Axi-Cel Retreatment Demonstrates Clinical Efficacy in Large B-Cell Lymphoma

Findings from an exploratory analysis of the phase 1/2 ZUMA-1 trial demonstrated clinical efficacy in patients with relapsed/refractory large B-cell lymphoma (LBCL) who were retreated with the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta).

The results showed that patients who achieved a CR with the first infusion of axi-cel had a higher likelihood of attaining a CR during retreatment.

With the first infusion, 7 of the 14 patients who were retreated achieved a CR, 6 achieved a partial response (PR), and 1 had stable disease prior to progression. The median duration of response (DOR) was 3.3 months (range, 1.8-10.9).

Upon retreatment, 57% achieved a response, consisting of 5 CRs and 3 PRs. Additionally, the median DOR to retreatment was 9.4 months, and 2 patients remained in response for 18.2 months and 11.2 months after retreatment.

“While axi-cel has demonstrated durable responses in a subset of patients, approximately half of all responders relapse,” study author, Javier Munoz, MD, MS, FACP, of Banner MD Anderson Cancer Center, said in a virtual presentation during the meeting. “Little is known about the efficacy of retreatment with CAR T-cell therapy.”

In October 2017, the FDA approved the CD19-directed CAR T-cell therapy as a treatment for adults with relapsed/refractory non-Hodgkin lymphoma, based on earlier data from the ZUMA-1 trial.

The trial was divided into 4 cohorts. In cohorts 1 to 3, patients could not have derived a response to their last chemotherapy or had relapsed within 12 months of autologous stem cell transplant (ASCT). Patients enrolled in cohort 4 had to have relapsed/refractory LBCL and received 2 or more prior lines of therapy.

In the trial, eligible patients with refractory LBCL underwent screening followed by leukapheresis and conditioning chemotherapy with 500 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine for 3 days.

On day 0, patients were hospitalized and received 2 x 10⁶ CAR+ cells/kg. Patients stayed in the hospital for 1 week before returning to have their tumors assessed on day 28.

If patients had no evidence of CD19 loss by local review or no dose-limiting toxicities during first treatment, patients underwent another round of conditioning chemotherapy and were retreated with an identical dose of axi-cel.

The 14 patients retreated with axi-cel had a median age of 59. Though, 5 patients were 65 years or older. Additionally, the majority of patients (79%) were male.

Over half of patients (57%) retreated with axi-cel had an ECOG performance score of 1 and 86% had stage III/IV LBCL. According to the Lymphoma International Prognostic Index (IPI), 64% of patients had a score of 3/4.

Although 0 patients had undergone prior ASCT, 71% had received 3 or more prior therapies. Of these patients, 71% had a diagnosis of diffuse large B-cell lymphoma, 14% had primary mediastinal B-cell lymphoma, and 14% had transformed follicular lymphoma.

Product characteristics of the axi-cel source material were similar between the first and second infusions. One patient had axi-cel manufactured from new apheresis material, 9 had axi-cel manufactured from frozen peripheral blood mononuclear cell from the first apheresis in a second round of manufacturing, and 4 patients received axi-cel from a second bag of initial manufacturing.

In the first infusion, the peak CAR T-cell expansion was 60.8 cells/µL blood. Peak expansion among retreated patients was 4.3 cells/µL blood. Additionally, lower median CAR T-cell expansion was associated with lower median tumor burden.

Additionally, retreatment with axi-cel was associated with significantly lower peak levels of interferon-γ (Wilcoxon test P = .00074; Wilcoxon paired test P = .0081) and interleukin (IL)-15 (Wilcoxon test P = .014; Wilcoxon paired test P = .0012) compared with first treatment. Although peak IL-6 levels were not found to be statistically significant, they were numerically lower with retreatment versus first treatment (Wilcoxon test P = .011; Wilcoxon paired test P = .078).

Regarding safety, comparable rates of cytokine release syndrome (CRS) were noted in first treatment and retreatment with axi-cel. In first treatment with axi-cel, 93% of patients experienced some degree of CRS versus 86% in retreatment. No grade 3/4 CRS was reported with axi-cel in either first or second treatment.

Notably, fewer incidences of grade 3/4 neurological events occurred during retreatment compared with first treatment, at 11 events versus 8 events, respectively.

“Based on this limited sample size, retreatment with axi-cel may have clinical efficacy in some patients with LBCL, especially patients who achieved CR with first treatment,” said Munoz. “Durability of response remains to be determined as several patients received consolidative allogeneic transplant. We look forward to additional studies to confirm and expand upon these results.”

Reference:

Locke FL, Bartlett NL, Jacobson CA, et al. Retreatment of patients with refractory large B cell lymphoma with axicabtagene ciloleucel (axi-cel) in ZUMA-1. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. Abstract EP1259.