Brexu-Cel Induces Responses in Real-World Population of High-Risk R/R MCL


Brexucabtagene autoleucel (brexu-cel; Tecartus) is protected and efficient in real-world sufferers with relapsed/refractory mantle cell lymphoma (MCL), whatever the presence of high-risk options, based on findings from a subgroup evaluation that had been offered through the 2023 ASH Annual Meeting.1 These findings are per these noticed in sufferers who acquired the agent within the pivotal part 2 ZUMA-2 trial (NCT02601313).

At a median follow-up of 12.3 months (vary, 2.9-28.6), the general response charges (ORRs) and full response (CR) charges had been constant throughout sufferers in all noticed high-risk subgroups. Within the general inhabitants, the ORR was 91%, with an 81% CR price. In sufferers with TP53/17p deletions, no TP53/17p deletions, a Ki-67 proliferation index of no less than 50%, a Ki-67 proliferation index of lower than 50%, ZUMA-2 trial eligibility, and ZUMA-2 trial ineligibility, the ORRs had been 95%, 90%, 92%, 93%, 90%, and 93%, respectively, and the CR charges had been 84%, 81%, 83%, 84%, 79%, and 84%, respectively.

“On this Heart for Worldwide Blood and Marrow Transplant Analysis [CIBMTR] registry evaluation, sufferers with high-risk options, together with TP53 deletions and a excessive Ki-67 [proliferation index], didn’t have important variations in efficacy outcomes in contrast with sufferers with out these high-risk options,” lead examine creator Swetha Kambhampati, MD, an assistant professor within the Division of Lymphoma, Division of Hematology & Hematopoietic Cell Transplantation, at Metropolis of Hope in Duarte, California, acknowledged throughout a presentation of the information. “Within the univariate evaluation, sufferers with out TP53 deletions did have a numerically longer [median] general survival [OS] than these with TP53 deletions, however this wasn’t statistically important.”

Sufferers with relapsed/refractory MCL and high-risk options, akin to TP53 mutations, TP53 deletions, or a excessive Ki-67 proliferation index, have traditionally had restricted remedy choices. The CAR T-cell remedy brexu-cel received FDA approval in 2020 for grownup sufferers with relapsed/refractory MCL primarily based on findings from ZUMA-2.2 A 3-year follow-up evaluation of the examine demonstrated comparable outcomes with brexu-cel throughout prespecified high-risk subgroups.3

This real-world evaluation describes outcomes with brexu-cel stratified by high-risk options, akin to TP53 deletions, 17p deletions, Ki-67 proliferation index, and ZUMA-2 trial eligibility.1

Between 2020 and 2022, 500 grownup sufferers who had been receiving brexu-cel for relapsed/refractory MCL throughout 85 facilities in the USA had been prospectively enrolled within the CIBMTR registry. Of those sufferers, 456 from 84 remedy facilities had been included on this real-world examine. Forty-three sufferers had been excluded due to a previous historical past of non-transplant mobile remedy (n = 7), a scarcity of efficacy and/or security follow-up information (n = 15), or lacking information (n = 21).

Of the evaluable sufferers, 42% had TP53 or 17p deletions (n = 44) and/or a Ki-67 proliferation index of no less than 50% (n = 146). Moreover, 183 sufferers had no TP53 or 17p deletions, and 111 sufferers had a Ki-67 proliferation index of lower than 50%. Furthermore, 57% of sufferers wouldn’t have met the ZUMA-2 eligibility standards, largely due to the presence of comorbidities previous to brexu-cel infusion.

Within the general inhabitants, the median age was 67 years (vary, 34-84), and 61% of sufferers had been no less than 65 years of age. Six p.c of sufferers had an ECOG efficiency standing (PS) of two or larger previous to brexu-cel infusion, 76% of sufferers had clinically important comorbidities, and 91%, 47%, and 71% of sufferers had stage III to IV illness at analysis, elevated lactate dehydrogenase (LDH) ranges at analysis, and had been chemoresistant previous to brexu-cel infusion, respectively. Sufferers had acquired a median of three prior traces of remedy (vary, 1-12), and 32%, 87%, and 44% of sufferers had acquired prior hematopoietic cell transplantation (HCT), prior BTK inhibitors, or any kind of bridging remedy. Moreover, 9% of sufferers acquired deliberate outpatient brexu-cel infusion.

In contrast with the general inhabitants, the cohort of sufferers with TP53 or 17p deletions had fewer sufferers over the age of 65 years (41%), a better proportion of sufferers who had been chemoresistant previous to brexu-cel infusion (81%), and a decrease proportion of sufferers who had acquired prior HCT (12%). In contrast with the general inhabitants, the cohort of sufferers with a Ki-67 proliferation index of no less than 50% had decrease proportions of sufferers with elevated LDH ranges at analysis (41%), prior BTK inhibitor publicity (81%), and bridging remedy (37%). In contrast with the general inhabitants, the cohort of sufferers who would have been ineligible for enrollment in ZUMA-2 had larger proportions of sufferers with an ECOG PS of two or larger (10%), clinically important comorbidities (87%), and chemoresistance previous to brexu-cel infusion (76%), in addition to a decrease proportion of sufferers with prior publicity to BTK inhibitors (78%).

Within the general inhabitants, the median length of response (DOR) was not reached (NR). The estimated 6- and 12-month DOR charges in sufferers who achieved a greatest response of CR had been 83% and 69%, respectively. In all responders, these charges had been 78% and 65%, respectively.

Amongst all sufferers evaluable for survival (n = 456), the median OS was NR (95% CI, 18.9 months-NR), and the estimated 6- and 12-month OS charges had been 86% and 75%, respectively. Amongst all progression-free survival (PFS)–evaluable sufferers (n = 442), the median PFS was 19.3 months (95% CI, 14.2-24.4), and the estimated 6- and 12-month PFS charges had been 75% and 61%, respectively. Compared, the 12-month PFS and OS charges within the major evaluation of ZUMA-2 had been 61% and 83%, respectively.

The 6- and 12-month cumulative incidence charges of relapse or progressive illness (PD) had been 19% and 30%, respectively, and the median time to relapse or PD amongst evaluable sufferers (n = 442) was 27.5 months.

Univariate analyses revealed no statistically important variations in OS or PFS at any time level between any high-risk affected person subgroups. In sufferers with TP53 or 17p deletions, the 12-month OS and PFS charges had been 57% (95% CI, 40%-71%) and 53% (95% CI, 35%-68%), respectively. In sufferers with out TP53 or 17p deletions, the 12-month OS and PFS charges had been 76% (95% CI, 69%-82%) and 60% (95% CI, 51%-67%), respectively.

In sufferers with a Ki-67 proliferation index of no less than 50%, the 12-month OS and PFS charges had been 74% (95% CI, 66%-81%) and 63% (95% CI, 54%-71%), respectively. In sufferers with a Ki-67 proliferation index of lower than 50%, the 12-month OS and PFS charges had been 76% (95% CI, 66%-83%) and 57% (95% CI, 46%-66%), respectively.

In sufferers who would have been eligible for enrollment in ZUMA-2, the 12-month OS and PFS charges had been 75% (95% CI, 69%-81%) and 58% (95% CI, 50%-64%), respectively. In sufferers who wouldn’t have met the eligibility standards for enrollment in ZUMA-2, the 12-month OS and PFS charges had been 75% (95% CI, 68%-81%) and 66% (95% CI, 58%-73%), respectively.

Upon multivariable adjustment, the efficacy of brexu-cel in sufferers with TP53 or 17p deletions and/or a Ki-67 proliferation index of no less than 50% was per that of the agent in sufferers with out these high-risk options. Concerning TP53 or 17p deletion standing, the ORs for ORR and CR had been 1.91 and 1.21, respectively, and the respective HRs for DOR, PFS, OS, and relapse or PD had been 1.49, 1.19, 1.75, and 1.05. Concerning Ki-67 proliferation index, the ORs for ORR and CR had been 1.20 and 0.96, respectively, and the respective HRs for DOR, PFS, OS, and relapse or PD had been 1.40, 1.24, 1.24, and 1.45.

Security outcomes with brexu-cel didn’t fluctuate considerably throughout high-risk subgroups. Within the general inhabitants, grade 3 or larger cytokine launch syndrome (CRS), grade 3 or larger immune effector cell–related neurotoxicity syndrome (ICANS), extended neutropenia, and extended thrombocytopenia had been noticed in 11% (95% CI, 8%-14%), 29% (95% CI, 25%-33%), 15%, and 19% of sufferers, respectively. When hostile results had been stratified by sufferers with TP53 or 17p deletions, these with no TP53 or 17p deletions, these with a Ki-67 proliferation index of no less than 50%, these with a Ki-67 proliferation index of lower than 50%, those that met the ZUMA-2 eligibility standards, and people who didn’t meet the ZUMA-2 eligibility standards, grade 3 or larger CRS was noticed in 9%, 9%, 10%, 8%, 11%, and 10% of sufferers, respectively; grade 3 or larger ICANS was noticed in 37%, 30%, 23%, 28%, 27%, and 31% of sufferers, respectively; extended neutropenia was noticed in 25%, 13%, 14%, 12%, 15%, and 16% of sufferers, respectively; and extended thrombocytopenia was noticed in 28%, 16%, 20%, 19%, 23%, and 14% of sufferers, respectively. Non-relapse mortality (NRM) charges had been constant throughout all subgroups, and the 1-year NRM price was 8%.

Upon multivariable adjustment, all security outcomes had been comparable between sufferers with a Ki-67 proliferation index of no less than 50% and people with a Ki-67 proliferation index of lower than 50%. Concerning Ki-67 proliferation index, the respective ORs for grade 3 or larger CRS, grade 3 or larger ICANS, extended neutropenia, and extended thrombocytopenia had been 0.86, 1.28, 0.84, and 0.93, respectively, and the HRs for an infection and NRM had been 1.11 and 1.13, respectively.

The incidence of grade 3 or larger CRS, grade 3 or larger ICANS, infections, and NRM had been comparable between sufferers with and with out TP53 or 17p deletions. Concerning TP53 or 17p deletion standing, the respective ORs for grade 3 or larger CRS, grade 3 or larger ICANS, extended neutropenia, and extended thrombocytopenia had been 1.06, 1.40, 2.72, and a couple of.27, and the HRs for an infection and NRM had been 1.21 and 1.29, respectively.

Kambhampati famous within the presentation that limitations of this examine embody its brief length of follow-up and lacking granular information concerning high-risk options, akin to Mantle Cell Lymphoma Worldwide Prognostic Index rating at analysis; complicated karyotype; cytology; and stage of p53 expression; none of which had been captured within the CIBMTR registry. One other limitation is the lack of know-how concerning TP53 mutations and aberrations, because the registry captured solely TP53 deletion standing.

These findings warrant additional follow-up of the sufferers on this examine with high-risk options.

“That is the most important real-world brexu-cel examine so far, and additional helps the usage of brexu-cel throughout a various relapsed MCL inhabitants, together with these with high-risk options, a affected person inhabitants with restricted remedy choices and dire prognosis with commonplace therapies,” Kambhampati concluded.

Disclosures: Dr Kambhampati studies analysis funding from ADC Therapeutics, Genentech, and Genmab.

References

  1. Kambhampati S, Ahmed N, Hamadani M, et al. Actual-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory (R/R) mantle cell lymphoma (MCL): a CIBMTR subgroup evaluation of high-risk traits. Blood. 2023;142(suppl_1):107. doi:10.1182/blood-2023-179269
  2. U.S. FDA approves Kite’s Tecartus, the primary and solely CAR T remedy for relapsed or refractory mantle cell lymphoma. Information Launch. Gilead. Printed 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 sufferers with relapsed/refractory mantle cell lymphoma, together with high-risk subgroups, within the ZUMA-2 examine. J Clin Oncol. 2023;41(3):555-567. doi:10.1200/JCO.21.02370



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