The European Commission (EC) has granted approval for the use of axicabtagene ciloleucel (Yescarta®; Gilead/Kite), a CD19-directed genetically modified autologous T-cell immunotherapy, for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) who relapse within 12 months from completion of, or are refractory to, first-line chemo-immunotherapy.

Diffuse large B-cell lymphoma (DLBCL) is the most common sub-type of non-Hodgkin lymphoma (NHL), representing around 30% of cases. High-grade B-cell lymphoma (HGBL) is a recently introduced, rare subset of LBCL marked by aggressive B-cell lymphomas including tumors with Burkitt-like or blastoid tumors without double-hit characteristics.

In Europe it is estimated that up to 38,000 new cases of large B-cell lymphoma (LBCL) were diagnosed in 2020. Although first-line treatment can be effective in around 60% of cases, 40% will relapse or not respond and need second-line treatment. For people who relapse, or who do not respond to first-line treatment, outcomes are often poor. Most patients with refractory (no response) LBCL have no curative treatment options.

The approval is based on results from the pivotal Phase 3 ZUMA-7 study, the largest and longest trial of a CAR T-cell therapy versus Standard of Care in this patient population. axicabtagene ciloleucel, a CD19-directed genetically modified autologous T cell immunotherapy, is now the first Chimeric Antigen Receptor (CAR) T-cell therapy approved for patients in Europe who do not respond to first-line treatment.

This provides an important additional treatment option for the most common form of non-Hodgkin lymphoma. Although 60% of newly diagnosed LBCL patients, including those with DLBCL, will respond to their initial treatment, 40% will relapse or will not respond and need second-line treatment.

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“We are very proud to announce Kite’s fifth approved indication in Europe in our continued commitment to the research and delivery of cell therapies with curative potential to patients who might benefit around the world,” said Christi Shaw, CEO, Kite.

“Today’s approval marks an important step by providing patients in Europe this option of CAR T-cell therapy earlier in their treatment journey,” Shaw added.

Current standard of care
The standard of care (SOC) therapy for this patient population has historically been a multi-step process expected to end with a stem cell transplant. The process starts with chemoimmunotherapy, and if a patient responds to and can tolerate further treatment, they move on to high-dose chemotherapy (HDT) followed by a stem cell transplant (ASCT).

“This approval marks a major shift in the treatment of LBCL when initial treatment has failed. In ZUMA-7, treatment with axicabtagene ciloleucel resulted in an overall better outcome for patients than standard of care, especially in terms of event-free survival, marking a new era for treatment earlier in the disease pathway for more patients,” said Professor John Gribben, Professor of Medical Oncology at the Cancer Research UK Barts Centre, London.

“The ZUMA-7 data has also broadened our understanding of this CAR T-cell therapy, allowing us to better manage or prevent side-effects, which is important as it moves earlier in the treatment pathway and for older patients and those with medical conditions for whom the standard of care might have been difficult,” Gribben further noted.

Clinical development
ZUMA-7 is an ongoing, randomized, open-label, global, multicenter (US, Australia, Canada, Europe, Israel) Phase 3 study of 359 patients at 77 centers, evaluating the safety and efficacy of a single-infusion of axicabtagene ciloleucel versus current SOC for second-line therapy (platinum-based salvage combination chemotherapy regimen followed by high-dose chemotherapy and autologous stem cell transplant in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. The primary endpoint is event free survival (EFS). Key secondary endpoints include objective response rate (ORR) and overall survival (OS). Additional secondary endpoints include patient reported outcomes and safety.

In the analysis of patient reported outcomes (PROs), patients receiving Yescarta and eligible for the PROs portion of the study (n=165), showed statistically significant improvements in Quality of Life (QoL) at Day 100 compared with those who received SOC (n=131), using a pre-specified analysis for three PRO-domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QOL, and EQ-5D-5L visual analog scale [VAS]). There was also a trend toward faster recovery to baseline QoL in the Yescarta arm versus SOC.

The ZUMA-7 study demonstrated that at a median follow-up of two years, axicabtagene ciloleucel-treated patients had a four-fold greater improvement in the primary endpoint of event-free survival (EFS; hazard ratio 0.40; 95% CI: 0.31-0.51, P<0.001) over the current SOC (8.3 months vs 2.0 months). Additionally, axicabtagene ciloleucel demonstrated a 2.5 fold increase in patients who were alive at two years without disease progression or need for additional cancer treatment vs SOC (41% v 16%). Improvements in EFS with axicabtagene ciloleucelwere consistent across key patient subgroups, including elderly patients (HR: 0.28 [95% CI: 0.16-0.46]), primary refractory patients (HR: 0.43 [95% CI: 0.32- 0.57]), high-grade B-cell lymphoma (HR: 0.28 [95% CI: 0.14-0.59]), and double-expressor lymphoma patients (HR: 0.42 [95% CI: 0.27-0.67]).

In the ZUMA-7 trial, axicabtagene ciloleucel had a safety profile that was consistent with previous studies. Among the 170 axicabtagene ciloleucel-treated patients evaluable for safety, Grade ≥3 cytokine release syndrome (CRS) and neurologic events were observed in 6% and 21% of patients, respectively. No Grade 5 CRS or neurologic events occurred. In the SOC arm, 83% of patients had Grade ≥3 events, mostly cytopenias (low blood counts).

Regulatory approval
Axicabtagene ciloleucel was first approved in Europe in 2018 and is currently indicated for five types of blood cancer: Diffuse Large B-Cell Lymphoma (DLBCL); Large B-Cell Lymphoma (LBCL); High-Grade B-Cell Lymphoma (HGBL); Primary Mediastinal Large B-Cell Lymphoma (PMBCL); and Follicular Lymphoma (FL).

Clinical trials
Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7) – NCT03391466

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

European Prescribing Information
Axicabtagene ciloleucel (Yescarta®; Gilead/Kite)[Prescribing information]

[1] Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. doi: 10.1056/NEJMoa2116133. Epub 2021 Dec 11. PMID: 34891224. [Article]

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