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High rate of rapid and complete responses with axi-cel in high-risk large B-cell lymphoma

Expert
Dr Sattva S. Neelapu, MD Anderson Cancer Center, Houston, USA

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Conference
ASH 2021
Trial
ZUMA-12
ZUMA-12 is the first study evaluating CAR T-cell therapy as part of the first-line therapy in patients with high-risk large B-cell lymphoma (LBCL), defined by the histology and/or International Prognostic Index (IPI) and by dynamic risk assessment with PET scan [1]. In this population, axi-cel demonstrated a high rate of rapid and complete responses.

Patients with high-risk LBCL have poor outcomes, including lower response rates to available therapies and poorer overall survival (OS) outcomes [2]. Patients with early disease resistance after first-line rituximab (anti-CD20)-based chemoimmunotherapy, as assessed by dynamic PET scan, have an increased risk of death [3;4]. This highlights the need for novel treatments.

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CAR T-cell therapy in R/R LBCL

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, approved for the treatment of adults with relapsed/refractory (R/R) LBCL and adults with R/R follicular lymphoma, both after ≥2 lines of systemic therapy. A long-term follow-up analysis of axi-cel in refractory LBCL, presented at the ASH 2021 meeting, demonstrated a 5-year OS rate of 43% after a median follow-up of 63 months [5].

ZUMA-12 (NCT03761056) is a phase 2, multicentre, single-arm study investigating axi-cel as part of first-line therapy in patients with high-risk LBCL. Dr Sattva S. Neelapu (MD Anderson Cancer Center, Houston, USA) presented the efficacy, safety, and pharmacokinetic and pharmacodynamic (PK/PD) results from the primary analysis of this trial.
Improved outcomes

Eligible adults had high-risk LBCL, defined by histology or by an IPI score ≥3, in combination with a positive interim PET (Deauville score 4 or 5) after 2 cycles of chemoimmunotherapy. In total, 42 patients were enrolled of whom 40 were treated with axi-cel.

Of these patients, 37 patients were evaluable for response, with confirmed double‑ or triple-hit histology or an IPI score ≥3. After a median follow-up of 15.9 months, the complete response (CR) rate, the primary endpoint of this study, was 78%.

Secondary endpoints included objective response rate (ORR), defined as a combination of CR and partial response. ORR was achieved in 89% of the patients, with a median time to initial response of 1 month. At data cut-off, 73% of the response-evaluable patients showed ongoing responses.

Medians for duration of response (DoR), event-free survival (EFS), and progression-free survival (PFS) were not reached; 12-month estimates were 81%, 73%, and 75%, respectively. The 12-month estimated OS was 91%.
PK/PD and safety profile

Compared with the ZUMA-1 trial, the ZUMA-12 trial displayed a higher frequency of CCR7+CD45RA+ T cells in the axi-cel product. This result was associated with greater CAR T-cell expansion [6] and suggests improved T-cell fitness in first-line treatment.

The safety profile of axi-cel was manageable and comparable to previous reports [7]. All 40 treated patients had adverse events (AEs); 85% of the patients had grade ≥3 AEs, most commonly cytopenia (68%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 3 patients (8%) and 9 patients (23%), respectively.
Conclusion

Axi-cel demonstrated a high rate of rapid and durable responses in the current patient population. Overall, the ZUMA-12 trial showed that axi-cel may benefit patients exposed to fewer prior therapies and those with high-risk LBCL. Further trials of axi-cel contributing to first-line therapy for high-risk patients with LBCL are warranted.

    1. Neelapu SS, 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). Abstract 739, ASH 2021 Annual Meeting, 11-14 Dec. 

    2. Sehn LH, Salles G. N Engl J Med 2021;384:842-858.

    3. Mamot C, et al. J Clin Oncol. 2015;33:2523-9.

    4. Casasnovas RO, et al. Blood. 2017;130:1315-1326.

    5. Jacobson CA, et al. Abstract 1764, ASH 2021 Annual Meeting, 11-14 Dec.

    6. Locke FL, et al Blood advances. 2020;4(19):4898-4911.

    7. Neelapu SS, et al. N Engl J Med 2017;377:2531-2544.

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