Analyses of Kite’s Yescarta® CAR T-Cell Therapy Support Curative Potential in Patients With Non-Hodgkin Lymphomas

– ZUMA-1 Post-Hoc Analysis Shows Five-Year Lymphoma-Related Event-Free Survival in a Substantial Proportion of Patients with Refractory Large B-cell Lymphoma –

– Four-Year Follow-up from ZUMA-5 Demonstrates Continued Durable Response and Long-Term Survival in Patients with Relapsed/Refractory Follicular Lymphoma –

– ZUMA-7 Overall Survival Subgroup Analysis in Patients Aged 65+ Shows that Age Alone is not a Barrier to Receiving CAR T –

SANTA MONICA, Calif.–(BUSINESS WIRE)–Kite, a Gilead Company (Nasdaq: GILD), today announced data from follow-up analyses of three studies of Yescarta^® (axicabtagene ciloleucel) that demonstrate the long-term survival potential for patients living with several sub-types of relapsed or refractory (R/R) non-Hodgkin lymphoma, which were presented at the 65^th American Society of Hematology (ASH) Annual Meeting & Exposition. This included ZUMA-1 (Abstract #4864) showing that patients with refractory large B-cell lymphoma (LBCL) who maintained a complete response (CR) at 12- and 24-months following treatment with Yescarta had a 72-month estimated disease-specific survival (DSS) of 94.4% and 100%, respectively. Long-term data from the ZUMA-5 (Abstract #4868) and ZUMA-7 (Abstract #1761) studies were also presented.

“As we continue to follow up with patients living with difficult-to-treat types of lymphomas, we are witnessing a pattern of longer-term survival with a one-time treatment with Yescarta,” said Frank Neumann, MD, PhD, Senior Vice President, Global Head of Clinical Development, Kite. “The results of these studies, coupled with our rapid and reliable manufacturing, add to our body of knowledge on the benefits and utility of Yescarta as a treatment with curative intent, changing the way these cancers are treated and providing hope to thousands of lymphoma patients.”

Detailed Information on Yescarta Abstracts:

Abstract #4864

Curative Potential of Axicabtagene Ciloleucel (Axi-Cel): an Exploratory Long-Term Survival Assessment in Patients with Refractory Large B-Cell Lymphoma from ZUMA-1

ZUMA-1 is an ongoing, multicenter, single-arm, open-label Phase 1/2 trial evaluating the safety and efficacy of Yescarta CAR T-cell therapy in adult patients with refractory LBCL. In this post hoc analysis of ZUMA-1, with up to six years of follow-up, the five-year long-term lymphoma-related event-free survival (LREFS) was used as a measure to explore Yescarta’s curative potential. Yescarta had long-term LREFS in a substantial proportion of patients, with a five-year rate of 34% (57% among patients who achieved a CR). Additionally, this exploratory analysis found that, at six years, median overall survival (OS) remained consistent with prior analyses at 25.8 months (95% Confidence Interval [CI], 12.8-63.7) and patients who had a CR at 12 and 24 months had a 72-month DSS of 94.4% and 100%, respectively, which may be predictive of extended OS. Among patients who had a CR to therapy, the leading risks of death were reasons other than progression or adverse events after month 24 post-infusion.

Abstract #4868

Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: 4-Year Follow-Up from the Phase 2 ZUMA-5 Trial

ZUMA-5 is an ongoing, single-arm, open-label, international, multicenter Phase 2 trial evaluating 122 adult patients with R/R indolent non-Hodgkin lymphoma (iNHL; follicular lymphoma [FL] and marginal zone lymphoma [MZL]). In this study, at a median follow-up of 52.5 months (range, 20.3-69.4; FL: 53.7, MZL: 43.8), the overall response rate (ORR) remained consistent with prior analyses (90% ORR, 75% CR rate) and the median duration of response (DOR) was 55.5 months (95% CI, 38.6-not estimable [NE]; FL: 55.5, MZL: not reached). At data cutoff, four years of follow-up, median progression free survival (PFS) was 57.3 months (95% CI, 34.9-NE; FL: 57.3, MZL: 46.9) and the 48-month OS rate was 72% (FL: 72%, MZL: 68%). No new neurologic events, hypogammaglobulinemia cases, Grade ≥3 cytopenias or Grade ≥3 infections occurred in the four-year analysis compared to the three-year analysis.

“Taken together with other studies, the results we saw in our four-year analysis from the ZUMA-5 trial and up to six years of follow-up from the ZUMA-1 trial support the durability and safety of axi-cel in patients with follicular lymphoma and large B-cell lymphoma who have progressed following previous lines of therapy,” said Dr. Sattva S. Neelapu, The University of Texas MD Anderson Cancer Center. “We are encouraged by these data, particularly the continued durable response and long-term survival in these patient populations that speak to the potentially curative benefit of this therapy. As we continue to follow these patients, our hope is that these positive survival trends are sustained.”

Abstract #1761

Improved Overall Survival With Axicabtagene Ciloleucel vs Standard of Care in Second-Line Large B-Cell Lymphoma Among the Elderly: A Subgroup Analysis of ZUMA-7

ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 trial evaluating the safety and efficacy of Yescarta versus standard of care (SOC; [chemoimmunotherapy followed by HDT-ASCT in patients who had a response]) for treatment of adult patients with refractory LBCL or relapse within 12 months of first-line therapy. In this analysis, investigators reported updated efficacy and safety results from the primary OS analysis among ZUMA-7 patients aged ≥65 years and ≥70 years. At a median follow-up of 46.6 months, OS was prolonged in the Yescarta vs. SOC arm in patients aged ≥65 years (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). PFS assessed by investigator confirmed benefit of Yescarta over SOC in patients aged ≥65 years (HR, 0.406; 95% CI, 0.230‑0.715) and in patients aged ≥70 years (HR, 0.206; 95% CI, 0.078‑0.547). No new treatment-related deaths occurred since the primary event-free survival (EFS) analysis for ZUMA-7.

	Yescarta Age 65+	SOC Age 65+	Yescarta Age 70+	SOC Age 70+
Median OS (months)	43.5 (95% CI, 20.9-NE)	19.5 (95% CI, 12.3-NE)	24.7 (95% CI, 12.8-NE)	11.2 (95% CI, 6.1-NE)
Median PFS (months)	28.6 (95% CI, 5.1-NE)	5.0 (95% CI, 2.8-7.3)	11.4 (95% CI, 4.1-NE)	2.7 (95% CI, 1.7-5.0)

“Traditionally, older patients with relapsed/refractory large B-cell lymphoma have not been able to access some treatments due to presumed concerns regarding increased toxicity related to their age and comorbidities,” said Professor Marie José Kersten, Amsterdam University Medical Centers. “However, what we’re seeing with this subgroup analysis from the landmark ZUMA-7 trial, is that the data clearly support the consideration of axi-cel also for older patients with relapsed/refractory large B-cell lymphoma. As more data become available, my hope is that patients can receive the therapies that offer them the greatest chance for response and prolonged survival, regardless of age.”

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 Follicular Lymphoma

FL is a form of iNHL in which malignant tumors slowly grow but can become more aggressive over time.

FL 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.

Despite advances in management and substantial improvements in long-term survival, patients living with FL have varied outcomes. Currently, there are no standard of care treatments for relapsed and refractory FL after two or more lines of therapy.

About Large B-Cell Lymphoma

Globally, LBCL is the most common type of 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.

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 ability of Gilead and Kite to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical studies, including those involving Yescarta; the possibility that Gilead and Kite may make a strategic decision to discontinue development of programs for indications that are currently under evaluation and, as a result, these programs may never be successfully commercialized for such indications; the risk that physicians may not see the benefits of prescribing Yescarta; and any assumptions underlying any of the foregoing.

Contacts

Jacquie Ross, Investors

[email protected]

Meaghan Smith, Gilead Media

[email protected]

Anna Padula, Kite Media

[email protected]

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