-- Use of Corticosteroids Prior to Yescarta Infusion Has the Potential to Impact the Benefit/Risk Profile Based on Data from a Cohort of ZUMA-1 Patients --
-- Response Rates Observed in New Analysis Remain Consistent with Pivotal Cohorts --
Kite, a Gilead Company (Nasdaq: GILD), today announced findings from a new analysis of the ZUMA-1 trial of Yescarta ® (axicabtagene ciloleucel) in adult patients with relapsed or refractory large B-cell lymphoma (LBCL). Results were presented today in an oral session at the Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy (ASTCT) and Center for International Blood & Marrow Transplant Research (CIBMTR) (Abstract #70).
In a new ZUMA-1 safety management cohort (Cohort 6), the primary objective was to assess the impact of prophylactic use of corticosteroids and earlier treatment with corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events. Patients with relapsed or refractory LBCL received dexamethasone 10 mg orally on the day of Yescarta infusion and each of the two following days. Corticosteroids and tocilizumab were started earlier, at lower grades of CRS and neurologic events, in Cohort 6 than in the ZUMA-1 pivotal cohorts (Cohorts 1 and 2). All 40 patients enrolled in Cohort 6 received at least one dose of corticosteroids.
In the Cohort 6 primary analysis, no Grade ≥3 CRS occurred. Grade ≥3 neurologic events occurred in 13 percent of patients and no patients experienced Grade 5 neurologic events at the time of data cut-off. Median time to onset of any grade CRS was five days and any grade neurologic events was six days. Sixty-eight percent of patients had no CRS or neurologic events within 72 hours of Yescarta infusion. Ninety-five percent of patients in Cohort 6 responded to Yescarta, including 80 percent of patients who achieved a complete response; 63 percent of patients were in an ongoing response at the time of the data cut-off (median study follow-up of 8.9 months). The median duration of response has not yet been reached.
A post-hoc propensity score-matching analysis was performed by selecting closely matched subgroups from Cohort 6 and pivotal cohorts based on pre-specified prognostic factors for patients with LBCL. This analysis provided a more robust comparison of the safety, efficacy and pharmacokinetic/pharmacodynamic profiles of Cohort 6 with pivotal cohorts. In this propensity score-matched subset, incidence of Grade ≥3 CRS was lower in Cohort 6 (0 percent) than in matched patients from the pivotal cohorts (13 percent) and median time to CRS onset was delayed (5 days versus 2 days). Severity and onset of neurologic events were generally similar between cohorts after propensity score-matching. The propensity score-matching analysis suggested that response rates in Cohort 6 were comparable to those observed in the pivotal cohorts.
"While previous analyses demonstrated a decrease in severity of CRS and neurologic events with earlier steroid intervention, this study suggests that prophylactic corticosteroids may also provide a benefit without compromising efficacy," said Olalekan O. Oluwole, MBBS, MPH, ZUMA-1 Cohort 6 lead investigator and Associate Professor of Medicine, Vanderbilt University Medical Center. "With two-thirds of patients experiencing no CRS or neurologic events up to three days after Yescarta and a five day time to onset of CRS, it is highly encouraging that use of prophylactic steroids may play a significant role in reducing the severe side effects of CAR T."
"As we work to bring the benefits of Yescarta to more patients, these results provide important insights into the use of Yescarta in LBCL, and for safety management protocols for trials with our CAR T-cell therapies," said Frank Neumann, MD, PhD, Kite's Global Head of Clinical Development.
Yescarta was the first CAR T-cell therapy to be 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, and 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, and Yescarta is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Important Safety Information.
Prophylactic use of corticosteroids has not been approved by any regulatory agency in conjunction with Yescarta therapy. The safety and efficacy of this prophylactic adverse event management protocol requires further clinical investigation.
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 and Tecartus REMS Program.
CYTOKINE RELEASE SYNDROME (CRS) occurred in 94% of patients, with 13% ≥ 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 Yescarta infusion. Following infusion, monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. 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 occurred in 87% of patients, 98% of which 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 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, as well as fatal and serious cases of cerebral edema have occurred. Following Yescarta infusion, monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.
REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program called the Yescarta and Tecartus REMS Program which requires that: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab 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.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
HYPERSENSITIVITY REACTIONS: Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of Yescarta.
SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients. Grade ≥3 infections occurred in 23% of patients; those due to 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 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. In immunosuppressed patients, including those who have received Yescarta, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. 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 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 infusion.
HYPOGAMMAGLOBULINEMIA and B-cell aplasia 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 may develop. Monitor life-long for secondary malignancies. In the event that one 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 (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.
Please see full Prescribing Information, including BOXED WARNING and Medication Guide.
Kite, a Gilead Company, is a biopharmaceutical company based in Santa Monica, California, with commercial manufacturing operations in North America and Europe. 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 biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates 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 the risk that physicians and patients may not see the potential benefits of Yescarta therapy and the possibility of unfavorable results from other ongoing and additional clinical studies 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 September 30, 2020, 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.
Kite, the Kite logo, Yescarta, Tecartus and GILEAD are trademarks of Gilead Sciences, Inc. or its related companies.
For more information on Kite, please visit the company's website at www.kitepharma.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. Follow Kite on social media on Twitter ( @KitePharma ) and LinkedIn .
Jacquie Ross, Investors
Nathan Kaiser, Media