Axi-Cel Responses Sustained With Longer Follow-Up for NHL

Sattva S. Neelapu, MD

Axi-cel (axicabtagene ciloleucel; Yescarta) maintained a complete remission (CR) rate of 40% with a median follow-up of 15.4 months for patients with refractory, aggressive non-Hodgkin lymphoma (NHL), according to updated findings from the pivotal ZUMA-1 trial presented at the 2017 ASH Annual Meeting.

In the updated assessment, 42% of patients treated with axi-cel remained progression-free and 56% remained alive. The 18-month progression-free survival (PFS) rate was 41% and the 18-month overall survival (OS) rate was 52%. At the time of the analysis, the median duration of response for those achieving a CR was not yet reached.

“Long-term follow-up of ZUMA-1 confirms that these responses can be durable and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission,” lead study author Sattva S. Neelapu, MD, professor at The University of Texas MD Anderson Cancer Center, said in a statement. “With existing therapy, the median survival for people with this disease is only 6 months. Here, we see more than half of patients—59%—are still alive over a year after treatment.”

One hundred eight patients were available for the updated assessment, consisting of 101 from the phase II portion of the trial and 7 from the phase I group. In phase II, patients were enrolled into 2 cohorts consisting of those with diffuse large B-cell lymphoma (n = 77) and those with primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma (TFL; n = 24).

Prior to infusion of axi-cel, a conditioning regimen of fludarabine (30 mg/m²) and cyclophosphamide (500 mg/m²) was administered for 3 days. Axi-cel was administered as a single infusion of modified autologous T cells at a target dose of 2 x 10⁶ CAR-positive T cells/kg. The treatment was manufactured successfully for 99% of patients, and 91% of patients received treatment with the CAR T-cell therapy.

For the 108 patients in the combined analysis, the median age of patients was 58 years (range, 23-76) and 25% were 65 or older. All patients had chemorefractory disease and 70% of patients had received ≥3 prior therapies. Forty-four percent of patients had an IPI score of 3 or 4 and 83% had stage III/IV disease. Overall, 74% of patients were refractory to their second- or later-line of therapy, with 65% having progressive disease as their best response to prior treatment. Twenty-three percent relapsed on prior autologous stem cell transplant (ASCT).

In the combined assessment for best response achieved, the objective response rate (ORR) with axi-cel was 82%, with a CR rate of 58%. In the ongoing cohort at 15.4 months, the ORR was 42% and the CR rate was 40%. In the primary cohort of 101 patients alone, the ongoing ORR was 44% and the CR rate was 39%. The median time for conversation from a partial response (PR) to a CR was 54 days (range, 49-424).

The median duration of ORR was 11.1 months. Forty-three percent of patients from the phase I cohort had a CR at 24 months. The median duration of PR was 1.9 months. The median PFS was 5.8 months, with a 12-month PFS rate of 44%. The median OS had not been reached, with a 12-month OS rate of 59%.

"There is a plateauing of the OS curve at the 16-month time point. The median OS has not yet been reached," said Neelapu. "Durable responders were observed with and without detectable persistent CAR T cells."

There were no new cases of cytokine release syndrome (CRS), neurotoxicity, or grade 5 adverse events (AEs), since the primary assessment, Neelapu noted. In the combined cohort, grade ≥3 AEs were experienced by 97% of patients and grade ≥3 serious AEs were seen in 46% of patients. At the 15.4-month assessment, grade ≥3 CRS was experienced by 12% of patients and grade ≥3 neurotoxicity was seen in 31% of patients. Four percent of patients had a grade 5 AE.

Most patients experienced B cell aplasia and hypogammaglobulinemia, with 8% receiving IVIG during the study. The most common grade ≥3 AEs were neutropenia (79%), anemia (45%), and thrombocytopenia (40%). Infections were the most common new-onset serious AE seen in the extended analysis. These events occurred in 8 patients.

"Late onset AEs were primarily infections and manageable," said Neelapu. "There was no late-onset CRS or neurologic events due to anti-CD19 CAR T cells. No replication-competent retrovirus or insertional mutagenesis was observed."

In October 2017, the FDA approved axi-cel as a treatment for adults with relapsed or refractory NHL, based on findings form the ZUMA-1 trial. The European Medicines Agency is currently reviewing a marketing authorization application for axi-cel for patients with DLBCL. A decision is anticipated in the first half of 2018.

Neelapu SS, Locke FL, Bartlett NL, et al. Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL). Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 578.