Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL).

Abstract

7002 Background: ZUMA-3 is a Phase 1/2 multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in adult pts with R/R B-ALL. Phase 1 efficacy results at the recommended Phase 2 dose (1×106 CAR T cells/kg) were encouraging (Shah et al. ASCO 2019 #7006). Here, we present the pivotal Phase 2 results. Methods: Eligible adults had R/R B-ALL, > 5% bone marrow (BM) blasts by local evaluation, and ECOG 0–1. Pts received a single infusion of KTE-X19 after conditioning chemotherapy. The primary endpoint was the overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) by central review. Key secondary endpoints were duration of remission (DOR), relapse-free survival (RFS), overall survival (OS), measurable residual disease negativity (MRD–) rate by flow cytometry, and safety. Data are reported in all treated pts. Results: As of 9/2020, 55 of 71 enrolled pts received KTE-X19, with a median follow-up of 16.4 mo (range, 10.3–22.1). Adverse events (AEs; n = 8) and ineligibility (n = 4) were the most common reasons enrolled pts did not receive KTE-X19 infusion. Median age was 40 y (range, 19–84), median BM blasts at screening were 65% (range, 5–100), and 47% of pts had ≥3 prior therapies, with 45%, 22%, and 42% having previously received blinatumomab, inotuzumab ozogamicin, or allogeneic stem cell transplant (alloSCT), respectively. The CR/CRi rate was 71% (95% CI, 57–82; 56% CR, 15% CRi); 31% of responders had ongoing responses. Median (95% CI) DOR, RFS, and OS were 12.8 mo (8.7–not estimable [NE]), 11.6 mo (2.7–15.5), and 18.2 mo (15.9–NE), respectively. In responders, median (95% CI) RFS and OS were 14.2 mo (11.6–NE) and not reached (16.2–NE). The MRD– rate was 97% among pts with CR/CRi. Among 25 pts with prior blinatumomab treatment, the CR/CRi rate was 60%. Ten pts (18%) received subsequent alloSCT at a median 98 days post–KTE-X19 infusion. Median DOR remained unchanged when not censoring for alloSCT. Grade ≥3 AEs occurred in 95% of pts, most commonly anemia (49%) and neutropenia (49% [febrile 13%]). Grade ≥3 cytokine release syndrome (CRS; per Lee at al. Blood 2014) and neurologic events occurred in 24% and 25% of pts, respectively, and were generally reversible. Two Grade 5 KTE-X19–related events occurred (brain herniation, n = 1; septic shock, n = 1). Median times to onset of CRS and neurologic events were 5 d and 9 d, with median durations of 7.5 d and 7 d, respectively. Median peak CAR T-cell levels (cells/µL) were 40.5 (range, 1.3–1533.4) in pts with CR and 0 in nonresponders. CAR T cells were undetectable by 9 mo in ongoing responders. Conclusions: After a median follow-up of 16.4 mo, KTE-X19 demonstrated compelling clinical benefit in heavily pretreated adults with R/R B-ALL, with the median OS not yet reached for responding pts and a manageable safety profile. Clinical trial information: NCT02614066.

CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities

“…CAR T cells represent a “living drug” that targets patients with r/r B-ALL with impressive results [ 112 , 113 , 114 ]. Many studies on the targets of immunotherapy against T-cell malignancies, especially T-ALL, are in the preclinical or early clinical research stage.…”

Donor T cells for CAR T cell therapy

“…Initial results have shown that multiple genomic modifications of T cells are feasible, and it is expected that this will lead to more multiplexed genome-edited anti-cancer cellular products. However, there is still much to be done before allogeneic CAR T cells can fully replace autologous CAR T cells, since most of the current clinical trials to confirm high efficacy and long-term safety are done with autologous cellular therapies [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Despite encouraging results, most studies with sophisticated allogeneic products are still in the preclinical stage due to design and/or production challenges, particularly those manufactured using nonviral vectors or involving genome editing, since potential oncogenicity or off-target mutagenesis must first be eliminated before progression to clinical use.…”

“…Chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in treating B cell malignancies such as B cell acute lymphoblastic leukemia (B-ALL), B cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma (FL) and multiple myeloma (MM), although more improvements are needed for treating chronic lymphocytic leukemia (CLL) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. However, currently approved clinical treatments are expensive and complicated to manufacture, delaying patient access to treatments.…”

Do CAR-T and Allogeneic Stem Cell Transplant Both Have a Place in Lymphoid Neoplasms?

“…The year 2018 represents a historic moment for cancer immunotherapy: the first two products containing chimeric antigen receptor (CAR)-T cells, tisagenlecleucel and axicabtageneciloleucel, were approved for commercial use, revolutionizing the treatment landscape for relapsed or refractory (R/R) B acute lymphoblastic leukemia (ALL) and R/R B-cell non-Hodgkin lymphoma (NHL) [ 6 , 7 , 8 ]. Subsequently, regulators approved lisocabtagene maraleucel in R/R B-cell NHL [ 9 ], brexucabtagene autoleucel in R/R mantle cell lymphoma (MCL) [ 10 ] and adult patients with R/R B-ALL [ 11 ], idecabtagene vicleucel [ 12 ] and ciltacabtagene autoleucel in R/R multiple myeloma (MM) [ 13 ]. Table 1 summarizes the main characteristics of the constructs and the clinical indications.…”