world” population could tolerate the engineering process.

The researchers conducted a retrospective analysis of adult patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas treated with axi-cel. Patients were treated between December 2017 and October 2018 at 1 of 7 centers.

A total of 122 patients who received axi-cel were included in the modified intention-to-treat (mITT) analysis. Of these patients, 46 (38%) would have been eligible for the ZUMA-1 trial based on their characteristics and that of their disease, and 76 (62%) would not have been eligible.

In the ZUMA-1–eligible group, the median age was 60 years (range, 21-78) and patients had an ECOG performance status of 0 (39%) or 1 (61%) only. The majority of patients (70%) had a low International Prognostic Index (IPI) score before lymphodepletion of 0 to 2. Thirty-nine percent of patients had a diagnosis of diffuse large B-cell lymphoma (DLBCL), 28% had transformed follicular lymphoma, and 26% had double-hit lymphoma.

Among the ineligible patients, the median age was 62 (range, 25-79) and ECOG performance status scores ranged from 0 (24%) to 4 (3%), although most had a score of 1 (61%). The majority of patients (55%) had a higher International Prognostic Index (IPI) score before lymphodepletion of 3 to 5. Almost half of the patients had DLBCL (46%), about a quarter had transformed follicular lymphoma (26%), and 17% had triple-hit lymphoma.

The reasons why these patients would not have been eligible for the trial included bridging therapy in 55%, best response of greater than stable disease in 12%, different histology in 9%, ECOG performance status above 1 in 9%, allogeneic transplantation in 5%, prior CD19- or CD20-directed CAR T-cell therapy in 4%, ejection fraction of less than 50% in 2%, central nervous system (CNS) disease in 1%, and HIV positive in 1%.

Overall, the best ORR among all treated patients was 70%, which included CRs in 50% and partial responses in 50%. The patients who were eligible for the trial had an ORR of 70% compared with 68% among the patients who would not have been eligible.

“Our analysis demonstrates that relaxation of eligibility had no effect on ORR,” the study authors reported.

Eighty-four patients achieved a CR at first restaging, and after at least 6 months of follow-up, 79% maintained their CR for an overall 6-month CR rate of 41%.

“Although ORR did not differ by ZUMA-1 eligibility, CR rates, DOR, and survival were inferior in ineligible patients. These differences are important, because this therapy’s power is its response durability. This warrants additional investigation into a possible set of patient/disease characteristics that could predict treatment failure,” Jacobson et al wrote.

The median DOR was 11.0 months overall but was not reached in patients who achieved a CR at first restaging. Median PFS was 4.5 months in all treated patients and was not reached in patients who achieved a CR at first restaging. The median OS was not reached; at 1 year, the OS rate was 67%. These outcomes were similar to findings observed in the ZUMA-1 trial.

Cytokine release syndrome (CRS) was reported in 93% of patients, and 16% of cases were grade ≥3 in severity. Only 1 fatality was due to CRS. CRS occurred after a median of 3 days (range, 0-20) and lasted for a median of 6 days (range, 1-27).

Neurotoxicity was observed in 70% of patients and was grade ≥3 in severity in 35% with 1 event leading to death. The median time to onset of neurotoxicity was 5 days (range, 0-34), and it lasted for a median of 7 days (range, 1-52).

Nonrelapse related mortality was seen in 6% of patients. Twenty-eight percent of patients were transferred to an intensive care unit and 18% were readmitted to a hospital, most often due to CAR T-cell–related complications.

Mortality rates were higher among patients who did not meet the ZUMA-1 trial criteria compared with those who did (43% vs 11%; P <.001); all treatment-related deaths were reported in patients who were ineligible.

_References

1. _{Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity. J Clin Oncol. Published online July 15, 2020. doi:10.1200/JCO.19.02103}
2. _{Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7}