CAR T-cell Therapy Hopes to Move to Second Line in Diffuse Large B-cell Lymphoma

Study Title: Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7)

Clinicaltrials.gov Identifier: NCT03391466

Sponsor: Kite, a Gilead Company

Participating Centers: 77 globally

Accrual Goal: 350 patients

Study Design: This is an international, randomized, open-label, phase III clinical trial evaluating the efficacy of the autologous CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy axicabtagene ciloleucel (axi-cel), versus second-line salvage chemoimmunotherapy (salvage) and consolidation with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (ASCT) as second line in relapsed diffuse large B-cell lymphoma (DLBCL).¹  Approximately 350 patients will be randomized 1:1. Eligible patients will have relapsed or refractory DLBCL after first-line therapy that included an anti-CD20 monoclonal antibody and an anthracycline, and intend to proceed to ASCT if responding to salvage. Patients with active infection, prior anti-CD19 antibody therapy, or prior ASCT are excluded. Patients in the axi-cel arm will have leukapheresis and undergo lymphodepletion with fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² daily for three days, followed by a single infusion of axi-cel at a dose of 2 million CAR-T cells/kg. Bridging corticosteroid therapy is allowed during the axi-cel manufacturing period. Patients randomly assigned to standard of care will receive two to three cycles of one of four salvage regimens of the investigators’ choice. Those with an objective response to salvage therapy will go on to receive ASCT.²  The primary outcome measure is event-free survival from randomization to disease progression, start of new lymphoma therapy, or death. Secondary objectives include response rate, progression-free survival, overall survival, safety, and patient reported outcomes.

Rationale: The standard of care for almost 30 years in patients with DLBCL who relapsed or were refractory to first-line therapy is combination chemoimmunotherapy followed by consolidation with high-dose chemotherapy and ASCT for fit responding patients, based on the results of the PARMA group trial.³  An optimal second-line salvage regimen has not emerged, with a large randomized trial showing comparable results between rituximab, ifosfamide, etoposide, and carboplatin, and rituximab, dexamethasone, high-dose cytarabine, and cisplatin.⁴  ASCT is associated with significant morbidity, with treatment-related mortality generally being less than 5 percent. Approximately 25 percent of patients will benefit with durable long-term remission following this approach, with those nonresponsive to salvage having no benefit from ASCT.

Axi-cel, initially developed at the National Cancer Institute,⁵  was approved for commercial use in DLBCL after two prior lines of therapy, based upon the pivotal phase II ZUMA-1 trial that showed durable responses beyond two years in approximately 40 percent of chemorefractory patients.⁶  Results with axi-cel appear to be significantly better than historical cohorts of refractory patients,⁷  and axi-cel has successfully been employed as a standard of care.⁸  Axi-cel is associated with typically reversible cytokine release syndrome and immune cell–associated neuroencephalopathy syndrome,⁹  as well as an estimated 3 percent treatment-related mortality.

Comment: Several nonrandomized pivotal trials have demonstrated that CD19 CAR-T therapies are effective in relapsed DLBCL: ZUMA-1 for axi-cel, JULIET for tisagenlecleucel,¹⁰  and TRANSCEND for lisocabtagene maraleucel.¹¹  ZUMA-7 is one of three phase III randomized trials testing these against the current second-line standard of care (NCT03570892, NCT03575351), and its results may solidify the current standard or drastically change treatment paradigms.

If CAR-T therapy is proven as preferred second-line treatment, new questions will emerge. First, if the trials show improvement in event-free survival without improvement in overall survival, concerns about the safety profile and costs of CAR-T therapy will remain. Second, appropriate therapy in patients relapsing after second-line CAR-T will need to be defined, preferably via randomized trials. Third, CAR-Ts need time for manufacturing, and alterations in community oncologist referral timing may be required.

If the standard of care is verified, uncertainties will remain. Patients with a positron emission tomography–positive partial response to salvage therapy fare worse after ASCT than those with a complete response.¹²  Since axi-cel became commercially available, the number of ASCTs performed for the treatment of DLBCL has decreased, possibly due to decreased willingness to move forward in patients unable to achieve a complete response.¹³  ZUMA-7 stipulates that patients with positron emission tomography–positive partial response to salvage proceed to ASCT, and the question of whether to proceed with ASCT, or shift to CAR-T therapy for such patients, will remain. Importantly, the optimal CAR-T therapy in DLBCL is unclear. Differences in the pivotal trials’ design make comparison difficult, and randomized trials or elegant observational cohort studies must be considered.