Will CAR T-Cell Therapy Be the Preferred Modality in Frontline Treatment of Large B-Cell Lymphoma?

STUDY TITLE: Study to Compare Axicabtagene Ciloleucel With Standard of Care Therapy as First-line Treatment in Participants With High-risk Large B-cell Lymphoma (ZUMA-23)

CLINICAL TRIALS.GOV IDENTIFIER: NCT05605899

PARTICIPATING CENTERS: Recruiting globally

ACCRUAL GOAL: 300

STUDY DESIGN: ZUMA-23 is a randomized, controlled, phase III trial evaluating axicabtagene ciloleucel versus the standard of care as frontline treatment for patients with high-risk large B-cell lymphoma.

RATIONALE: Chimeric antigen receptor (CAR) T-cell therapy resulted in favorable responses in patients receiving third-line treatment and those with later-stage aggressive large B-cell lymphoma (LBCL), leading to approval of three CD19-directed autologous CAR T-cell therapies based on single-arm, phase II trials. Three randomized trials set out to explore CAR T-cell therapy versus standard-of-care platinum-based salvage chemotherapy for patients with LBCL and early-relapse (within 12 months) LBCL.^1-3  Results from ZUMA-7 led to approval of axicabtagene ciloleucel (axi-cel) as second-line therapy for patients with early relapse based on a superior event-free survival (EFS) rate when compared with that for the standard of care, and recent reports suggest axi-cel results in a significant improvement in overall survival (OS), as well.

ZUMA-12 was a single-arm phase II trial examining axi-cel as part of first-line therapy in 40 patients with high-risk LBCL.⁴  In this study, high-risk LBCL was defined as an International Prognostic Index (IPI) of ≥3 or as double- or triple-hit lymphoma and an incomplete response after two cycles of an anthracycline-based regimen (per an interim positron emission tomography [PET]/CT scan with a Deauville score of 4 or 5). The complete response (CR) rate with axi-cel in this cohort was 78%, and, over nearly 16 months of follow-up, 73% of patients sustained response. There were no treatment-related grade 5 adverse events, and acute toxicity was comparable with what has been reported in other axi-cel studies. Despite the favorable safety and efficacy observed in ZUMA-12, the obvious question is whether the patients that were responding, but not achieving a CR, enrolled in this study were better served by switching to CAR T-cell therapy during frontline treatment.

ZUMA-23 is a global, randomized phase III study that will address whether axi-cel as part of frontline therapy for patients with high-risk LBCL is more effective than the standard of care. Eligible patients include those 18 years of age or older with diffuse LBCL, not otherwise specified; high-grade B-cell lymphoma (HGBCL); transformed follicular or marginal zone lymphoma; and an IPI of ≥4. After receiving one cycle of rituximab and anthracycline-based chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin [R-EPOCH]), patients will be randomized 1:1 to receive axi-cel (plus 1 additional cycle of chemotherapy as bridging after leukapheresis) or to continue with five additional cycles of chemotherapy.

Patients will be stratified according to tumor bulk (≥7.5 cm), performance status (0-1 vs. 2), and whether they have HGBCL. Endpoints include EFS, progression-free survival (PFS), OS, CR rate, safety, and patient-reported outcomes. The only potential criticisms of the current design are the inclusion of R-EPOCH and the omission of polatuzumab plus R-CHOP in the control arm. Nevertheless, if it produces positive results, ZUMA-23 will provide axi-cel as early as frontline for high-risk LBCL. This study is currently recruiting at several centers in the U.S. and internationally and should be considered for patients with high-risk LBCL.

COMMENT: ZUMA-23 builds off lessons learned from ZUMA-12, which demonstrated that axi-cel can be successfully administered after two cycles of chemoimmunotherapy in patients with high-risk LBCL. This study will expand upon the definition of high-risk LBCL to include transformed lymphoma from follicular or marginal zone lymphoma. The IPI score threshold was increased to four or higher. Patients will be enrolled up front and will receive a cycle of chemotherapy prior to randomization. This protocol change will help reduce the barrier to enrolling patients with high-risk LBCL who cannot afford to wait to start effective therapy and, therefore, will recruit those most in need. This study has also eliminated the interim PET as an entry point, which was controversial in ZUMA-12, given the lingering questions about the positive predictive value of interim PET in LBCL.