ZUMA-7 Meets Primary Endpoint and Key Secondary Endpoint in R/R LBCL

Frederick L. Locke, MD

A primary analysis of the ZUMA-7 (NCT03391466) showed that the study met the primary end point of event-free survival (EFS) with a hazard ratio of 0.398 (P < 0.001) and had an overall survival (OS) trend that favored axicabtagene ciloleucel (Yescarta) compared with the standard of care therapy for patients with relapsed or refractory large B-cell lymphoma (LBCL), according to results from an interim analysis.¹

The randomized phase 3 global, multicenter study looked at a one-time infusion of the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel compared to the standard of care treatment in the second line for patients with R/R LBCL. Standard of care in the second line consisted of clinicians reintroducing immunochemotherapy and if the patient can tolerate further treatment they would move to a high dose of chemotherapy plus stem-cell transplant. The primary analysis also showed that the study had met its secondary endpoint of objective response rate (ORR).

“The top-line results of the randomized ZUMA-7 trial paint the picture of a potential paradigm shift in the treatment of large B-cell lymphoma,” said Frederick L. Locke, MD, ZUMA-7 lead principal investigator and co-leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida, in a press release. “The outcomes for patients relapsing after frontline chemotherapy in this study are dramatically improved with rapid referral (to a CAR T center) and a single infusion of axicabtagene ciloleucel as compared to chemotherapy and consolidative autologous transplant, the longstanding second-line standard of care.”

At this time, the data is immature and further study is planned and to then be presented at a future medical conference. ZUMA-7 was initiated in 2017 with 359 patients enrolled on the trial and the results of the primary analysis are the longest follow-up time of the study to date at a median of 2 years.

Safety results from the analysis were consistent with previous safety profiles of axicabtagene ciloleucel for the treatment of R/R LBCL in the third-line setting. Grade 3 or higher cytokine release syndrome was experienced by 6% of patients on the trial with a median onset of 3 days. Twenty-one percent experienced Grade 3, or higher, neurological events, but no new safety concerns were seen in the second-line setting.

“Over 40 years ago, we learned the important role T-cells play in fighting cancer, and 20 years ago autologous stem cell transplant became an option to treat lymphoma. Today's results show us the potential power of cell therapy for patients with lymphoma when used earlier, and instead of standard treatment options,” said Frank Neumann, MD, PhD, global head of Clinical Development at Kite, the manufacturer of axicabtagene ciloleucel, in the release.

Patients enrolled into ZUMA-7 had to have histologically proven LBCL, along with patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma with MYC and BLC2 or BCL6 rearrangement, DLBCL arising from follicular lymphoma, T-cell/histiocyte rich LBCL, DLBCL linked with chronic inflammation, primary cutaneous DLBCL, and patients with Epstein-Barr virus plus DLBCL. Patients also had to have R/R disease following chemoimmunotherapy after receiving frontline therapy of an anti-CD20 monoclonal antibody and an anthracycline-containing chemotherapy regimen. Their ECOG performance status was either 0 or 1 with acceptable bone marrow, renal, hepatic, cardiac, and pulmonary function.

Patients randomized to axicabtagene ciloleucel underwent leukapheresis, then lymphodepleting fludarabine at 30 mg/m²/d and 500 mg/m² of cyclophosphamide for 3 days followed by a single infusion of axicabtagene ciloleucel at 2 × 10⁶ CAR T cells/kg.²

“Yescarta has been instrumental in transforming outcomes for patients with third-line LBCL. Our goal has always been to bring the benefit of CAR T-cell therapy to more patients, earlier in their treatment, where the potential for benefit may be even greater,” said Christi Shaw, chief executive officer of Kite, in the release. “As the leader in cell therapy, Kite is honored to deliver this landmark study and would like to thank the patients, families, physicians and care teams around the world that made this possible.”

Kite plans to initiate discussions with the FDA, European Medicines Agency regarding submission of these data for a supplemental biologics license application to expand the currently approved indications for axicabtagene ciloleucel. The CD19-directed CAR T-cell therapy is currently approved for adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy, including patients with DLBCL not otherwise specified, primary mediastinal LBCL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

_References:

_{1. Kite announces Yescarta CAR T-cell therapy improved event-free survival by 60% over chemotherapy plus stem cell transplant in second-line relapsed or refractory large B-cell lymphoma. News release. June 28, 2021. Accessed June 28, 2021. https://bwnews.pr/3A6VTII}

_{2. Oluwole OO, Bishop MR, Gisselbrecht C, et al. ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard-of-care (SOC) therapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). J Clin Oncol. 2018;36(suppl 15):TPS7585. doi:10.1200/JCO.20218.36.15_suppl.TPS7585}