Findings from two new analyses from the ZUMA-1 trial of axicabtagene ciloleucel (Yescarta?;Kite Pharma) in adult patients with relapsed or refractory large B-cell lymphoma demonstrate high rates of durable response and overall survival (OS).
These results include a two-year sub-population analysis of efficacy and safety in ZUMA-1 patients (registrational Cohorts 1 and 2) by age, as well as preliminary data from a separate safety management study of patients receiving early steroid intervention for cytokine release syndrome (CRS)* and neurologic events. 
The results were presented earlier today during the annual meeting of American Society of Clinical Oncology (ASCO), held in Chicago, May 31 ? June 4, 2019
?Longer-term data from ZUMA-1 have shown more than half of patients were still alive two years after treatment with Yescarta,? said John McHutchison, AO, MD, Chief Scientific Officer and Head of Research and Development, Gilead Sciences, the parent company of Kite Pharma.
?We are committed to further defining the clinical profile of Yescarta, including evaluation of new safety management protocols to further enhance patient care and help move the cell therapy field forward,? McHutchison added.
First CAR T-cell Therapy
Axicabtagene ciloleucel was the first CAR T-cell therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.
Analysis of ZUMA-1
Patients with relapsed large B-cell lymphoma in the two-year follow-up of ZUMA-1 were analyzed in two groups ? those 65 years or older (?65) (n=24) and those younger than 65 years (<65) (n=77). 
With a median follow-up of 27.1 months, the objective response rate (ORR) per investigator assessment was 92% among ?65 patients and 81% in the <65 group, with 75% and 53% of patients in the respective groups achieving a complete response.
At two years, 42% of ?65 patients and 38% of <65 patients were in an ongoing response. The 24-month overall survival rate was 54% and 49% in each respective group.
Among all patients in the safety analysis (27 patients ?65 and 81 patients <65), most (98%) experienced Grade ?3 adverse events. Grade ?3 neurologic events occurred in 12 patients ?65 (44%) and in 23 patients <65 (28%).
Grade ?3 CRS occurred in 2 patients ?65 (7%) and in 10 patients <65 (12%).
?Patients with refractory large B-cell lymphoma who have exhausted treatment options and are still facing progressive disease are often older,? said Sattva S. Neelapu, MD, ZUMA-1 co-lead investigator and Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.
?Our results showed axicabtagene ciloleucel offered clinical benefit with a manageable safety profile in people aged 65 and over, which reinforces this therapy?s use in these patients who otherwise have limited treatment options,? Neelapu added.
Various studies to further evaluate the efficacy and safety profile of axicabtagene ciloleucel, including clinical trials evaluating use of bridging chemotherapy and other combination approaches are currently ongoing.
In a ZUMA-1 safety management study (Cohort 4), patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel received earlier steroid intervention beginning when patients experienced Grade 1 neurologic events and at Grade 1 CRS when no improvement was observed after three days of supportive care.
As of the abstract data cut-off, 21 of 40 planned patients had received axicabtagene ciloleucel, with a median follow-up of 7.7 months; 76% of patients received corticosteroids and 86% received tocilizumab. Grade ?3 adverse events occurred in 95% of patients; Grade ?3 events included decreased neutrophil count (33%) and anemia (24%).
Grade 1 or 2 neurologic events and CRS occurred in 48% and 100% of patients, respectively. No patients experienced Grade ?3 CRS, and Grade ?3 neurologic events occurred in only 10% of patients, both numerically lower than in the registrational cohorts of ZUMA-1. There were no deaths due to adverse events in Cohort 4.
ORR per investigator assessment was 81% in the cohort, and 62% of patients achieved a complete response. The median duration of response has not yet been reached.
?Preliminary results of the ZUMA-1 expansion cohort suggest early steroid interventions may reduce the incidence of severe CRS and neurologic events associated with axicabtagene ciloleucel without impacting the high response rates to  therapy [with axicabtagene ciloleucel] in relapsed or refractory large B-cell lymphoma,? said Max S. Topp, MD, ZUMA-1 cohort 4 lead investigator and Professor and Head of Hematology, University Hospital of Wuerzburg, Germany.
?While longer follow-up in a greater number of patients is required, response rates thus far have been comparable to the pivotal ZUMA-1 study cohorts and rates of Grade 3 or higher CRS and neurologic events have been lower in this preliminary analysis, suggesting that early adverse event management with steroids may further improve the benefit/risk profile of CAR T therapy,? Topp concluded.
Adverse events – Boxed Warning
Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the European Union and the United States for patients with relapsed or refractory Large B-Cell Lymphoma with ? 2 prior systemic therapies. The prescribing information for axicabtagene ciloleucel in the United States has a BOXED WARNING, type of warning on the prescription’s drug label designed to call attention to serious or life-threatening risks, in this case the risks of Cytokine Release Syndrome and neurologic toxicities. This information is, in part, based on earlier, registration studies.
Cytokine Release Syndrome (CRS)*, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel. CRS occurred in 94% of patients, including 13% with ? Grade 3. Among patients who died after receiving axicabtagene ciloleucel, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving axicabtagene ciloleucel, including concurrently with CRS or after CRS resolution.
Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with axicabtagene ciloleucel. Fatal and serious cases of cerebral edema have occurred in patients treated with axicabtagene ciloleucel.
Risk Evaluation and Mitigation Strategy
A REMS strategy is a drug safety program that the FDA require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. They are designed to reinforce medication use behaviors and actions that support the safe use of that medication. While all medications have labeling that informs health care professionals and patients about medication risks, only a few medications require a REMS.
This means that healthcare facilities that dispense and administer axicabtagene ciloleucel must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after administration of axicabtagene ciloleucel, if needed for treatment of CRS. Certified healthcare facilities are also required to ensure that healthcare providers who prescribe, dispense or administer axicabtagene ciloleucel are trained about the management of CRS and neurologic toxicities.
*Cytokine Release Syndrome or CRS is a condition that may occur after treatment with some types of immunotherapy, such as monoclonal antibodies and CAR T-cells. It is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy. Cytokines are immune substances that have many different actions in the body. Signs and symptoms of cytokine release syndrome include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing. Most patients have a mild reaction, but in some instances the reaction may be severe or even life threatening. 
 Neelapu SS, Jacobson CA, Oluwole OO, Munoz J, Deol A, Miklos DB, Bartlett NL, et al. Outcomes of patients (pts) ? 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL). J Clin Oncol 37, 2019 (suppl; abstr 7555) [Abstract]
 Topp MS, Van Meerten T, Wermke M, Lugtenburg EJ, Minnema MC, Song KW, Thieblemont C, et al. Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). J Clin Oncol 37, 2019 (suppl; abstr 7558) [Abstract]
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