Brexu-cel Shows Safe and Efficacious Response in Advanced MCL

The phase ZUMA-2 trial showed safe and efficacious responses for patients with relapsed/refractory mantle cell lymphoma treated with brexucabtagene autoleucel.

Overall response rates (ORR) and complete response (CR) rates were improved when brexucabtagene autoleucel (brexu-cel; Tecartus) was used in patients with relapsed/refractory mantle cell lymphoma (MCL) in a real-world subgroup study of the phase 2 ZUMA-2 trial (NCT02601313) presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

At a median follow-up of 12.3 months (range, 2.9-28.6), the overall response rates (ORRs) and complete response (CR) rates were consistent across patients in all observed high-risk subgroups. In the overall population, the ORR was 91%, with an 81% CR rate. In patients with TP53/17p deletions, no TP53/17p deletions, a Ki-67 proliferation index of at least 50%, a Ki-67 proliferation index of less than 50%, ZUMA-2 trial eligibility, and ZUMA-2 trial ineligibility, the ORRs were 95%, 90%, 92%, 93%, 90%, and 93%, respectively, and the CR rates were 84%, 81%, 83%, 84%, 79%, and 84%, respectively.

“In this Center for International Blood and Marrow Transplant Research [CIBMTR] registry analysis, patients with high-risk features, including TP53 deletions and a high Ki-67 [proliferation index], did not have significant differences in efficacy outcomes compared with patients without these high-risk features,” lead study author Swetha Kambhampati, MD, an assistant professor in the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, at City of Hope in Duarte, California, stated during a presentation of the data. “In the univariate analysis, patients without TP53 deletions did have a numerically longer [median] overall survival [OS] than those with TP53 deletions, but this wasn’t statistically significant.”

Patients with relapsed/refractory MCL and high-risk features, such as TP53 mutations, TP53 deletions, or a high Ki-67 proliferation index, have historically had limited treatment options. The CAR T-cell therapy brexu-cel received FDA approval in 2020 for adult patients with relapsed/refractory MCL based on findings from ZUMA-2.² A 3-year follow-up analysis of the study demonstrated comparable outcomes with brexu-cel across prespecified high-risk subgroups.³

This real-world analysis describes outcomes with brexu-cel stratified by high-risk features, such as TP53 deletions, 17p deletions, Ki-67 proliferation index, and ZUMA-2 trial eligibility.

Between 2020 and 2022, 500 adult patients who were receiving brexu-cel for relapsed/refractory MCL across 85 centers in the United States were prospectively enrolled in the CIBMTR registry. Of these patients, 456 from 84 treatment centers were included in this real-world study. Forty-three patients were excluded because of a prior history of non-transplant cellular therapy (n = 7), a lack of efficacy and/or safety follow-up data (n = 15), or missing data (n = 21).

Of the evaluable patients, 42% had TP53 or 17p deletions (n = 44) and/or a Ki-67 proliferation index of at least 50% (n = 146). Furthermore, 183 patients had no TP53 or 17p deletions, and 111 patients had a Ki-67 proliferation index of less than 50%. Moreover, 57% of patients would not have met the ZUMA-2 eligibility criteria, mostly because of the presence of comorbidities prior to brexu-cel infusion.

In the overall population, the median age was 67 years (range, 34-84), and 61% of patients were at least 65 years of age. Six percent of patients had an ECOG performance status (PS) of 2 or higher prior to brexu-cel infusion, 76% of patients had clinically significant comorbidities, and 91%, 47%, and 71% of patients had stage III to IV disease at diagnosis, elevated lactate dehydrogenase (LDH) levels at diagnosis, and were chemoresistant prior to brexu-cel infusion, respectively. Patients had received a median of 3 prior lines of therapy (range, 1-12), and 32%, 87%, and 44% of patients had received prior hematopoietic cell transplantation (HCT), prior BTK inhibitors, or any type of bridging therapy. Furthermore, 9% of patients received planned outpatient brexu-cel infusion.

Compared with the overall population, the cohort of patients with TP53 or 17p deletions had fewer patients over the age of 65 years (41%), a higher proportion of patients who were chemoresistant prior to brexu-cel infusion (81%), and a lower proportion of patients who had received prior HCT (12%). Compared with the overall population, the cohort of patients with a Ki-67 proliferation index of at least 50% had lower proportions of patients with elevated LDH levels at diagnosis (41%), prior BTK inhibitor exposure (81%), and bridging therapy (37%). Compared with the overall population, the cohort of patients who would have been ineligible for enrollment in ZUMA-2 had higher proportions of patients with an ECOG PS of 2 or higher (10%), clinically significant comorbidities (87%), and chemoresistance prior to brexu-cel infusion (76%), as well as a lower proportion of patients with prior exposure to BTK inhibitors (78%).

In the overall population, the median duration of response (DOR) was not reached (NR). The estimated 6- and 12-month DOR rates in patients who achieved a best response of CR were 83% and 69%, respectively. In all responders, these rates were 78% and 65%, respectively.

Among all patients evaluable for survival (n = 456), the median OS was NR (95% CI, 18.9 months-NR), and the estimated 6- and 12-month OS rates were 86% and 75%, respectively. Among all progression-free survival (PFS)–evaluable patients (n = 442), the median PFS was 19.3 months (95% CI, 14.2-24.4), and the estimated 6- and 12-month PFS rates were 75% and 61%, respectively. In comparison, the 12-month PFS and OS rates in the primary analysis of ZUMA-2 were 61% and 83%, respectively.

The 6- and 12-month cumulative incidence rates of relapse or progressive disease (PD) were 19% and 30%, respectively, and the median time to relapse or PD among evaluable patients (n = 442) was 27.5 months.

Univariate analyses revealed no statistically significant differences in OS or PFS at any time point between any high-risk patient subgroups. In patients with TP53 or 17p deletions, the 12-month OS and PFS rates were 57% (95% CI, 40%-71%) and 53% (95% CI, 35%-68%), respectively. In patients without TP53 or 17p deletions, the 12-month OS and PFS rates were 76% (95% CI, 69%-82%) and 60% (95% CI, 51%-67%), respectively.

In patients with a Ki-67 proliferation index of at least 50%, the 12-month OS and PFS rates were 74% (95% CI, 66%-81%) and 63% (95% CI, 54%-71%), respectively. In patients with a Ki-67 proliferation index of less than 50%, the 12-month OS and PFS rates were 76% (95% CI, 66%-83%) and 57% (95% CI, 46%-66%), respectively.

In patients who would have been eligible for enrollment in ZUMA-2, the 12-month OS and PFS rates were 75% (95% CI, 69%-81%) and 58% (95% CI, 50%-64%), respectively. In patients who would not have met the eligibility criteria for enrollment in ZUMA-2, the 12-month OS and PFS rates were 75% (95% CI, 68%-81%) and 66% (95% CI, 58%-73%), respectively.

Upon multivariable adjustment, the efficacy of brexu-cel in patients with TP53 or 17p deletions and/or a Ki-67 proliferation index of at least 50% was consistent with that of the agent in patients without those high-risk features. Regarding TP53 or 17p deletion status, the ORs for ORR and CR were 1.91 and 1.21, respectively, and the respective HRs for DOR, PFS, OS, and relapse or PD were 1.49, 1.19, 1.75, and 1.05. Regarding Ki-67 proliferation index, the ORs for ORR and CR were 1.20 and 0.96, respectively, and the respective HRs for DOR, PFS, OS, and relapse or PD were 1.40, 1.24, 1.24, and 1.45.

Safety outcomes with brexu-cel did not vary significantly across high-risk subgroups. In the overall population, grade 3 or higher cytokine release syndrome (CRS), grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS), prolonged neutropenia, and prolonged thrombocytopenia were observed in 11% (95% CI, 8%-14%), 29% (95% CI, 25%-33%), 15%, and 19% of patients, respectively. When adverse effects were stratified by patients with TP53 or 17p deletions, those with no TP53 or 17p deletions, those with a Ki-67 proliferation index of at least 50%, those with a Ki-67 proliferation index of less than 50%, those who met the ZUMA-2 eligibility criteria, and those who did not meet the ZUMA-2 eligibility criteria, grade 3 or higher CRS was observed in 9%, 9%, 10%, 8%, 11%, and 10% of patients, respectively; grade 3 or higher ICANS was observed in 37%, 30%, 23%, 28%, 27%, and 31% of patients, respectively; prolonged neutropenia was observed in 25%, 13%, 14%, 12%, 15%, and 16% of patients, respectively; and prolonged thrombocytopenia was observed in 28%, 16%, 20%, 19%, 23%, and 14% of patients, respectively. Non-relapse mortality (NRM) rates were consistent across all subgroups, and the 1-year NRM rate was 8%.

Upon multivariable adjustment, all safety outcomes were comparable between patients with a Ki-67 proliferation index of at least 50% and those with a Ki-67 proliferation index of less than 50%. Regarding Ki-67 proliferation index, the respective ORs for grade 3 or higher CRS, grade 3 or higher ICANS, prolonged neutropenia, and prolonged thrombocytopenia were 0.86, 1.28, 0.84, and 0.93, respectively, and the HRs for infection and NRM were 1.11 and 1.13, respectively.

The incidence of grade 3 or higher CRS, grade 3 or higher ICANS, infections, and NRM were comparable between patients with and without TP53 or 17p deletions. Regarding TP53 or 17p deletion status, the respective ORs for grade 3 or higher CRS, grade 3 or higher ICANS, prolonged neutropenia, and prolonged thrombocytopenia were 1.06, 1.40, 2.72, and 2.27, and the HRs for infection and NRM were 1.21 and 1.29, respectively.

Kambhampati noted in the presentation that limitations of this study include its short duration of follow-up and missing granular data regarding high-risk features, such as Mantle Cell Lymphoma International Prognostic Index score at diagnosis; complex karyotype; cytology; and level of p53 expression; none of which were captured in the CIBMTR registry. Another limitation is the lack of information regarding TP53 mutations and aberrations, as the registry captured only TP53 deletion status.

These findings warrant further follow-up of the patients in this study with high-risk features.

“This is the largest real-world brexu-cel study to date, and further supports the use of brexu-cel across a diverse relapsed MCL population, including those with high-risk features, a patient population with limited treatment options and dire prognosis with standard therapies,” Kambhampati concluded.

Disclosures: Dr Kambhampati reports research funding from ADC Therapeutics, Genentech, and Genmab.

References

1. Kambhampati S, Ahmed N, Hamadani M, et al. Real-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory (R/R) mantle cell lymphoma (MCL): a CIBMTR subgroup analysis of high-risk characteristics. Blood. 2023;142(suppl_1):107. doi:10.1182/blood-2023-179269
2. U.S. FDA approves Kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News Release. Gilead. Published July 24, 2020. Accessed December 9, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/us-fda-approves-kites-tecartus-the-first-and-only-car-t-treatment-for-relapsed-or-refractory-mantle-cell-lymphoma
3. Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol. 2023;41(3):555-567. doi:10.1200/JCO.21.02370