Three-year follow-up of outcomes with KTE-X19 in patients with relapsed/refractory mantle cell lymphoma in ZUMA-2.
Authors: Wang Michael , Munoz Javier , Goy Andre , Locke Frederick L. , Jacobson Caron Alyce , Hill Brian T , Timmerman John , Holmes Houston , Flinn Ian W. , Miklos David Bernard , Pagel John M. , Kersten Marie José , Houot Roch , Beitinjaneh Amer , Peng Weimin , Fang Xiang , Shen Rhine , Siddiqi Rubina , Kloos Ioana , Reagan Patrick Michael 
Published: June 2022

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Background: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL). In ZUMA-2, a 93% objective response rate (ORR; 67% complete response [CR] rate) was reported with KTE-X19 in pts with R/R MCL (median follow-up: 12.3 mo; 60 efficacy-evaluable pts; Wang et al. N Engl J Med. 2020). Here, we present updated outcomes with 2 years of additional follow-up. Methods: Adult pts (≥18 years) with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19. Minimal residual disease (MRD) was an exploratory endpoint (sensitivity 10-5) evaluated in peripheral blood using next-generation sequencing. Updated results are reported for all 68 treated pts. Results: After 35.6 mo median follow-up, the ORR (CR + partial response) was 91% (95% CI, 81.8-96.7), with a 68% CR rate (95% CI, 55.2-78.5). The median duration of response (DOR) was 28.2 mo (95% CI, 13.5-47.1), with 25 of 68 treated pts (37%) still in ongoing response (all CR) at data cutoff. Late relapse > 24 mo post-infusion was infrequent (n = 3). The medians for progression-free survival (PFS) and overall survival (OS) were 25.8 mo (95% CI, 9.6-47.6) and 46.6 mo (95% CI, 24.9-not estimable), respectively. MRD was analyzed in 29 pts total; 24 of 29 were MRD-negative at mo 1, and 15 of 19 with available data were MRD-negative at mo 6. At data cutoff, the medians for DOR, PFS, and OS in the 15 MRD-negative pts were all not reached, vs 6.1, 7.1, and 27.0 mo, in the 4 MRD-positive pts, respectively. MRD-negative status at mo 1, 3, and 6 was associated with durable response, with 55%, 71%, and 69% of MRD-negative pts at those timepoints remaining in ongoing CR at data cutoff. Circulating tumor DNA analysis of MRD at mo 3 and 6 was predictive of relapse (AUC 0.80 and 0.75, respectively). No new safety signals were observed. Only 3% of treatment-emergent adverse events (AEs) of interest occurred since the primary report. The most frequent Grade ≥3 AE was neutropenia (1 [1%] Grade 3; 7 [10%] Grade 4). Two pts had KTE-X19-related Grade 3 serious infections: pneumonia and upper respiratory tract infection (n = 1); influenza (n = 1). There were no new cytokine release syndrome AEs and 1 new serious neurologic AE of Grade 3 encephalopathy (13.0 mo post-infusion) that was considered not related to study treatment. Three new Grade 5 AEs occurred, none of which were considered related to study treatment: Salmonella bacteremia (24.9 mo post-infusion), myelodysplastic syndrome (25.2 mo post-infusion), and acute myeloid leukemia (37.5 mo post-infusion). Conclusions: These data represent the longest follow-up of CAR T-cell therapy in pts with MCL to date and suggest that KTE-X19 induces durable long-term responses with manageable safety and low late relapse potential in R/R MCL. Clinical trial information: NCT02601313.