Frontline Axi-Cel Elicits Durable Responses in High-Risk LBCL

Sattva Neelapu, MD

Frontline treatment with axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated rapid and durable responses in patients with high-risk large B-cell lymphoma (LBCL), according to findings from the phase 2 ZUMA-12 trial (NCT03761056) that were presented during the 2021 American Society of Hematology Annual Meeting & Exposition.¹

In the primary analysis, efficacy-evaluable patients, meaning patients with centrally confirmed disease, experienced a high objective response rate (ORR) of 89% and a complete response (CR) rate of 78%, reported lead study author Sattva S. Neelapu, MD, professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, during a presentation of the data.¹ After a median follow-up of 15.9 months, 73% of patients continued to have a response at data cutoff.

With a median follow-up of 17.4 months (range, 6.0-26.7), investigators found the ORR to be 90% (95% CI, 76%-97%) and the CR rate to be 80% (95% CI, 64%-91%) among all treated patients (n = 40). Among efficacy-evaluable patients (n = 37) at a median follow-up of 15.9 months (range, 6.0-26.7), ORR was 89% (95% CI, 75%-97%) and the CR rate was 78% (95% CI, 62%-90%). Among all-treated patients, the duration of response (DOR), progression-free survival (PFS), and event-free survival (EFS) were not reached. Median overall survival (OS) was 24.5 months.

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (R/R) LBCL and adults with R/R follicular lymphoma after at least 2 lines of systemic therapy.

Patients were enrolled and given the option to receive nonchemotherapy bridging therapy. Patients were then given conditioning chemotherapy plus axi-cel. The conditioning therapy consisted of 30 mg/m² of fludarabine intravenously (IV) and 500 mg/m² of cyclophosphamide IV on days –5, –4, and –3. Patients were then given a single IV of 2 × 10⁶ of axi-cel CAR T cells/kg on day 0. To be considered eligible for ZUMA-12, patients had an IPI score of at least 3 any time before enrollment and a dynamic risk assessment, which included a positive interim PET, with a Deauville score (DS) of 4 or 5, after 2 cycles of an anti-CD20 monoclonal antibody-positive anthracycline-containing regimen. Patients must have had an ECOG score from 0 or 1.

The trial’s primary end point was CR by an investigator-assessed Lugano 2014 classification,² and its secondary end points were ORR, DOR, EFS, PFS, OS, safety, number of CAR T cells in the blood, and cytokine levels in serum.

The median age of patients was 61 years (range, 23-86) with 38% of patients aged more than 65 years. Of all patients, 68% were male, most (95%) had stage III or IV disease, and 48% had a DS of 4.

Axi-cel’s safety profile was manageable. All patients experienced any-grade adverse events (AEs) with pyrexia (100%), headache (70%), decreased neutrophil count (55%), and nausea (53%) being the most common. Grade 3 or higher AEs occurred in 85% of patients with decreased neutrophil count (53%), decreased white blood cell count (43%), decreased white blood cell count (43%) and anemia (30%) being the most common. One patient contracted COVID-19, labeled as a grade a 5 AE, but was determined to be unrelated to treatment.

Cytokine release syndrome (CRS) was reported in all patients; 8% of cases were grade 3. The most common CRS symptoms were pyrexia (100%), hypotension (30%), and chills (25%). No patients experienced grade 4 or 5 CRS events.

Neurologic events (NEs) occurred in 29 (73%) patients. The most common any-grade symptoms of NEs were confused state (28%), encephalopathy (25%), and tremor (25%). Grade 2 or higher NEs were seen in 38% of patients, grade 3 or higher NEs were seen in 23% of patients, 2 patients experienced a grade 4 NE, and no patients experienced a grade 5 NE.

The median number of CAR T cells infused was 165 (range, 95-200) × 106, and the median number of CCR7+CD45RA+ T cells infused was 105 (range, 33-254) × 106. Investigators found an association with levels of CCR7+CD45RA+ T cells in preinfusion with a favorable pharmacokinetic profile.³

Investigators concluded that axi-cel may benefit patients with high-risk LBCL who were exposed to fewer prior therapies. These results warrant further trials of axi-cel in the first-line setting.

References

1. Neelapu S, Dickinson M, Munoz J, et al. Primary analysis of zuma-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large b-cell lymphoma (LBCL). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 739
2. Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US lymphoma CAR T consortium. J Clin Oncol. 2020;38(27):3119-3128. doi:10.1200/JCO.19.02104
3. Locke FL, Rossi JM, Neelapu SS, et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(19):4898-4911. doi:10.1182/bloodadvances.2020002394 Abstract 739