Updated results from the pivotal ZUMA-5 clinical trial of axicabtagene ciloleucel (Yescarta®; Gilead/Kite), presented as a part of a late-breaking session during the 26th Annual Meeting of the European Hematology Association (EHA2021) taking place virtually this year from June 9-17, 2021 (Abstract #LB1904) shows that 94% of patients achieved a response at 18 months while and secondary endpoints of median progression-free survival (PFS) and overall survival (OS) were not yet reached.[1][2]

Follicular lymphoma is a form of indolent non-Hodgkin lymphoma (iNHL) in which malignant tumors slowly grow but can become more aggressive over time. FL is the most common form of indolent lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22% of all lymphomas diagnosed worldwide. Currently, there are limited options for the treatment of relapsed or refractory indolent FL after two or more lines of therapy

Axicabtagene ciloleucel, a CD19-directed genetically modified autologous T cell immunotherapy, is the first and only Chimeric Antigen Receptor T-cell (CAR T-cell) therapy approved for the treatment of patients with relapsed or refractory indolent follicular lymphoma (FL). The treatment is approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase 2 ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively.[3]

In a weighted analysis comparing the study results of patients participating in the ZUMA-5 study, an ongoing, single-arm, open-label, multicenter trial evaluating 146 patients (≥18 years old) with relapsed or refractory iNHL, including follicular lymphoma, who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent, with those observed in SCHOLAR-5, an external control cohort, axicabtagene ciloleucel demonstrated superior OS and PFS over currently available treatments. The data was based on a minimum of 18 months of follow-up of participating patients.

The efficacy of the treatment was established on the basis of objective response rate (ORR) and duration of response (DoR) as assessed by an independent review committee per the 2014 Lugano Classification.

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Comparison of outcomes
The outcomes from the ZUMA-5 study were compared to the results of SCHOLAR-5, an international, multicenter, retrospective external control cohort of patients with relapsed or refractory follicular lymphoma. Data were sourced from seven institutions across five countries from patients who initiated a third-line or higher therapy after July 2014.

In these later lines of treatment, therapeutic regimens are highly heterogeneous and without any clear standard of care. Data from the pivotal DELTA study with idelalisib (Zydelig®; Gilead) were also included. ZUMA-5 eligibility criteria were applied to the cohort, with patients excluded or censored upon transformation. Single-agent anti-CD20 antibody was not counted as a line of therapy for eligibility, similar to ZUMA-5 eligibility requirements.

A common non-Hodgkin lymphoma
“Follicular lymphoma is one of the most common non-Hodgkin lymphomas, and patients can experience frequent relapses, which quickly leaves us short of treatment options,” said Professor John Gribben, Professor of Medical Oncology at the Cancer Research UK Barts Centre, London, UK, and study author.

“We are very encouraged by these data that suggest a significant and sustained survival benefit with Yescarta even after multiple rounds of prior treatment,” Gribben added.

The propensity score analysis compared follow-up data (median follow-up of 23.3 months; in at least 80 patients with FL) from the pivotal Phase 2 ZUMA-5 study (n=86) to a weighted sample from the SCHOLAR-5 external control cohort of current therapies (n=85), balanced for patient characteristics through propensity scoring.

Ninety-four percent of patients in the ZUMA-5 cohort achieved a response compared to 50% of patients in the control cohort (median follow-up of 26.2 months), with an odds ratio of 16.2 (95% confidence interval [CI]: 5.6-46.9). Yescarta demonstrated a 58% reduction in the risk of death (HR: 0.42; 95% CI: 0.21-0.83, p=0.01) and 70% reduction in the risk of disease progression, relapse or death (HR: 0.30; 95% CI: 0.18-0.49, p<0.001) versus current therapies in the control cohort. While median OS and PFS were both not reached in ZUMA-5, median PFS and OS were 12.7 months and 59.8 months, respectively, in the control cohort.

In the ZUMA-5 safety analysis set (n=146), Grade 3 or higher cytokine release syndrome (CRS) and neurologic toxicities occurred in 8% and 21% of patients, respectively.

“In an indolent disease like follicular lymphoma, longer-term data that demonstrate durable responses are critical. After a patient with follicular lymphoma relapses, the duration of response shortens with each new therapy,” said Caron A. Jacobson, MD, MMSc, Medical Director, Immune Effector Cell Therapy Program, Dana-Farber Cancer Institute and Assistant Professor of Medicine, Harvard Medical School.

“The continued durable benefit demonstrated by axicabtagene ciloleucel at nearly two years is exciting, and the substantial survival benefit over current therapies that we’re seeing in the SCHOLAR-5 analysis is encouraging. These follow-up data reinforce axicabtagene ciloleucel as an important advance for a group of patients who have historically had few options.”

Accelerated approval
Axicabtagene ciloleucel received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in March 2021.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).

Clinical trials
A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5) – NCT03105336
Efficacy and Safety Study of Idelalisib in Participants With Indolent B-Cell Non-Hodgkin Lymphomas (DELTA) – NCT01282424

Highlights of Prescribing Information
Axicabtagene ciloleucel (Yescarta®; Gilead/Kite)[Prescribing Information]
Idelalisib (Zydelig®; Gilead)[Prescribing Information]

Risk Evaluation and Mitigation Strategy (REMS)
Yescarta REMS Program or 1-844-454-KITE (5483).

[1] Ghione P, Patel A, Bobillo S, Deighton K, Jacobson C, Nahas M, Hatswell A, Kanters S, Thornton Snider J, et al. A Comparison of Clinical Outcomes from ZUMA-5 (Axicabtagene Ciloleucel) and the International SCHOLAR-5 External Control Cohort in Relapsed/Refractory Follicular Lymphoma (R/R FL). Abstract #LB1904 ; Presented at: European Hematology Association (EHA2021 Virtual Congress), held June 9 – 17, 2021.
[2] Slater H. Interim Phase 2 ZUMA-5 Results Show Promise for Axi-Cel in R/R iNHL. Oncology (Williston Park). 2020 Jul 15;34(7):260. PMID: 32674213.
[3] Nastoupil LJ, Jain MD, Feng L, Spiegel JY, Ghobadi A, Lin Y, Dahiya S, Lunning M, Lekakis L, Reagan P, Oluwole O, McGuirk J, Deol A, Sehgal AR, Goy A, Hill BT, Vu K, Andreadis C, Munoz J, Westin J, Chavez JC, Cashen A, Bennani NN, Rapoport AP, Vose JM, Miklos DB, Neelapu SS, Locke FL. 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 Sep 20;38(27):3119-3128. doi: 10.1200/JCO.19.02104. Epub 2020 May 13. PMID: 32401634; PMCID: PMC7499611.

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