-- First Treatment in Nearly 30 Years to Show Statistically Significant OS, With a Median Follow-Up of 47.2 Months, for Initial Treatment of R/R LBCL Versus Historical SOC in the Curative Setting --
-- Yescarta Results in a 27.4% Reduction in Risk of Death, Corresponding to a 38% Relative Improvement in OS, Despite 57% of Patients Subsequently Receiving Cell Therapy Off Protocol --
-- Data Highlighted as Late-Breaking News at ASCO 2023 and Simultaneously Published in the New England Journal of Medicine --
Kite, a Gilead Company (Nasdaq: GILD), today announces detailed results from the overall survival (OS) analysis of the landmark Phase 3 ZUMA-7 study of Yescarta® (axicabtagene ciloleucel [axi-cel]) CAR T-cell therapy compared with historical standard of care (SOC) as initial treatment in the curative setting for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). Yescarta is the first treatment in nearly 30 years to demonstrate a significant improvement in survival in this patient population. The late-breaking data are being presented orally at the 2023 American Society of Clinical Oncology Annual Meeting (Abstract #LBA107) and published simultaneously in the New England Journal of Medicine.
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With a median follow-up of 4 years (47.2 months), a one-time treatment with Yescarta demonstrated significantly longer overall survival (hazard ratio [HR] 0.726; 95% CI: 0.540-0.977, stratified one-sided log rank p-value = 0.0168) compared to SOC with a 27.4% reduction in the risk of death, which corresponds to a 38% relative improvement in overall survival, for patients with R/R LBCL within 12 months completion of first-line therapy.
SOC therapy for this patient population has historically been a multi-step process expected to end with stem-cell transplant. The process starts with chemoimmunotherapy, and if a patient responds and can tolerate further treatment, they move on to high-dose chemotherapy (HDT), followed by stem cell transplant (ASCT). It is notable that despite this process being the historical SOC, less than 40% of patients were able to make it through to complete their stem cell transplant compared with 94% of patients in the ZUMA-7 study who received Yescarta CAR T-cell therapy.
“As the first treatment in nearly three decades to significantly improve survival for patients with relapsed/refractory large B-cell lymphoma, axi-cel can potentially change the standard of care for these patients who previously had very limited options for successful curative therapy,” said Jason Westin, MD, MS, FACP, ZUMA-7 Principal Investigator, Director, Lymphoma Clinical Research, and Associate Professor, Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. “The totality of the ZUMA-7 data provides a compelling case for axi-cel to be used as soon as patients with large B-cell lymphoma do not respond to or relapse from first-line treatment.”
The primary OS analysis, conducted per protocol five years after the first subject was randomized, demonstrated superior OS with Yescarta over the SOC arm, despite more than half (57%) of patients in the SOC arm subsequently receiving cellular immunotherapy off protocol; of these, 77% of patients received Yescarta. Median OS was longer with Yescarta versus SOC (not reached versus 31.1 months, respectively) and 48-month OS estimates were higher with Yescarta (54.6% versus 46.0%, respectively). Yescarta’s OS benefit versus SOC was also similar across key patient subgroups, including patients with high-risk features, such as those with primary refractory disease, high-grade B-cell lymphoma (including double-hit lymphomas) and aged 65 and above. Progression-free survival (PFS) by investigator review confirmed the benefit of Yescarta over SOC (HR 0.506; 95% CI: 0.383-0.669), with 48-month PFS estimates of 41.8% with Yescarta versus 24.4% with SOC.
Yescarta’s safety profile remains consistent with prior studies, and no new treatment-related deaths occurred since the primary EFS analysis. The primary EFS analysis showed that Grade 3 or higher adverse events (AEs) occurred in 91% of patients treated with axi-cel compared with 83% of those treated with SOC. The most common grade 3 or higher AEs were neutropenia (69% vs 41%, respectively), anemia (30% vs 39%), and leukopenia (29% vs 22%).
“Overall survival is the gold standard in cancer treatment and confirms Yescarta’s place as a treatment of curative intent for patients with relapsed/refractory large B-cell lymphoma,” said Frank Neumann, MD, PhD, SVP, Kite’s Global Head of Clinical Development. “Kite shares this momentous achievement with all of the patients and researchers who participated in the ZUMA-7 study since the first patient was randomized five years ago.”
About ZUMA-7 Study
Based on the results of primary efficacy endpoint of event-free survival (EFS) in the pivotal ZUMA-7 trial, the U.S. Food & Drug Administration approved Yescarta as initial treatment of R/R LBCL in April 2022. The EU granted approval in October 2022, followed by approvals in several other countries such as: Australia, Canada, Great Britain, Israel, Japan and Switzerland.
ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 study evaluating the safety and efficacy of Yescarta versus SOC for second-line therapy in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. The SOC for initial treatment of R/R LBCL has been a multi-step process involving platinum-based salvage combination chemotherapy regimen, and for responders, high-dose therapy (HDT) and autologous stem cell transplant (ASCT). In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or SOC second-line treatment. The primary endpoint was EFS as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate (ORR) per blinded central review and overall survival (OS). Additional secondary endpoints included patient reported outcomes (PROs) and safety. Per hierarchical testing of primary and key secondary endpoints and group sequential testing of OS, an interim analysis of OS occurred at the time of the primary EFS.
Yescarta demonstrated a 2.5-fold increase in patients who were alive at two years and did not experience cancer progression or require additional cancer treatment (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared to SOC (hazard ratio 0.398; 95% CI: 0.308-0.514, P<0.0001). The ZUMA-7 study is the largest and longest study of its kind.
Nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (35%) who received on-protocol HDT+ASCT. More patients responded to Yescarta (ORR: 83% vs. 50%, odds ratio: 5.31 [95% CI: 3.1-8.9; P<0.0001]) and achieved a complete response (CR) with Yescarta (CR rate: 65% vs. 32%) than with SOC.
The prespecified primary OS analysis was to be conducted after approximately 210 deaths or no later than five years after the first patient was randomized, whichever came first, and was triggered by the latter criterion.
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.
Globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.
Please see full Prescribing Information, including BOXED WARNING and Medication Guide.
YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
- Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
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.
Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
- Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION
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)
CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (56/2) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 days) for patients with iNHL.
Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.
Ensure that 2 doses of tocilizumab are available prior to YESCARTA 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 (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range:1-133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.
The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.
The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.
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.
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).
Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.
Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL. Grade 3 or higher infections occurred in 17% of patients, including ≥ Grade 3 or higher infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. 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 antimicrobials according to local guidelines.
Febrile neutropenia was observed in 36% of all patients with NHL 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, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
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 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.
B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. 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 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.
The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.
The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.
The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.
Kite, a Gilead Company, is a global biopharmaceutical company based in Santa Monica, California, focused on cell therapy to treat and potentially cure cancer. As the global cell therapy leader, Kite has treated more patients with CAR T-cell therapy than any other company. Kite has the largest in-house cell therapy manufacturing network in the world, spanning process development, vector manufacturing, clinical trial supply and commercial product manufacturing. For more information on Kite, please visit www.kitepharma.com. Follow Kite on social media on Twitter (@KitePharma) and LinkedIn.
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.
Forward Looking Statements
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 possibility of unfavorable results from ongoing or additional clinical trials involving Yescarta; Kite’s ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, including those involving Yescarta; Kite’s ability to receive regulatory approvals in a timely manner or at all, including additional regulatory approvals of Yescarta, and the risk that any such approvals may be subject to significant limitations on use; the risk that physicians may not see the benefits of prescribing Yescarta; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2023, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Kite and Gilead, and Kite and Gilead assume no obligation and disclaim any intent to update any such forward-looking statements.
Kite, the Kite logo, Yescarta, Tecartus, XLP and GILEAD are trademarks of Gilead Sciences, Inc. or its related companies.