EFFICACY

DISCOVER THE TREATMENT RESPONSE OF PATIENTS TREATED WITH YESCARTA®

EFFICACY AND SAFETY ESTABLISHED IN THE ZUMA-1 PIVOTAL TRIAL AND ADDITIONAL SAFETY STUDY1-4

STUDY DESIGN

  • YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial of 101 adults with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma, comprising the pivotal trial (Cohorts 1 and 2) upon which YESCARTA was FDA approved
    • The additional safety study (Cohort 4) was a subsequent, open-label, safety-management cohort of 46 patients with large B-cell lymphoma, 41 of whom were treated with YESCARTA to assess the early use of corticosteroids and/or tocilizumab for Grade 1 cytokine release syndrome or neurologic toxicity
      • Optional bridging chemotherapy was permitted in Cohort 4
  • Patients had refractory disease to the most recent therapy or relapsed within 1 year after autologous stem cell transplantation (ASCT)
  • Patients received lymphodepleting chemotherapy: 500 mg/m2 intravenous (IV) cyclophosphamide and 30 mg/m2 IV fludarabine (-5, -4, and -3 days before infusion)
  • YESCARTA was administered as a single infusion to a target dose of 2 x 106 viable CAR T cells/kg body weight (maximum of 2 x 108 viable CAR T cells)
  • Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted in Cohorts 1 and 2*

*In the commercial setting, the use of bridging therapy after leukapheresis and before lymphodepleting chemotherapy is at the discretion of the treating physician.1

THE ZUMA-1 POPULATION (COHORTS 1 AND 2) SPANNED A WIDE RANGE OF PATIENTS WITH PROGRESSIVE DISEASE

3
77% refractory to at least 2 lines of therapy
21% relapsed within 1 year of ASCT

YESCARTA DELIVERS DURABLE, COMPLETE REMISSIONS

COMPELLING RESPONSE RATES IN COHORTS 1 AND 2: 1- AND 2-YEAR ANALYSES1,5,6

Objective Response Rate (ORR) Complete Remission (CR) Rate Partial Remission (PR) Rate
1-YEAR FOLLOW-UP (11.6-month median follow-up)
INDEPENDENT REVIEW COMMITTEE (N=101) 72% 51% 21%
INVESTIGATOR REVIEW (N=101) 83% 58% 25%
2-YEAR FOLLOW-UP (27.1-month median follow-up)
INDEPENDENT REVIEW COMMITTEE (mITT) (N=101) 74% 54% 20%
INDEPENDENT REVIEW COMMITTEE (ITT) (N=111)§ 68% 50% 18%
1-YEAR FOLLOW-UP (11.6-month median follow-up) 2-YEAR FOLLOW-UP (27.1-month median follow-up)
INDEPENDENT REVIEW COMMITTEE (N=101) INVESTIGATOR REVIEW (N=101) INDEPENDENT REVIEW COMMITTEE (mITT) (N=101) INDEPENDENT REVIEW COMMITTEE (ITT) (N=111)§
Objective Response Rate (ORR) 72% 83% 74% 68%
Complete Remission (CR) Rate 51% 58% 54% 50%
Partial Remission (PR) Rate 21% 25% 20% 18%

ITT=intent-to-treat; mITT=modified intent-to-treat.

Data from the 27.1-month median follow-up of ZUMA-1 are not included in the PI and should be carefully interpreted.1,5

Data from the investigator analysis of ZUMA-1 is based on assessments performed by individual investigators at their respective trial sites and should be interpreted with caution. Investigator-assessed data are not included in the full PI. For FDA approval, efficacy was established on the basis of CR rate and duration of response (DOR), as determined by an IRC.1,5

§The ITT population included all 111 patients leukapheresed in the phase 2 segment of ZUMA-1; efficacy assessments were based on data from the mITT population (N=101) comprising all patients enrolled and treated with the target dose of YESCARTA.5 ITT data are not included in the PI for YESCARTA.1

IRC=independent review committee.

DECISION TO REMISSION IN <2 MONTHS

(27.1-month median follow-up)

With a median time from leukapheresis to complete remission of 1.9 months (range: 1.4, 16.4), some patients have achieved remission in <2 months.

ǁ“Decision” refers to time of leukapheresis. These data are not included in the PI for YESCARTA.

SUBGROUP RESPONSE RATES

INVESTIGATOR-ASSESSED RESPONSE RATES AT A MEDIAN FOLLOW-UP OF 8.7 MONTHS
ORR 95% CI
65 years# (n=24) 92% 0.73, 0.99
<65 years# (n=77) 79% 0.68, 0.88
Refractory to 2
lines of therapy
(n=78)
83% 0.73, 0.91
Relapsed after
ASCT
(n=21)
76% 0.53, 0.92
History of primary
refractory disease
(n=26)
88% 0.70, 0.98
History of refractory
disease to
2 consecutive
lines of therapy
** (n=54)
78% 0.64, 0.88
INVESTIGATOR-ASSESSED RESPONSE RATES AT A MEDIAN FOLLOW-UP OF 8.7 MONTHS
65 years# (n=24) <65 years# (n=77) Refractory to 2
lines of therapy
(n=78)
Relapsed after
ASCT
(n=21)
History of primary
refractory disease
(n=26)
History of refractory
disease to 2
consecutive
lines of therapy
** (n=54)
ORR 92% 79% 83% 76% 88% 78%
95% CI 0.73, 0.99 0.68, 0.88 0.73, 0.91 0.53, 0.92 0.70, 0.98 0.64, 0.88

Data from the investigator analysis of ZUMA-1 are based on assessments performed by individual investigators at their respective trial sites and should be interpreted with caution. Investigator-assessed data are not included in the full PI. For FDA approval, efficacy was established on the basis of CR rate and DOR, as determined by an IRC.1,5

Subgroup data not included in the full PI. The efficacy in these subgroups was not a study objective and the study was not powered to assess efficacy in these subgroups.

#GERIATRIC USE: Clinical trials of YESCARTA did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently or have different safety outcomes as compared with younger patients.1

**Post hoc subgroup analysis.

CI=confidence interval.

MANY PATIENTS IN COHORTS 1 AND 2 ACHIEVED DURABLE, COMPLETE RESPONSES2

IRC-ASSESSED Duration of Response (DOR)

2-YEAR ANALYSIS: MEDIAN DOR NOT YET REACHED AT 27.1-MONTH MEDIAN FOLLOW-UP2,8

ZUMA-1 duration of response KM curve: Median duration of response not reached.

The tick marks represent censored patients. Patients who did not progress, have not died, or received new anti-cancer therapy (including stem cell transplant) prior to documented progression were censored at their last evaluable disease assessment.9

Data from the 27.1-month median follow-up of ZUMA-1 are not included in the PI and should be carefully interpreted.1,5

NR=not reached.

PATIENTS AT RISK
Time (months) ORR CR PR
0755520
1685216
2615110
354495
451474
547452
643412
743412
843412
941392
1039372
1137352
1236351
1335341
1434331
1532311
1632311
1732311
1831301
1931301
2031301
2129290
222828 
231818 
2444 
2533 
2633 
2733 
2833 
2922 
3000 
  • At the time of FDA approval, the median follow-up was 11.6 months. Efficacy was established on the basis of CR rate and DOR, as determined by an IRC1,6
11.6-MONTH MEDIAN FOLLOW-UP1,6
Median DOR
All responders (n=73) 9.2 months (95% CI: 5.4, NR)
If best response was…
CR (n=52) Not reached (95% CI: 8.1, NR)
PR (n=21) 2.1 months (95% CI: 1.3, 5.3)
  • In the pivotal trial, of the 52 patients who achieved CR, 14 initially had stable disease (7 patients) or PR (7 patients), with a median time to improvement of 2.1 months (range: 1.6 to 5.3 months)1
27.1-MONTH MEDIAN FOLLOW-UP2,8
Median DOR
All responders (n=75) Not reached (95% CI: 10.91, NR)
If best response was…
CR (n=55) Not reached (95% CI: NR, NR)
PR (n=20) 2.07 months (95% CI: 1.28, 11.07)
  • Two patients previously read as not evaluable at an 11.6-month median follow-up were determined to be in CR upon follow-up disease assessments, leading to a prolongation of the DOR10
  • Data from the 27.1-month median follow-up of ZUMA-1 are not included in the PI and should be carefully interpreted1,5

5 AND ALIVE WITH YESCARTA: 43% OF PATIENTS ALIVE AT 5 YEARS WITH A MEDIAN OS OF 25.8 MONTHS11

THE ONLY CAR T TO PRESENT OVERALL SURVIVAL (OS) DATA WITH AT LEAST 5 YEARS OF FOLLOW-UP11,12

  • OS was a secondary endpoint of the ZUMA-1 phase 2, single-arm, open-label study1,2
  • OS data are descriptive and should be carefully interpreted in light of the single-arm design. OS data are not included in the PI for YESCARTA
  • Not all data continued to be captured at the 5-year follow-up; CR status and other treatments are unknown. Only OS, investigator-assessed response, and adverse event reporting were captured13
  • The KM estimate of the 5-year OS rate was 43%.11
ZUMA-1 overall survival KM curve: 43% alive at 5 years.

The tick marks represent censored patients. Patients who have not died by the data cutoff date were censored at the last date known to be alive.9

KM median OS: 25.8 months (95% CI: 12.8, NE).11

KM=Kaplan-Meier; mOS=median overall survival.

Time, Months Patients at risk (Patients censored)
0101(0)
297(0)
493(0)
680(0)
874(0)
1069(0)
1261(0)
1460(0)
1654(0)
1853(0)
2053(0)
2251(0)
2451(0)
2650(0)
2850(0)
3050(0)
3250(0)
3450(0)
3647(0)
3847(0)
4047(0)
4246(0)
4446(0)
4645(0)
4844(0)
5028(15)
5216(27)
546(37)
561(42)
580(43)

UPDATED SAFETY-MANAGEMENT STUDY (COHORT 4)1

STUDY DESIGN1-4

  • YESCARTA was studied in a phase 2, open-label, single-arm, multicenter trial of 101 adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, comprising the pivotal trial (Cohorts 1 and 2), upon which YESCARTA was FDA approved
  • The additional safety study (Cohort 4) was a subsequent, open-label, safety-management cohort of 46 patients with large B-cell lymphoma, 41 of whom were treated, who received corticosteroids and/or tocilizumab for Grade 1 cytokine release syndrome or neurologic toxicity
    • Optional bridging chemotherapy was permitted in Cohort 4

UPDATED SAFETY-MANAGEMENT STRATEGY1

  • Cytokine release syndrome (CRS): Grade 3 incidence, 2%; overall incidence, 93%
  • Neurologic toxicities: Grade 3 incidence, 20%; overall incidence, 78%
  • There was no incidence of Grade 4/5 CRS or neurologic toxicities

See more CRS or neurologic toxicity data from the safety-management study.

RESPONSE RATES AND DURATION OF RESPONSE DATA1,4

MEDIAN FOLLOW-UP TIME FOR THE SAFETY-MANAGEMENT STUDY: 8.7 MONTHS
  • Response rate and DOR data from the safety-management study are descriptive, no formal hypothesis testing was performed, and these data should be carefully interpreted in light of the single-arm design. Efficacy data are not included in the Prescribing Information for YESCARTA
  • Differences in disease characteristics and eligibility criteria between the safety-management study and pivotal trial may have affected outcomes
  • The safety-management study allowed bridging therapy, which may have resulted in lower tumor burden at baseline
  • Response assessment was based on investigator assessment and responses were not confirmed by IRC
SAFETY MANAGEMENT GROUP (COHORT 4)1,4
(n=41)
Objective Response Rate
73%
Complete Remission Rate
51%
Median DOR (months)
8.9

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated 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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

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), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade 3 in 8% (11/146). 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 (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). 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, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. 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 that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving YESCARTA, including Grade 3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade 3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. 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 for patients with iNHL. 98% 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 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). 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. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing 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). The most common neurologic toxicities were consistent with the overall LBCL population treated with YESCARTA. 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 47% (119/254) of all patients with NHL. Grade 3 infections occurred in 19% of patients, Grade 3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, 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 anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% 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. 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 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% 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 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 adverse reactions (incidence 20%) in patients with LBCL 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.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated 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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

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), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade 3 in 8% (11/146). 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 (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). 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, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. 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 that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving YESCARTA, including Grade 3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade 3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. 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 for patients with iNHL. 98% 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 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). 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. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing 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). The most common neurologic toxicities were consistent with the overall LBCL population treated with YESCARTA. 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 47% (119/254) of all patients with NHL. Grade 3 infections occurred in 19% of patients, Grade 3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, 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 anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% 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. 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 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% 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 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 adverse reactions (incidence 20%) in patients with LBCL 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.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

INDICATION

YESCARTA® is a CD19-directed genetically modified autologous T cell immunotherapy indicated 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.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.

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), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade 3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade 3 in 13%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade 3 in 8% (11/146). 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 (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). 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, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. 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 that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving YESCARTA, including Grade 3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade 3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. 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 for patients with iNHL. 98% 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 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). 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. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing 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). The most common neurologic toxicities were consistent with the overall LBCL population treated with YESCARTA. 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 47% (119/254) of all patients with NHL. Grade 3 infections occurred in 19% of patients, Grade 3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, 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 anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% 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. 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 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% 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 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 adverse reactions (incidence 20%) in patients with LBCL 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.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Authorized Treatment Centers are independent facilities certified to dispense Kite CAR T therapies. Choice of an Authorized Treatment Center is within the sole discretion of the physician and patient. Kite does not endorse any individual treatment sites.

References: 1. YESCARTA® (axicabtagene ciloleucel). Prescribing information. Kite Pharma, Inc; 2021. 2. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. 3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. 4. Topp MS, van Meerten T, Houot R, et al. Earlier steroid use with axicabtagene ciloleucel (Axi-Cel) in patients with relapsed/refractory large B cell lymphoma. Presented at: 61st ASH Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 243. 5. Data on file [1]. Kite Pharma, Inc; 2018. 6. Locke FL, Ghobadi A, Jacobson CA, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 3003. 7. Data on file. Kite Pharma, Inc; 2020. 8. Data on file [2]. Kite Pharma, Inc; 2018. 9. Data on file [1]. Kite Pharma, Inc; 2019. 10. Data on file [2]. Kite Pharma, Inc; 2019. 11. Data on file. Kite Pharma, Inc; 2021. 12. Chong EA, Ruella M, Schuster SJ, et al. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N Engl J Med. 2021;384(7):673-674. 13. Data on file [3]. Kite Pharma, Inc; 2019.