Brexu-Cel Shows Real-World Safety and Tolerability in Higher-Risk R/R MCL

Yucai Wang, MD, PhD

Despite patients having broader characteristics and higher-risk features than patients included in the ZUMA-2 study, brexucabtagene autoleucel (Tecartus; brexu-cel) is safe and efficacious in patients outside of the academic setting with relapsed/refractory mantle cell lymphoma (MCL), according to a retrospective analysis presented at the 63rd American Society of Hematology Annual Meeting and Exposition.

Brexu-cel was approved by the FDA in this patient population based on results of the ZUMA-2 study (NCT02601313). During the study, brexu-cel showed an objective response rate of 93% and a complete response rate of 67%. The 12-month progression-free survival (PFS) rate was 61% and the overall survival rate was 85%. In order to participate in the original ZUMA-2 study, patients must have received between 1 and 5 prior lines of therapy, including an anti-CD20, anthracycline or bendamustine, and ibrutinib or acalabrutinib (Calquence), no central nervous system involvement, an ECOG performance status of less than 2, adequate blood counts, adequate hepatic and renal function, and no significant comorbidities.

The retrospective study included 107 cases reported from 14 cancer centers. All patients included underwent leukapheresis by June of 2021 with an intent to manufacture brexu-cel. Duration of response, PFS, and overall survival were analyzed with the Kaplan-Meier method.

“Eligibility for Zuma-2 was retrospectively determined at the time of leukapheresis. A total of 107 patients underwent leukapheresis between August 2020 And June 2021,” said Yucai Wang, MD, PhD, a hematologist oncologist at the Mayo Clinic, during the presentation.

Of the 107 patients included, 12 did not undergo transfusion. Six patients did not receive an infusion due to manufacture failure, 1 did not due to organ dysfunction, and 5 due to death. Ninety-Five patients went on to receive CAR T infusion.

The median age of patients in the real-world analysis was 67 (range, 34-89), 80% were male, 8% had an ECOG performance status of 2 or greater, and 57% were considered intermediate risk. Twelve percent of patients were classified as high-risk. Fifty-seven percent of patients had a Ki-67 score of 50% or more, 44% had a Tp53 mutation or deletion, and 29% had a complex karyotype. Eighty-seven percent of patients were stage III-IV, 7% had central nervous system involvement, 45% had bone marrow involvement, and 11% had bulky disease.

The median number of prior therapies was 3 (range, 1-10). Ninety-nine percent had received a prior CD20 antibody, 86% received prior anthracycline or bendamustine, 45% had received prior cytarabine, 28% had received prior autologous stem cell transplant, and 43% had received prior rituximab maintenance. Eighty-two percent had received prior BTK inhibitor therapy, 23% had received lenalidomide, and 35% had received prior venetoclax. Fifty-six percent of patients had relapsed after the last therapy line, and 44% were refractory to the last line of therapy. Sixty-seven percent of patients received bridging therapy.

The ORR for the general population was 89% (95% CI, 81-95) and the CR was 81% (95% CI, 72-88). For patients with classic/leukemic morphologic characteristics (n = 56), the ORR was 86% (95% CI, 75-94) and the CR was 77% (95% CI, 64-87), for patients with blastoids/pleomorphic (n = 39) morphologic characteristics, the ORR was 95% (95% CI, 83-99) and the CR was 87% (95% CI, . The ORR was 87% for both patients with TP53 wildtype (n = 39) (95% CI, 73-96) and TP53 deletion (n = 31) (95% CI, 70-96). The CR for patients with TP53 wildtype was 85% (95% CI, 69-94) and 71% (95% CI, 52-86) for those with TP53 mutations/deletion.

In patients with a Ki68 of <50% (n = 38), the ORR was 92 (95% CI, 79-98) and the CR was 87% (95% CI, 69-96). In patients with a Ki67 of ≥50% (n = 50), the ORR was 90% (95% CI, 78-97) and the CR rate was 78% (95% CI, 64-88).

For patients in a low MIPI risk group (n = 30), the ORR was 90% (95% CI, 73-98) and the CR rate was 87% (95% CI, 69-96). Patients with intermediate-risk disease (n = 54) had an ORR of 91% (95% CI, 80-97) and the CR rate was 81% (95% CI, 69-91). For patients with high risk (n = 11), the ORR was 82% (95% CI, 48-98) and the CR was 64% (95% CI, 31-89). For patients with central nervous system involvement (n = 7), the ORR was 86% (95% CI, 42-100) and the CR rate was 57% (95% CI, 18-90).

In patients who were BTK inhibitor naïve (n = 17), the ORR was 94% (95% CI, 71-100) and the CR rate was 88% (95% CI, 64-99). For patients who were BTK inhibitor therapy exposed (n = 78), the ORR was 88% (79-95) and the CR rate was 79% (95% CI, 69-88). For patients who were eligible for the ZUMA-2 study (n =21), the ORR was 86% (95% CI, 64-97) and the CR was 79% (95% CI, 69-88). For patients who were ZUMA-2 ineligible (n = 74), the ORR was 91% (95% CI, 81-96) and the CR was 80% (95% CI, 69-88). Patients who had received bridging therapy (n = 64) showed an ORR of 91% (95% CI, 81-96) and the CR rate was 83% (95% CI, 71-99). For patients who did not receive bridging therapy (n = 31), the ORR was 87% (95% CI, 70-96) and the CR rate was 77% (95% CI, 59-90).

The median time to initial response was 30 days (range, 16-104). Of the 20 patients with a partial response, 12 achieved a CR at a median of 64 days (range, 22-135). The median time to best response was 30 days (range, 16-168). At a median follow-up of 6.7 months (range, 0.5-13.6), the median duration of response was not reached, and the 6-month duration or response rate was 70%, which is comparable to that of the ZUMA-2 study. Similarly, PFS was not reached, with a 6-month rate of 66% and a 12-month rate of 51%. The 12-month PFS rate in the ZUMA-2 trial was 61%. Median OS was also not reached, with the 6-month rate being 81% and the 12-month rate being 72%. The 12-month overall survival was 83% in the ZUMA-2 study.

Cytokine release syndrome (CRS) occurred in 91%of patients in retrospective analysis, compared with 91% of patients in the ZUMA-2 study. In the retrospective analysis, 82% of patients experienced grade 1/2 CRS and 8% pf patients experienced grade 3/4 CRS. The median days to onset was 4 (range, 0-11) and the median days to max grade was 5 (range, 0-7). The median duration was 5 days. In the ZUMA-2 study, 76% of patients experienced grade 1/2 CRS and 15% of patients experienced grade 3/4 CRS. The median number of days to onset was 2 (range, 1-13) with a median duration of 11 days.

Immune effector cell-associated neurotoxicity syndrome (iCANS) occurred in 60% of patients in the retrospective compared with 63% of patients in ZUMA-2. In the retrospective, 25% of patients experienced grade 1/2 disease and 35% of patients experienced grade 3/4 disease. In the retrospective, the median days until onset was 6 (range, 1-15) and the median days to max grade was 7 (range, 3-15). The median duration was 6 days (range, 2-144+). In the ZUMA-2 study, 32% of patients experienced grade 1/2 iCANS and 31% experienced grade 3/4 ICANS. The median days to onset was 7 and the median duration was 12 days.

_REFERENCE:

_{Wang Y, Jain P, Locke F, et al. Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: Real world experience from the US Lymphoma CAR T Consortium.Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 3845.}