Axi-Cel Yields Long-Lasting Responses in High-Risk Large B-cell Lymphoma

The phase 2 trial included patients with high-risk LBCL with MYC, and BCL2 and/or BCL6 translocations, or LBCL with an international prognostic index score of 3 or more before enrollment.

Durable responses were observed when axicabtagene ciloleucel (axi-cel; Yescarta) was used as a first-line therapy for patients with high-risk large B-cell lymphoma (LBCL), according to results from the phase 2 ZUMA-12 trial (NCT03761056), which were presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

The overall complete response (CR) rate—the study’s primary end point—among patients treated with axi-cel was 86% (95% CI, 71%-95%), and the partial response (PR) was 5%, translating to an objective response rate of 92%. A total of 5% of patients had stable disease and 3% had progressive disease. It was noted that the key secondary end points of median duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) was not reached.

“Axi-cel may benefit patients exposed to fewer prior therapies and those with high-risk LBCL, a population with high unmet need and poor outcomes after standard first-line chemoimmunotherapy,” lead author Julio Chavez, MD, MS, associate member in the Lymphoma Section of the Department of Malignant Hematology at Moffitt Cancer Center, said during the presentation.

The phase 2 trial included patients with high-risk LBCL with MYC, and BCL2 and/or BCL6 translocations, or LBCL with an international prognostic index (IPI) score of 3 or more before enrollment. Patients also needed to have positive interim PET scans after 2 cycles of treatment with an anti-CD20 monoclonal antibody plus an anthracycline regimen. Additionally, they needed to be older than 18 years with an ECOG performance status of 0 or 1.

After enrollment, patients went on to undergo leukapheresis followed by an optional nonchemotherapy bridging therapy, lymphodepletion, and axi-cel infusion. Fludarabine was given at a dose of 30 mg/m² and cyclophosphamide was given at 500 mg/m² on days –5, –4, and –3, with both treatments given intravenously. Axi-cell was given as a single intravenous infusion of 2 x 10⁶ CAR T cells/kg on day 0.

The median follow-up was 40.9 months (range, 29.5-50.2) with a data cutoff of May 3, 2023, assessing 40 patients. A total of 37 patients were efficacy evaluable as described by Lugano classification. Those in this population were given axi-cel at least 1 x 10⁶ anti-CD19 CAR T cells/kg with centrally confirmed disease type of double-hit or triple-hit lymphoma or LBCL with an IPI score of more than 3. The safety analysis consisted of the 40 patients initially enrolled.

At the time of data cutoff, 73% of patients continued to have responses. A conversion from a PR to a CR occurred in 22% of patients and a stable disease to a CR in 3%.

The 3-year DOR rate was 81.8% (95% CI, 63.9%-91.4%), and for patients who achieved a CR as a best response, the 3-year DOR was 84.4% (95% CI, 66.5%-93.2%). The 3-year EFS was 73.0% (95% CI, 55.6%-84.4%), for those who had a CR as a best response the rate was 84.4% (95% CI, 66.5%-93.2%).

A multivariate analysis for EFS rates found similar results and little difference among key LBCL subgroups.

For patients who achieved a CR as the best response, the 3-year PFS was 84.4% (95% CI, 66.5%-93.2%) and the 3-year OS rate was 90.6% (95% CI, 73.6%-96.9%).

A total of 13% of patients had any treatment-emergent adverse effects (TEAEs) following the primary analysis, with 8% having grade 3 or higher toxicities. Serious TEAEs occurred in 8% of patients. Any infection or infestation was reported in 10% of patients with 5% having grade 3 or higher, 8% having COVID-19–related infections, 3% having device-related infection, and 3% having sinusitis.

A total of 8 patients died on the trial, with 5 having progressive disease, 1 from COVID-19, 1 from esophageal adenocarcinoma, and 1 from septic shock. There were no reports of new cytokine release syndrome or neurologic events at any grade since the previous data cutoff. Since the primary analysis, 1 patient had prolonged cytopenia and this was resolved by data cutoff.²

For patients with an ongoing CR or PR at the 30-month cutoff data (n = 27), the median post-infusion CAR T cell expansion by peak was 35.7 cells/μL and the area under the curve (AUC) on days 0 to 28 was and 368.0 cells/μL x days. For patients who relapsed (n = 6) compared with non-responders (n = 3) the median post-infusion CAR T cell expansion by peak was 45.1 cells/μL and 413.4 cells/μL x days, respectively.

References

1. Chavez, JC, Dickinson M, Munoz J, et al. 3-year analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel as first-line therapy in patients with high-risk large B-cell lymphoma. Blood. 2023;142(suppl 1):894. doi:10.1182/blood-2023-174510
2. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742. doi:10.1038/s41591-022-01731-4