-- Separate, Two-Year Follow-Up Analysis from ZUMA-1 Safety Management Cohort Shows Continued Benefit of Prophylactic Steroid Use with Yescarta Without Compromising Durability of Response or Survival in Patients with Relapsed or Refractory Large B-cell Lymphoma --
Kite, a Gilead Company (Nasdaq: GILD), today announced three-year follow-up data from the pivotal ZUMA-5 study for Yescarta® (axicabtagene ciloleucel) in relapsed or refractory (r/r) indolent non-Hodgkin lymphoma (iNHL), showing continued response in 52% of all enrolled patients, and prolonged duration of progression-free survival (PFS) in the Phase 2 study, presented at the 2022 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract #4660). In addition, two-year follow-up data from the ZUMA-1 safety cohort (Cohort 6) evaluating use of prophylactic corticosteroids in patients with r/r large B-cell lymphoma (LBCL) (Abstract #4667) were also presented.
“Multi-year follow-up continues to demonstrate the durable response achieved through a single treatment with Yescarta CAR T-cell therapy for difficult-to-treat types of lymphomas,” said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite. “These longer-term results, coupled with additional Yescarta data previously presented, are building a consistent, remarkable story that is changing the standard of care and giving hope to thousands of blood cancer patients.”
ZUMA-5 is a Phase 2, multi-center, single-arm study of Yescarta in patients with iNHL including follicular lymphoma (FL) and marginal zone lymphoma (MZL). Yescarta received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with r/r FL after two or more lines of systemic therapy in March 2021 and was approved in the European Union for the treatment of adult patients with r/r FL after three or more lines of therapy earlier this year. Yescarta is not approved anywhere in the world for MZL.
Abstract #4660
3-Year Follow-Up Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)
In the ZUMA-5 study, Yescarta demonstrated continued durable responses in all patients (n=159) with a median follow-up of 40.5 months [range, 8.3-57.4; FL: 41.7, marginal zone lymphoma (MZL): 31.8]. At the time of data cut-off, the overall response rate (ORR) was 90% (95% CI, 84‒94) and the CR rate was 75% among all patients. Patients with FL had an ORR of 94% (79% CR rate) and patients with MZL had an ORR of 77% (65% CR rate). Among all patients, median duration of response (DoR) was 38.6 months (FL: 38.6, MZL: not reached), median DoR was not reached in patients with a CR, and median progression-free survival (PFS) was 40.2 months (FL: 40.2, MZL not reached). Compared to findings from the study’s two-year analysis, both ORR and CR rates were similar; medians for PFS had increased in MZL and remained unchanged in FL. Since the two-year analysis, no new safety signals were observed and 10 additional patients died due to the following reasons: progression (n=1), adverse events (n=3; none related to Yescarta) and other causes (n=6).
“We continue to see durable responses three years out in patients who were treated with axicabtagene ciloleucel, and in the last year of follow-up very few patients progressed,” said Sattva S. Neelapu, MD, Professor, Department of Lymphoma-Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “These results are particularly meaningful as patients with follicular lymphoma who have relapsed twice have historically only had a five-year progression free survival rate of 20 percent.”
Abstract #4667
Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-Up of ZUMA-1 Cohort 6
A new analysis of the ZUMA-1 safety management cohort (Cohort 6) of patients with r/r LBCL (n=40) evaluating the longer-term impact of prophylactic use of corticosteroids and earlier treatment with corticosteroids and/or tocilizumab showed that the toxicity management strategy demonstrated improved long-term safety without compromising durability of response or survival in patients treated with Yescarta. Patients in the cohort received dexamethasone 10 mg orally on the day of Yescarta infusion and each of the two following days.
At the time of data cut-off, the median follow-up was 26.9 months (range, 24.0-30.1). The ORR was 95% (80% CR), which was consistent with results at the one-year analysis. Median DoR was 25.9 months (95% CI; 7.8-not estimable) and median PFS was 26.8 months (95% CI; 8.7-not estimable). No Grade ≥3 cytokine release syndrome (CRS) was observed. Grade ≥3 neurologic events increased to 18% at two years. The median time to onset of any grade CRS was five days with a median duration of four days. Two new neurologic events were observed (one Grade 2 dementia unrelated to Yescarta, one Yescarta-related leukoencephalopathy that was fatal). Median time to onset of any grade neurologic event was unchanged from the one-year analysis (6 days), and the median duration was similar (19.0 days vs 18.5 days, respectively). All patients in the cohort had treatment-emergent adverse events (TEAEs), including Grade ≥3 events. The most common Grade ≥3 TEAEs were neutropenia (80%), leukopenia (40%) and thrombocytopenia (28%).
“The two-year follow-up data of patients in ZUMA-1 Cohort 6 reinforce that prophylactic use of corticosteroids can improve the use of axicabtagene ciloleucel without compromising response durability or survival outcomes,” said Olalekan O. Oluwole, MBBS, MD, MPH, ZUMA-1 Cohort 6 lead investigator and Associate Professor of Medicine, Vanderbilt University Medical Center. “As knowledge and experience with axicabtagene ciloleucel continue to grow, it’s critical that we continue to utilize this data as the basis for our safety management protocols so that our patients attain the best possible outcomes.”
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.
About Indolent Non-Hodgkin Lymphoma
Follicular lymphoma and marginal zone lymphoma are both forms of indolent non-Hodgkin lymphoma (NHL) in which malignant tumors slowly grow but can become more aggressive over time.
Follicular lymphoma is the most common form of indolent lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22 percent of all lymphomas diagnosed worldwide. Marginal zone lymphoma is the third most common lymphoma, accounting for 8 to 12 percent of all B-cell NHLs.
Despite advances in management and substantial improvements in long-term survival, patients living with follicular lymphoma have varied outcomes. Currently, there are no standard of care treatments for relapsed and refractory follicular lymphoma after two or more lines of therapy, and there are limited options for the treatment of relapsed or refractory marginal zone lymphoma.
About Large B-Cell Lymphoma
Globally, large B-cell lymphoma (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.
About Yescarta
Please see full US 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 the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the 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% (256/276) 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 the 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
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 the 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 a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of 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.
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 in 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 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 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.
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 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.
HYPOGAMMAGLOBULINEMIA
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
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 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 an 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 an 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 an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.
About Kite
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 production and commercial product manufacturing. 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.
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 risk that physicians and patients may not see the potential benefits of Yescarta for the treatment of adult patients with relapsed or refractory large B-cell lymphoma or relapsed or refractory follicular lymphoma; the possibility of unfavorable results from ongoing and additional clinical trials involving Yescarta; and the possibility that Yescarta may not receive the necessary regulatory approvals for the treatment of adult patients with relapsed or refractory large B-cell lymphoma or relapsed or refractory follicular lymphoma in the anticipated timelines or at all, and the risk that any such approvals, if granted, may have significant limitation on its use. 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 September 30, 2022, 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. Investors are cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and are 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.
U.S. Prescribing Information for Yescarta, including BOXED WARNING, is available at www.kitepharma.com and www.gilead.com
Kite, the Kite logo, Yescarta, 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. Follow Kite on social media on Twitter (@KitePharma) and LinkedIn.
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Contacts
Jacquie Ross, Investors
investor_relations@gilead.com
Anna Padula, Kite Media
apadula@kitepharma.com
