Assessment of Durable Responses after Brexucabtagene Autoleucel (KTE-X19) in the ZUMA-2 Study in Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL)

Introduction: Brexucabtagene autoleucel (brexu-cel, formerly known as KTE-X19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the United States for the treatment of adults with R/R MCL and in the European Union for adults with R/R MCL after ≥2 prior therapies, including a Bruton tyrosine kinase inhibitor (BTKi). At a median 35.6-months (mo) follow-up in the Phase 2, multicenter ZUMA-2 study of brexu-cel in R/R MCL, the objective response rate was 91% (68% complete response [CR] rate), with a median duration of response (DOR) of 28.2 mo, and overall survival (OS) of 46.6 mo among all 68 treated patients (pts) and not reached in pts with a CR (Wang et al. J Clin Oncol. 2022). To identify factors associated with long-term response to KTE-X19, we evaluated patient and product characteristics by response status at 24 mo post infusion in ZUMA-2.

Methods: Adults (≥18 years) with R/R MCL who had received ≤5 prior regimens including a BTKi underwent leukapheresis and conditioning chemotherapy followed by a single infusion of brexu-cel (2×10⁶ anti-CD19 CAR T cells/kg). Post hoc assessments of patient, disease, pharmacokinetic, and product characteristics are reported by response status at 24 mo (ongoing vs relapsed).

Results: At a median follow-up of 35.6 mo (range, 25.9-56.3), 62 pts had achieved a CR or partial response; 3 did not reach the 24-mo assessment visit and were excluded from this analysis. Of the 59 evaluable pts with response, 29 (49%) had ongoing responses at 24 mo (ongoing responders), and 30 (51%) had relapsed prior to 24 mo (relapsed responders). At baseline, the median age was 65 years and median number of prior therapies was 3 in both subgroups. Among ongoing vs relapsed responders, 66% vs 43% had ibrutinib as last prior therapy and 14% vs 13% had acalabrutinib as last prior therapy, with a median (range) time from last prior therapy of 63 (26-748) vs 64.5 mo (22-443), respectively. A smaller proportion of ongoing responders compared with relapsed responders received bridging therapy (21% vs 53%) and prior platinum therapy (10% vs 40%), respectively; while similar proportions received prior bendamustine therapy (45% vs 53%), prior proteosome inhibitor therapy (41% and 37%), and prior autologous stem cell transplant (48% vs 37%), respectively.

At baseline, a greater proportion of ongoing responders had an ECOG score of 0 compared to relapsed responders (79% vs 57%, respectively), and the median (range) tumor burden (SPD) was 935.1 (260-6133) in ongoing responders and 4233.6 (386-14390) in relapsed responders. The incidence of high-risk features was similar between ongoing responders and relapsed responders, with 66% and 60% having a baseline Ki-67 proliferation index score of ≥30%, 10% of both subgroups having TP53 mutations, 45% and 37% having elevated lactose dehydrogenase levels (ULN to ≥1.5 ULN), and 10% and 13% having high-risk Simplified Mantle Cell Lymphoma International Prognostic Index scores (>6), respectively.

The median (range) DOR in ongoing responders with CR (n=28) was not reached (46.7-not estimable) and was 8.3 mo (5-13.6) in relapsed responders with CR (n=15). Of the relapsed responders, 67% had received subsequent anticancer therapy by data cutoff, the most common of which were radiotherapy (23%), dexamethasone (23%), rituximab (23%), venetoclax (20%), and lenalidomide (20%; patients could have received multiple subsequent therapies and multiple lines of subsequent therapy).

Median [range] peak (102.4 [0.3-2241.6] vs 59.9 [1.6-2589.5]) and area under the curve (1487 [3.8-16,700] vs 688.2 [19-27,200]) CAR T-cell levels were ~2x higher in ongoing responders than in relapsed responders, respectively. A modest increase in the median [range] total number of infused CCR7+ cells was observed in ongoing vs relapsed responders (119.8 [37-249.9] vs 89.1 [6.1-353.4]), suggesting a potential role of continuous memory T-cell differentiation in achieving durable responses.

Conclusions: After ~3-years median follow-up, brexu-cel continues to demonstrate durable responses with 49% of patients in ongoing response at 24 mo post infusion. In summary, ongoing responders had lower ECOG scores and tumor burden, as well as less frequent use of bridging therapy and less intense regimens for previous relapses, suggesting the potential for greater benefit with brexu-cel if given in earlier course of disease.