Axicabtagene Ciloleucel Demonstrates Durable Clinical Benefit in High-Risk Large B-Cell Lymphoma

Interim analysis of the phase 2 clinical trial of chimeric antigen receptor (CAR) T-cell therapy as first-line treatment of patients with high-risk large B-cell lymphoma shows that axicabtagene ciloleucel (Yescarta) has substantial benefit in patients with unmet medical needs.

The results were presented at the ASH 2020 annual meeting, showing that axicabtagene ciloleucel led to an overall response rate of 85% and a complete response rate of 74%. At data cutoff, after a median follow-up of 9.3 months, 70% of the patients had a response that was ongoing.

“Axicabtagene ciloleucel demonstrated significant clinical benefit, with high overall and complete response rates and a manageable safety profile,” said lead investigator Sattva S. Neelapu, MD, Deputy Chair, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX. “The study also provides new insights into the pharmacology of CAR T-cell therapy for patients exposed to fewer prior therapies.”

Patients with high-risk large B-cell lymphoma have reduced response rates and poor survival. Patients with early disease resistance, as assessed by dynamic positron emission tomography (PET) after first-line rituximab (Rituxan)-based chemoimmunotherapy also have an increased risk for death, said Dr Neelapu.

ZUMA-12 Phase 2 Clinical Trial

Axicabtagene ciloleucel is currently approved for treatment of adults with relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapies. In the pivotal ZUMA-1 study that led to the FDA approval of this CAR T-cell therapy, the overall response rate was 82%, with a complete response rate of 58%. At a median follow-up of 51.1 months, the median overall survival (OS) was 25.8 months, and the estimated 4-year OS was 44%.

ZUMA-12 is a phase 2, multicenter, open-label, single-arm study of axicabtagene ciloleucel as first-line therapy in patients with high-risk large B-cell lymphoma. Patients with high-grade B-cell lymphoma and MYC alterations and BCL2 and/or BCL6 translocations, or large B-cell lymphoma with an International Prognostic Index (IPI) score of ≥3 before enrollment were eligible for the study.

In addition, patients had to have a positive interim PET scan, with a Deauville score of 4 or 5 after 2 cycles of treatment with an anti‑CD20 monoclonal antibody and anthracycline-based regimen.

Patients underwent leukapheresis at least 2 weeks after receiving systemic therapy and optional nonchemotherapy bridging, at the investigator’s discretion, followed by conditioning chemotherapy and a single infusion of axicabtagene ciloleucel.

Responses Ongoing in Majority of Patients

At a median follow-up of 9.3 months, 27 patients (median age, 61 years) were evaluable for efficacy. As Dr Neelapu reported, 88% of patients had stage III or IV disease, 53% of patients had double- or triple-hit (ie, high-risk) lymphoma, and 72% of patients had an IPI score of ≥3.

“The best overall response rate was 85%, and the best complete response rate was 74%,” said Dr Neelapu. “With a median follow-up of 9.3 months, at least 70% of patients had at least 6 months of follow-up, and now 70% had ongoing response at data cutoff.”

The median time to objective response as well as to complete response was 1 month. In addition, 19% of patients who had partial remission or stable disease at the 1-month assessment, which was subsequently upgraded to a complete response, according to Dr Neelapu.

“The responses are ongoing in the majority of patients,” said Dr Neelapu. “The median duration of response, the median progression-free survival, and median overall survival were not reached at the data cutoff.”

Dr Neelapu suggested that CAR T-cell therapy in the first-line setting could significantly shorten the duration of treatment for patients with large B-cell lymphoma.

“The main advantage for axicabtagene ciloleucel is that it’s a single-infusion therapy,” Dr Neelapu said. “So far, the data look to be much more effective than standard front-line chemotherapy.”

Safety Profile

The most common grade ≥3 adverse events were cytopenias, said Dr Neelapu. He noted that neutropenia was observed in 44% of patients and was thought to be related to the conditioning chemotherapy in the majority of the patients.

The most common grade ≥3 adverse events with the CAR T-cell therapy were encephalopathy (16%), elevated alanine aminotransferase (9%), and neutropenia (9%).

All 32 patients had cytokine release syndrome (CRS), Dr Neelapu said, but most of these were grade 1 or 2. Only 9% of patients had grade ≥3 CRS.

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