-- Sub-Population Analysis Demonstrates High Rates of Durable Response and Overall Survival Regardless of Age at Two Years Post-Treatment --
-- Safety Management Study Shows Early Use of Steroids May Help Manage Severe Cytokine Release Syndrome and Neurologic Events without Effect on Response Rates --
Kite, a Gilead Company (GILD), today announced findings from two new analyses from the ZUMA-1 trial of Yescarta® (axicabtagene ciloleucel) in adult patients with relapsed or refractory large B-cell lymphoma. 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 today at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting May 31 – June 4, in Chicago.
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“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. “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.”
Yescarta 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. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities; see below for Important Safety Information.
Two-Year Analysis of ZUMA-1 by Age Supports Clinical Benefit of Yescarta in Patients 65 and Older (Abstract #7555)
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 percent among ≥65 patients and 81 percent in the <65 group, with 75 percent and 53 percent of patients in the respective groups achieving a complete response. At two years, 42 percent of ≥65 patients and 38 percent of <65 patients were in an ongoing response. The 24-month overall survival rate was 54 percent and 49 percent in each respective group. Among all patients in the safety analysis (27 patients ≥65 and 81 patients <65), most (98 percent) experienced Grade ≥3 adverse events. Grade ≥3 neurologic events occurred in 12 patients ≥65 (44 percent) and in 23 patients <65 (28 percent). Grade ≥3 CRS occurred in 2 patients ≥65 (7 percent) and in 10 patients <65 (12 percent).
“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.”
Preliminary Results Expand Understanding of CAR T Safety Profile (Abstract #7558)
Kite is currently conducting various studies to further evaluate the efficacy and safety profile of Yescarta, including clinical trials evaluating use of bridging chemotherapy and other combination approaches.
In a ZUMA-1 safety management study (Cohort 4), patients with relapsed or refractory large B-cell lymphoma treated with Yescarta 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 Yescarta, with a median follow-up of 7.7 months; 76 percent of patients received corticosteroids and 86 percent received tocilizumab. Grade ≥3 adverse events occurred in 95 percent of patients; Grade ≥3 events included decreased neutrophil count (33 percent) and anemia (24 percent). Grade 1 or 2 neurologic events and CRS occurred in 48 percent and 100 percent of patients, respectively. No patients experienced Grade ≥3 CRS, and Grade ≥3 neurologic events occurred in only 10 percent 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 percent in the cohort, and 62 percent 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 Yescarta without impacting the high response rates to Yescarta therapy 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.”
U.S. Important Safety Information for Yescarta
BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES
- Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
- Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
- Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 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. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.
NEUROLOGIC TOXICITIES: 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 Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.
YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta 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 Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).
HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.
SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.
HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.
SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.
Kite, a Gilead Company, is a biopharmaceutical company based in Santa Monica, California. Kite is engaged in the development of innovative cancer immunotherapies. The company is focused on chimeric antigen receptor and T cell receptor engineered cell therapies. For more information on Kite, please visit www.kitepharma.com.
About Gilead Sciences
Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California. For more information on Gilead Sciences, please visit the company’s website at www.gilead.com.
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Kite’s ability to complete the ZUMA-1 trial of Yescarta in adult patients with relapsed or refractory large B-cell lymphoma in the currently anticipated timelines, or at all. In addition, there is the possibility of unfavorable results from other ongoing and additional clinical trials involving Yescarta. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2019, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead and Kite, and Gilead and Kite assume no obligation to update any such forward-looking statements.
Yescarta is a registered trademark of Gilead Sciences, Inc., or its related companies.
For more information on Kite, please visit the company’s website at www.kitepharma.com. Learn more about Gilead at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.