YESCARTA 0.4-2 x 10{8} CELULE DISPERSIE PERFUZABILA perfusable dispersion cells medication leaflet

Yescarta 0.4 - 2 × 108 cells dispersion for infusion

2.1 General description

Yescarta (axicabtagene ciloleucel) is a genetically modified autologous cell-based product containing

T cells transduced ex vivo using a retroviral vector expressing an anti-CD19 chimeric antigen receptor(CAR) comprising a murine anti-CD19 single chain variable fragment (ScFv) linked to CD28co-stimulatory domain and CD3-zeta signalling domain.

2.2 Qualitative and quantitative composition

Each patient-specific infusion bag of Yescarta contains axicabtagene ciloleucel at a batch-dependentconcentration of autologous T cells genetically modified to express an anti-CD19 chimeric antigenreceptor (CAR-positive viable T cells). The medicinal product is packaged in one infusion bag overallcontaining a cell dispersion for infusion of a target dose of 2 × 106 anti-CD19 CAR-positive viable

T cells per kg of body weight (range: 1 × 106 - 2 × 106 cells/kg), with a maximum of2 × 108 anti-CD19 CAR-positive viable T cells suspended in a cryopreservative solution.

Each infusion bag contains approximately 68 mL of dispersion for infusion.

Each infusion bag of Yescarta contains 300 mg sodium and 3.4 mL of dimethyl sulfoxide (DMSO).

Yescarta may contain residual amounts of gentamicin.

For the full list of excipients, see section 6.1.

Dispersion for infusion.

A clear to opaque, white to red dispersion.

Yescarta is indicated for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL)and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or isrefractory to, first-line chemoimmunotherapy.

Yescarta is indicated for the treatment of adult patients with relapsed or refractory (r/r) DLBCL andprimary mediastinal large B-cell lymphoma (PMBCL), after two or more lines of systemic therapy.

Yescarta is indicated for the treatment of adult patients with r/r follicular lymphoma (FL) after three ormore lines of systemic therapy.

Yescarta must be administered in a qualified treatment centre by a physician with experience in thetreatment of haematological malignancies and trained for administration and management of patientstreated with the medicinal product.

In the event of cytokine release syndrome (CRS), at least 1 dose of tocilizumab, and emergencyequipment must be available prior to infusion. The qualified treatment centre must have access to anadditional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case wheretocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortagecatalogue, suitable alternative measures to treat CRS instead of tocilizumab must be available prior toinfusion.

Yescarta is intended for autologous use (see section 4.4).

Treatment consists of a single dose for infusion containing a dispersion for infusion of CAR-positiveviable T cells in one infusion bag. The target dose is 2 × 106 CAR-positive viable T cells per kg ofbody weight (within a range of 1 × 106 - 2 × 106 cells/kg), with a maximum of 2 × 108 CAR-positiveviable T cells for patients 100 kg and above.

The availability of Yescarta must be confirmed prior to starting the lymphodepleting regimen.

Pre-treatment (lymphodepleting chemotherapy)

* A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m2intravenously and fludarabine 30 mg/m2 intravenously must be administered prior to infusing

Yescarta. The recommended days are on the 5th, 4th, and 3rd day before infusion of Yescarta.

Pre-medication

* It is recommended that pre-medication with paracetamol 500-1 000 mg given orally anddiphenhydramine 12.5 to 25 mg intravenously or orally, or equivalent medicinal products, beadministered approximately 1 hour before the infusion of Yescarta to reduce the possibility ofan infusion reaction.

* Prophylactic use of systemic corticosteroids is not recommended (see section 4.5).

* Patients must be monitored daily for the first 7 days following infusion for signs and symptomsof potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisationfor the first 7 days or at the first signs or symptoms of CRS and/or neurologic events.

* After the first 7 days following the infusion, the patient is to be monitored at the physician’sdiscretion.

* Patients must remain within proximity of a qualified clinical facility for at least 4 weeksfollowing infusion.

Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus(HCV) infection

There is limited clinical experience in patients with active HIV, HBV or HCV infection.

No dose adjustment is required in patients ≥ 65 years of age.

The safety and efficacy of Yescarta in children and adolescents below 18 years of age have not yetbeen established. No data are available.

Yescarta is to be administered via intravenous infusion.

Yescarta must not be irradiated. A leukodepleting filter must not be used.

Before administration, it must be confirmed that the patient’s identity matches the unique patientinformation on the Yescarta infusion bag and cassette.

* A leukodepleting filter must not be used.

* Tocilizumab and emergency equipment must be available prior to infusion and during themonitoring period. In the exceptional case where tocilizumab is not available due to a shortagethat is listed in the European Medicines Agency shortage catalogue, suitable alternativemeasures to treat CRS instead of tocilizumab must be available prior to infusion.

* Yescarta is intended for autologous use only, it must be confirmed that the patient’s identitymatches the patient identifiers on the Yescarta infusion bag.

* Once the tubing has been primed, the entire content of the Yescarta infusion bag must beinfused within 30 minutes by either gravity or a peristaltic pump.

For detailed instructions on preparation, administration, measures to take in case of accidentalexposure and disposal of Yescarta, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or togentamicin (a possible trace residue).

Contraindications of the lymphodepleting chemotherapy must be considered.

The traceability requirements of cell-based advanced therapy medicinal products must apply. Toensure traceability the name of the product, the batch number and the name of the treated patient mustbe kept for a period of 30 years after expiry date of the medicinal product.

Autologous use

Yescarta is intended solely for autologous use and must not, under any circumstances, be administeredto other patients. Before infusion, the patient’s identity must match the patient identifiers on the

Yescarta infusion bag and cassette. Yescarta must not be administered if the information on thepatient-specific infusion bag and cassette label does not match the patient’s identity.

Warnings and precautions of lymphodepleting chemotherapy must be considered.

Reasons to delay treatment

Due to the risks associated with Yescarta treatment, infusion must be delayed if a patient has any ofthe following conditions:

* Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, orhypotension) including from preceding chemotherapies.

* Active uncontrolled infection.

* Active graft-versus-host disease (GvHD).

In some cases, the treatment may be delayed after administration of the lymphodepletingchemotherapy regimen. If the infusion is delayed for more than 2 weeks after the patient has receivedthe lymphodepleting chemotherapy, lymphodepleting chemotherapy regimen must be administeredagain (see section 4.2)

Monitoring after infusion

Patients must be monitored daily for the first 7 days following infusion for signs and symptoms ofpotential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for thefirst 7 days or at the first signs or symptoms of CRS and/or neurologic events. After the first 7 daysfollowing infusion, the patient is to be monitored at the physician’s discretion.

Patients must remain within proximity of a qualified treatment centre for at least 4 weeks followinginfusion and seek immediate medical attention should signs or symptoms of CRS or neurologicaladverse reactions occur. Vital signs and organ function must be monitored depending on the severityof the reaction.

Transmission of an infectious agent

Although Yescarta is tested for sterility and mycoplasma, a risk of transmission of infectious agentsexists. Healthcare professionals administering Yescarta must, therefore, monitor patients for signs andsymptoms of infection after treatment and treat appropriately, if needed.

Serological testing

Screening for HBV, HCV, and HIV must be performed before collection of cells for manufacturing of

Yescarta (see section 4.2).

Blood, organ, tissue and cell donation

Patients treated with Yescarta must not donate blood, organs, tissues, or cells for transplantation.

Concomitant disease

Patients with active central nervous system (CNS) disorder or inadequate renal, hepatic, pulmonary, orcardiac function are likely to be more vulnerable to the consequences of the adverse reactionsdescribed below and require special attention.

Primary CNS lymphoma

There is no experience of use of Yescarta in patients with primary CNS lymphoma. Therefore, therisk/benefit of Yescarta has not been established in this population.

Cytokine release syndrome

Nearly all patients experienced some degree of CRS. Severe CRS, including life-threatening and fatalreactions, was very commonly observed with Yescarta with a time to onset of 1 to 12 days in

ZUMA-1 and ZUMA-7, and 1 to 11 days in ZUMA-5 (see section 4.8). CRS should be managed at thephysician’s discretion, based on the patient’s clinical presentation and according to the CRSmanagement algorithm provided in Table 1. Interleukin-6 (IL-6) receptor inhibitor based therapy suchas tocilizumab has been administered for moderate or severe CRS associated with Yescarta.

Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, includinginfection.

Management of cytokine release syndrome associated with Yescarta

At least 1 dose per patient of tocilizumab, an interleukin 6 (IL 6) receptor inhibitor, must be on siteand available for administration prior to Yescarta infusion. The qualified treatment centre must haveaccess to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptionalcase where tocilizumab is not available due to a shortage that is listed in the European Medicine

Agency shortage catalogue, the treatment centre must have access to suitable alternative measuresinstead of tocilizumab to treat CRS.

Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced bypatients on Yescarta. These include the use of tocilizumab or tocilizumab and corticosteroids formoderate, severe, or life-threatening CRS as summarised in Table 1. Patients who experience Grade 2or higher CRS (e.g. hypotension, not responsive to fluids, or hypoxia requiring supplementaloxygenation) must be monitored with continuous cardiac telemetry and pulse oximetry. For patientsexperiencing severe CRS, consider performing an echocardiogram to assess cardiac function. Forsevere or life-threatening- CRS, consider intensive-care supportive therapy.

Yescarta must not be administered to patients with active infections or inflammatory disease untilthese conditions have resolved.

CRS has been known to be associated with end organ dysfunction (e.g., hepatic, renal, cardiac, andpulmonary). In addition, worsening of underlying organ pathologies can occur in the setting of CRS.

Patients with medically significant cardiac dysfunction must be managed by standards of critical careand measures such as echocardiography are to be considered.

Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)is to be considered in patients with severe or unresponsive CRS.

Yescarta continues to expand and persist following administration of tocilizumab and corticosteroids.

Tumour necrosis factor (TNF) antagonists are not recommended for management of

Yescarta-associated CRS.

Table 1: CRS grading and management guidance

CRS Gradea Tocilizumab Corticosteroids

Grade 1 If not improving after 24 hours, N/A

Symptoms require symptomatic manage as Grade 2.treatment only (e.g., fever, nausea,fatigue, headache, myalgia,malaise).

Grade 2 Administer tocilizumabc 8 mg/kg Manage per Grade 3 if no

Symptoms require and respond to intravenously over 1 hour (not to improvement within 24 hours aftermoderate intervention. exceed 800 mg). starting tocilizumab.

Oxygen requirement less than40% FiO2 or hypotension Repeat tocilizumab every 8 hoursresponsive to fluids or low dose of as needed if not responsive toone vasopressor or Grade 2 organ intravenous fluids or increasingtoxicityb. supplemental oxygen.

Limit to a maximum of 3 doses ina 24 hour period; maximum totalof 4 doses if no clinicalimprovement in the signs andsymptoms of CRS, or if noresponse to second or subsequentdoses of tocilizumab, consideralternate measures for treatment of

CRS.

Grade 3 Per Grade 2 Administer methylprednisolone

Symptoms require and respond to 1 mg/kg intravenously twice dailyaggressive intervention. or equivalent dexamethasone (e.g.,

Oxygen requirement greater than 10 mg intravenously every 6or equal to 40% FiO2 or hours).hypotension requiring high-dose Continue corticosteroids use untilor multiple vasopressors or Grade the event is Grade 1 or less, then3 organ toxicity or Grade 4 taper.transaminitis. If not improving, manage as Grade4 (below).

Grade 4 Per Grade 2 Administer methylprednisolone

Life-threatening symptoms. 1 000 mg intravenously per day

Requirements for ventilator for 3 days; if improves, thensupport or continuous manage as above.veno-venous haemodialysis or

Grade 4 organ toxicity (excluding Consider alternatetransaminitis). immunosuppressants if noimprovement or if conditionworsens.

N/A = not available/not applicable(a) Lee et al 2014(b) Refer to Table 2 for management of neurologic adverse reactions(c) Refer to tocilizumab summary of product characteristics for details

Neurologic adverse reactions

Severe neurologic adverse reactions, also known as immune effector cell-associated neurotoxicitysyndrome (ICANS), have been very commonly observed in patients treated with Yescarta, whichcould be life-threatening or fatal. The median time to onset was 6 days (range: 1 to 133 days) in

ZUMA-1 and ZUMA-7, and 7 days (range: 1 to 177 days) in ZUMA-5 following Yescarta infusion(see section 4.8). Patients with a history of CNS disorders such as seizures or cerebrovascularischaemia may be at increased risk. Fatal and serious cases of cerebral oedema have been reported inpatients treated with Yescarta.

Patients who experience Grade 2 or higher neurologic toxicities/ICANS must be monitored withcontinuous cardiac telemetry and pulse oximetry. Intensive-care supportive therapy must be providedfor severe or life-threatening neurologic toxicities/ICANS. Non-sedating, anti-seizure medicines are tobe considered as clinically indicated for Grade 2 or higher adverse reactions. Treatment algorithmshave been developed to ameliorate the neurologic adverse reactions experienced by patients on

Yescarta. These include the use of tocilizumab (if concurrent CRS) and/or corticosteroids formoderate, severe, or life-threatening neurologic adverse reactions as summarised in Table 2.

Table 2: Neurologic adverse reaction/ICANS grading and management guidance

Grading Concurrent CRS No concurrent CRSassessment

Grade 2 Administer tocilizumab per Table 1 for Administer dexamethasone 10 mgmanagement of Grade 2 CRS. intravenously every 6 hours.

If no improvement within 24 hours after Continue dexamethasone use until thestarting tocilizumab, administer event is Grade 1 or less, then taper.dexamethasone 10 mg intravenously every6 hours if not already taking othercorticosteroids. Continue dexamethasoneuse until the event is Grade 1 or less, thentaper.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizureprophylaxis.

Grade 3 Administer tocilizumab per Table 1 for Administer dexamethasone 10 mgmanagement of Grade 2 CRS. intravenously every 6 hours.

In addition, administer dexamethasone Continue dexamethasone use until the10 mg intravenously with the first dose of event is Grade 1 or less, then taper.tocilizumab and repeat dose every 6 hours.

Continue dexamethasone use until theevent is Grade 1 or less, then taper.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizureprophylaxis.

Grade 4 Administer tocilizumab per Table 1 for Administer methylprednisolone 1 000 mgmanagement of Grade 2 CRS. intravenously per day for 3 days; ifimproves, then manage as above.

Administer methylprednisolone 1 000 mgintravenously per day with first dose of If not improving, consider 1 000 mg oftocilizumab and continue methylprednisolone intravenously 3 timesmethylprednisolone 1 000 mg a day or alternate therapy.aintravenously per day for 2 more days; ifimproves, then manage as above.

If not improving, consider 1 000 mg ofmethylprednisolone intravenously 3 timesa day or alternate therapya

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizureprophylaxis.

a. Alternate therapy includes (but is not limited to): anakinra, siltuximab, ruxolitinib, cyclophosphamide, IVIG and ATG

Infections and febrile neutropenia

Serious infections have been very commonly observed with Yescarta (see section 4.8). Inimmunosuppressed patients, life-threatening and fatal opportunistic infections including disseminatedfungal infections have been reported.

Patients must be monitored for signs and symptoms of infection before, during, and after Yescartainfusion and treated appropriately. Prophylactic anti-microbials should be administered according tostandard institutional guidelines.

Febrile neutropenia has been observed in patients after Yescarta infusion (see section 4.8) and may beconcurrent with CRS. In the event of febrile neutropenia, infection is to be considered and managedwith broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occurin patients treated with drugs directed against B-cells.

Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy(PML), has been reported in patients treated with Yescarta who have also received prior treatmentwith other immunosuppressive medications. Cases with fatal outcome have been reported. Thepossibility of PML should be considered in immunosuppressed patients with new onset or worseningneurological symptoms and appropriate diagnostic evaluations should be performed.

Other life-threatening and fatal cases of viral reactivation with HHV-6 have been reported.

Prolonged cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and

Yescarta infusion and must be managed according to standard guidelines. Grade 3 or higher prolongedcytopenias following Yescarta infusion occurred very commonly and included thrombocytopenia,neutropenia, and anaemia. Patient blood counts must be monitored after Yescarta infusion.

B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with

Yescarta. Hypogammaglobulinaemia has been very commonly observed in patients treated with

Yescarta (see section 4.8). Hypogammaglobulinaemia predisposes patients to have infections.

Immunoglobulin levels should be monitored after treatment with Yescarta and managed usinginfection precautions, antibiotic prophylaxis, and immunoglobulin replacement in case of recurrentinfections and must be taken according to standard guidelines.

Allergic reactions may occur with the infusion of Yescarta. Serious hypersensitivity reactionsincluding anaphylaxis, may be due to DMSO or residual gentamicin in Yescarta.

Secondary malignancies including of T-cell origin

Patients treated with Yescarta may develop secondary malignancies. T-cell malignancies have beenreported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR

T-cell therapy, including Yescarta. T-cell malignancies, including CAR-positive malignancies, havebeen reported within weeks and up to several years following administration of a CD19- or BCMA-directed CAR T-cell therapy. There have been fatal outcomes. Patients are to be monitored life-longfor secondary malignancies. In the event that a secondary malignancy of T-cell origin occurs, thecompany is to be contacted to obtain instructions on patient samples to collect for testing.

TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients withelevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis,prior to Yescarta infusion. Signs and symptoms of TLS must be monitored and events managedaccording to standard guidelines.

CD19-negative disease

There is limited experience with Yescarta in patients exposed to prior CD19-directed therapy.

Yescarta is not recommended if the patient has relapsed with CD19-negative disease after prioranti-CD19 therapy.

There are limited data available on CD19-negative patients treated with Yescarta and it is possible that

CD19-negative patients may have less benefit compared with CD19-positive patients. Patients with

CD19-negative status by immunohistochemistry may still express CD19 and have been shown tobenefit from treatment with Yescarta. The potential risks and benefits associated with treatment of

CD19-negative patients with Yescarta should be considered.

Long-term follow-up

Patients are expected to enrol in a registry in order to better understand the long-term safety andefficacy of Yescarta.

Excipients (sodium)

This medicinal product contains 300 mg sodium per infusion bag, equivalent to 15% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed with Yescarta.

Prophylactic use of systemic corticosteroids may interfere with the activity of Yescarta. Prophylacticuse of systemic corticosteroids is therefore not recommended before infusion (see section 4.2).

Administration of corticosteroids as per the toxicity management guidelines does not impact theexpansion and persistence of CAR T cells.

Live vaccines

The safety of immunisation with live viral vaccines during or following treatment with Yescarta hasnot been studied. As a precautionary measure, vaccination with live vaccines is not recommended forat least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, anduntil immune recovery following treatment.

The pregnancy status of women of child bearing potential must be verified before starting Yescartatreatment.

See the prescribing information for lymphodepleting chemotherapy for information on the need foreffective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration ofcontraception following treatment with Yescarta.

There are no available data with Yescarta use in pregnant women. No reproductive and developmentaltoxicity animal studies have been conducted with Yescarta to assess whether it can cause foetal harmwhen administered to a pregnant woman (see section 5.3).

It is not known if Yescarta has the potential to be transferred to the foetus. Based on the mechanism ofaction, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-celllymphocytopenia. Therefore, Yescarta is not recommended for women who are pregnant, or forwomen of childbearing potential not using contraception. Pregnant women must be advised on thepotential risks to the foetus. Pregnancy after Yescarta therapy must be discussed with the treatingphysician.

Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with Yescarta mustbe considered.

It is unknown whether Yescarta is excreted in human milk or transferred to the breast-feeding child. Arisk to the breast-fed infant cannot be excluded. Breast-feeding women must be advised of thepotential risk to the breast-fed child. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Yescarta therapy taking into account the benefit of breast feeding forthe child and the benefit of therapy for the woman.

No clinical data on the effect of Yescarta on fertility are available. Effects on male and female fertilityhave not been evaluated in animal studies.

Yescarta has major influence on the ability to drive and use machines.

Due to the potential for neurologic events, including altered mental status or seizures, patients mustrefrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks afterinfusion or until resolution of neurologic adverse reactions.

The safety data described in this section are from a total of 397 adult patients treated with Yescarta inthree multi-centre pivotal clinical studies (ZUMA-1, ZUMA-5 and ZUMA-7) and post-marketingexperience. Adverse reactions are adverse events from pivotal clinical studies and post-marketingexperience medically assessed as reasonably attributed to axicabtagene ciloleucel.

Relapsed or refractory DLBCL, PMBCL and DLBCL arising from follicular lymphoma after two ormore lines of systemic therapy

Safety data from ZUMA-1 reflects exposure to Yescarta in a Phase 1/2 study in which 108 patientsreceived CAR-positive T cells based on a recommended dose which was weight-based. The datadescribed are from the 54-month follow-up analysis where the median actual duration of follow-upwas 23.5 months (range: 0.3 to 68.2 months).

The most significant and frequently occurring adverse reactions were CRS (93%), encephalopathy(60%), and infections (40%).

Serious adverse reactions occurred in 51% of patients. The most common (≥ 5%) serious adversereactions included encephalopathy (22%), unspecified pathogen infections (15%), bacterial infection(6%), viral infection (6%), febrile neutropenia (5%), and fever (5%).

The most common (≥ 5%) Grade 3 or higher non-haematological adverse reactions includedencephalopathy (31%), unspecified pathogen infections (19%), CRS (11%), bacterial infection (9%),delirium (6%), hypertension (6%), hypotension (6%), transaminases increased (6%), and viralinfection (6%). The most common Grade 3 or higher haematological adverse reactions includedlymphopenia (99%), leukopenia (96%), neutropenia (94%), anaemia (65%), and thrombocytopenia(56%).

DLBCL and HGBL that relapses within 12 months from completion of, or is refractory to, first-linechemoimmunotherapy

Safety data from ZUMA-7 reflects exposure to Yescarta in a Phase 3 study in which 170 patientsreceived CAR-positive T cells based on a recommended dose which was weight-based. The datadescribed are from an analysis where the median actual duration of follow-up was 23.2 months (range:1.5 to 41.3 months).

The most significant and frequently occurring adverse reactions were CRS (92%), encephalopathy(49%), and infections (45%).

Serious adverse reactions occurred in 54% of patients. The most common (≥ 5%) serious adversereactions included CRS (17%), encephalopathy (16%), unspecified pathogen infections (8%), fever(6%) and viral infection (5%).

The most common (≥ 5%) Grade 3 or higher non-haematological adverse reactions includedencephalopathy (19%), unspecified pathogen infections (8%), CRS (6%), and bacterial infection (5%).

The most common Grade 3 or higher haematological adverse reactions included lymphopenia (99%),leukopenia (95%), neutropenia (94%), anaemia (41%), and thrombocytopenia (26%).

Follicular lymphoma after three or more lines of systemic therapy

Safety data from ZUMA-5 reflects exposure to Yescarta in a Phase 2 study in which 119 patients withrelapsed/refractory FL, received CAR-positive T cells based on a recommended dose which wasweight-based. The data described are from the 24-month follow-up analysis where the median actualduration of follow-up was 25.9 months (range: 0.3 to 44.3 months).

The most significant and frequently occurring adverse reactions were CRS (77%), infections (59%),and encephalopathy (47%).

Serious adverse reactions occurred in 45% of patients. The most common (≥ 5%) serious adversereactions included encephalopathy (16%), unspecified pathogen infections (12%), CRS (12%), andbacterial infection (5%).

The most common (≥ 5%) Grade 3 or higher non-haematological adverse reactions includedencephalopathy (14%), unspecified pathogen infections (11%), CRS (6%), and bacterial infection(5%). The most common Grade 3 or higher haematological adverse reactions included lymphopenia(99%), leukopenia (94%), neutropenia (92%), thrombocytopenia (34%), and anaemia (33%).

Adverse reactions described in this section were identified in patients exposed to Yescarta in ZUMA-1(n=108), ZUMA-5 (n=119), and ZUMA-7 (n=170) and from post-marketing reports. These reactionsare presented by system organ class and by frequency. Frequencies are defined as: very common(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100). Within each frequencygrouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse drug reactions identified with Yescarta

System Organ Class (SOC) Frequency Adverse reactions

Very common Unspecified pathogen infections

Viral infection

Bacterial infection

Common Fungal infection

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Rare Secondary malignancy of T-cellorigin

Very common Febrile neutropenia#

Neutropenia#

Lymphopenia#

Leukopenia#

Anaemia#

Thrombocytopenia#

Common Coagulopathya

Very common Cytokine Release Syndrome

Immunoglobulins decreasedb

Common Hypersensitivity

Uncommon Haemophagocyticlymphohistiocytosis*

Very common Hyponatraemia#

Hypophosphataemia#

Hyperuricemia#**

Hyperglycaemia#

Decreased appetitec

Common Hypokalaemia#

Hypocalcaemia#

Hypoalbuminaemia#

Dehydrationd

Weight decreased

Very common Deliriume

Insomnia

Common Anxiety

Affective disorderf

Very common Encephalopathyg

Tremorh

Headachei

Dizzinessj

Common Ataxiak

Seizures, including status epilepticus

Hemiparesis

Facial paralysisl

Neuropathy peripheralm

Myoclonus

Uncommon Quadriplegia

Spinal cord oedema

Myelitis

Dyscalculia

Common Visual impairmentn

Very common Tachycardiao

Arrhythmiap

System Organ Class (SOC) Frequency Adverse reactions

Common Cardiac arrest

Cardiac failureq

Very common Hypotensionr

Common Thrombosiss

Very common Cought

Common Respiratory failureu

Hypoxiav

Pleural effusion

Pulmonary oedema

Dyspnoeaw

Nasal inflammationx

Very common Vomiting

Diarrhoeay

Abdominal painz

Nausea

Common Dysphagia***

Dry mouthaa

Very common Transaminases increasedbb

Common Hyperbilirubinaemiacc

Very common Rashdd

Very common Motor dysfunctionee

Musculoskeletal painff

Uncommon Rhabdomyolysis

Common Renal impairmentgg

Very common Feverhh

Oedemaii

Fatiguejj

Chills

Common Infusion related reaction

Uncommon Multiple organ dysfunction syndrome

* Haemophagocytic lymphohistiocytosis has been reported in the setting of CRS

** Hyperuricemia was identified from a pooled analysis of 227 adult patients treated with Yescarta in ZUMA-1 and ZUMA-

*** Dysphagia has been reported in the setting of neurologic toxicity and encephalopathy# Frequency based on Grade 3 or higher laboratory parameter

a. Coagulopathy includes coagulopathy, blood fibrinogen decreased, blood fibrinogen increased, disseminated intravascularcoagulation, hypofibrinogenaemia, international normalized ratio increased, prothrombin level decreased, prothrombin timeprolonged

b. Immunoglobulins decreased includes blood immunoglobulin G decreased, hypogammaglobulinaemia

c. Decreased appetite includes decreased appetite, hypophagia

d. Dehydration includes dehydration, hypovolaemia

e. Delirium includes delirium, agitation, delusion, disorientation, hallucination, restlessness

f. Affective disorder includes impulsive behavior, mood altered, depression, panic attackg. Encephalopathy includes encephalopathy, agraphia, altered state of consciousness, amnesia, aphasia, aphonia, apraxia,cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia,dyskinesia, dyspraxia, hypersomnia, immune effector cell-associated neurotoxicity syndrome (ICANS), lethargy,leukoencephalopathy, loss of consciousness, memory impairment, mental impairment, mental status changes, metabolicencephalopathy, neurotoxicity, slow speech, somnolence, speech disorder, stupor, toxic encephalopathyh. Tremor includes tremor, head titubationi. Headache includes headache, head discomfort, tension headachej. Dizziness includes dizziness, dizziness postural, presyncope, syncope, vertigok. Ataxia includes ataxia, balance disorder, gait disturbancel. Facial paralysis includes facial paralysis, facial paresism. Neuropathy peripheral includes neuropathy peripheral, allodynia, cervical radiculopathy, hyperaesthesia, hypoaesthesia,lumbar radiculopathy, paraesthesia, peripheral sensory neuropathy, peroneal nerve palsyn. Visual impairment includes visual impairment, hemianopia, vision blurred, visual acuity reducedo. Tachycardia includes tachycardia, postural orthostatic tachycardia syndrome, sinus tachycardiap. Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, bundle branch blockright, electrocardiogram QT prolonged, extrasystoles, heart rate increased, heart rate irregular, sinus bradycardia,supraventricular extrasystoles, supraventricular tachycardia, ventricular arrhythmia, ventricular extrasystoles, ventriculartachycardiaq. Cardiac failure includes cardiac failure, acute left ventricular failure, ejection fraction decreased, stress cardiomyopathyr. Hypotension includes hypotension, capillary leak syndrome, diastolic hypotension, hypoperfusion, orthostatic hypotensions. Thrombosis includes thrombosis, axillary vein thrombosis, brachiocephalic vein thrombosis, deep vein thrombosis, deviceocclusion, embolism, jugular vein thrombosis, peripheral embolism, peripheral ischaemia, pulmonary embolism, splenic veinthrombosis, thrombosis in devicet. Cough includes cough, productive cough, upper-airway cough syndromeu. Respiratory failure includes respiratory failure, acute respiratory failurev. Hypoxia includes hypoxia, oxygen saturation decreasedw. Dyspnoea includes dyspnoea, dyspnoea exertionalx. Nasal inflammation includes rhinitis allergic, rhinorrhoeay. Diarrhoea includes diarrhoea, colitis, enteritisz. Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominaltenderness, dyspepsia, epigastric discomfortaa. Dry mouth includes dry mouth, lip drybb. Transaminases increased includes transaminases increased, alanine aminotransferase increased, aspartateaminotransferase increased, hepatic enzyme increased, hypertransaminasaemiacc. Hyperbilirubinaemia increased includes hyperbilirubinemia, blood bilirubin increaseddd. Rash includes rash, application site rash, dermatitis, dermatitis allergic, dermatitis bullous, erythema, pruritus, rasherythematous, rash macular, rash maculo-papular, rash pruritic, rash pustular, urticariaee. Motor dysfunction includes motor dysfunction, muscle contractions involuntary, muscle rigidity, muscle spasms, musclespasticity, muscle strain, muscle tightness, muscle twitching, muscular weaknessff. Musculoskeletal pain includes musculoskeletal pain, arthralgia, arthritis, back pain, bone pain, flank pain, groin pain,musculoskeletal chest pain, myalgia, neck pain, osteoarthritis, pain in extremitygg. Renal impairment includes acute kidney injury, blood creatinine increased, renal failurehh. Fever includes hyperthermia, pyrexiaii. Oedema includes oedema, face oedema, generalized oedema, localized oedema, oedema genital, oedema peripheral,peripheral swelling, swellingjj. Fatigue includes fatigue, asthenia, decreased activity, malaise

Cytokine release syndrome

In ZUMA-1 and ZUMA-7, CRS occurred in 92% of patients. Eight percent (8%) of patientsexperienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was3 days (range: 1 to 12 days) and the median duration was 7 days (range: 2 to 58 days). Ninety-ninepercent (99%) of patients recovered from CRS. No CRS was reported by patients treated with standardof care therapy (SOCT) in ZUMA-7.

In ZUMA-5, CRS occurred in 77% of patients. Six percent (6%) of patients experienced Grade 3 orhigher (severe, life-threatening, and fatal) CRS. The median time to onset was 4 days (range: 1 to11 days) and the median duration was 6 days (range: 1 to 27 days). Ninety-nine percent (99%) ofpatients recovered from CRS.

The most common adverse reactions (≥ 20%) that may be associated with CRS included pyrexia(89%), hypotension (50%), tachycardia (47%), chills (30%), and hypoxia (24%). Serious adversereactions that may be associated with CRS included pyrexia (12%), hypotension (5%), hypoxia (3%),arrhythmia (3%), cardiac failure (2%), fatigue (2%), headache (2%), tachycardia (2%), cardiac arrest(1%), dyspnoea (1%), and tachypnoea (1%). See section 4.4 for monitoring and managementguidance.

Neurologic adverse reactions

In ZUMA-1 and ZUMA-7, neurologic adverse reactions occurred in 63% of patients. Twenty-fivepercent (25%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions.

Neurologic toxicities occurred within the first 7 days of infusion for 75% of patients. The median timeto onset was 6 days (range: 1 to 133 days). The median duration was 10 days, with resolutionoccurring within 3 weeks for 66% of patients following infusion.

In ZUMA-5, neurologic adverse reactions occurred in 57% of patients. Sixteen percent (16%) ofpatients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. Neurologictoxicities occurred within the first 7 days of infusion for 65% of patients. The median time to onsetwas 7 days (range: 1 to 177 days). The median duration was 14 days, with resolution occurring within3 weeks for 60% of patients following infusion.

The most common (≥ 5%) neurologic adverse reactions included encephalopathy (51%), tremor(28%), and delirium (14%). Serious neurologic adverse reactions reported in patients includedencephalopathy (18%), tremor (2%), delirium (2%), hemiparesis (1%) and seizure (1%). In ZUMA-7,encephalopathy and tremor were reported in 49% and 25% of patients treated with Yescarta comparedto 8% and 1% treated with SOCT, respectively.

Other neurologic adverse reactions have been reported less frequently in clinical trials and includeddysphagia (3%), myelitis (0.2%), and quadriplegia (0.1%).

See section 4.4 for monitoring and management guidance.

Febrile neutropenia and infections

Febrile neutropenia was observed in 10% of patients after Yescarta infusion. Infections occurred in48% of patients. Grade 3 or higher (severe, life-threatening, or fatal) infections occurred in 19% ofpatients. Grade 3 or higher unspecified pathogen, bacterial, and viral infections occurred in 12%, 6%,and 5% of patients respectively. The most common site of unspecified pathogen infection was in therespiratory tract. In ZUMA-7, febrile neutropenia and viral infection were reported in 2% and 16% ofpatients treated with Yescarta compared to 27% and 5% treated with SOCT, respectively. Seesection 4.4 for monitoring and management guidance.

Prolonged cytopenias

Grade 3 or higher neutropenia (including febrile neutropenia), anaemia, and thrombocytopeniaoccurred in 68%, 31%, and 23% of patients, respectively. Prolonged (still present at Day 30 or with anonset at Day 30 or beyond) Grade 3 or higher neutropenia, thrombocytopenia, and anaemia occurredin 26%, 12%, and 6% of patients, respectively. In ZUMA-1, at the time of the 24-month follow-upanalysis, Grade 3 or higher neutropenia, thrombocytopenia, and anaemia present after Day 93 occurredin 11%, 7%, and 3% of patients, respectively. In ZUMA-7, Grade 3 or higher neutropenia andthrombocytopenia were reported in 94% and 26% of patients treated with Yescarta compared to 51%and 63% treated with SOCT, respectively. See section 4.4 for management guidance.

Hypogammaglobulinaemia was reported in 15% of patients treated with Yescarta. Cumulatively, 36(33%) of 108 patients in ZUMA-1 received intravenous immunoglobulin therapy by the time of the54-month analysis, 28 (16%) of 170 patients in ZUMA-7 received intravenous immunoglobulintherapy by the time of the 23.2 month analysis and 33 (28%) of 119 subjects in ZUMA-5 receivedintravenous immunoglobulin therapy at the time of the 24-month follow-up analysis. In ZUMA-7,immunoglobulins decreased was reported in 11% of patients treated with Yescarta compared to 1% ofpatients treated with SOCT. See section 4.4 for management guidance.

The immunogenicity of Yescarta has been evaluated using an enzyme-linked immunosorbent assay(ELISA) for the detection of binding antibodies against FMC63, the originating antibody of theanti-CD19 CAR. Eleven out of 278 patients (4%) tested positive for anti-FMC63 antibodies prior tobeing treated with Yescarta in ZUMA-1 and ZUMA-7, and 1 patient (1%) in ZUMA-7 who had anegative test result prior to treatment, had a positive test result after treatment in the screening ELISA.

Results of a confirmatory cell-based assay, leveraging a properly folded and expressed extracellularportion of the CAR (ScFv, hinge and linker) demonstrated that all patients treated with Yescarta thathad a positive result in the screening ELISA were antibody negative at all time points tested. There isno evidence that the kinetics of initial expansion and persistence of Yescarta, or the safety oreffectiveness of Yescarta, was altered in these patients. In ZUMA-5, 13 out of 116 patients (11%)tested positive for antibodies in the ELISA screening assay prior to being treated with Yescarta, and 2subjects who had negative results prior to treatment had positive test results after treatment. Results ofa confirmatory cell-based assay demonstrated that all patients treated with Yescarta that had an ELISApositive result were antibody negative, before, during and after treatment.

Special population

There is limited experience with Yescarta in patients ≥ 75 years of age. Generally, safety and efficacywere similar between patients ≥ 65 years and patients < 65 years of age treated with Yescarta.

Outcomes were consistent between patients with Eastern Cooperative Oncology Group (ECOG) of 0and 1 and by sex.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No data from clinical studies are available regarding overdose of Yescarta.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, antineoplastic cell andgene therapy, ATC code: L01XL03

Yescarta, an engineered autologous T-cell immunotherapy product, binds to CD19 expressing cancercells and normal B-cells. Following anti-CD19 CAR T-cell engagement with CD19 expressing targetcells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signalling cascades thatlead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatorycytokines and chemokines. This sequence of events leads to apoptosis and necrosis of CD19-expressing target cells.

After Yescarta infusion, pharmacodynamic responses were evaluated by measuring transient elevationof cytokines, chemokines, and other molecules in blood over a 4-week interval. Levels of cytokinesand chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and IL2Rα were analyzed. Peakelevation was observed within the first 14 days after infusion, and levels generally returned to baselinewithin 28 days.

Analyses performed to identify associations between cytokine levels and incidence of CRS orneurologic events showed that higher post-infusion levels (peak and AUC at 1 month) of multipleimmune-modulatory and pro-inflammatory analytes were associated with Grade 3 or higherneurologic adverse reactions and Grade 3 or higher CRS in ZUMA-1, ZUMA-7 and ZUMA-5.

Due to the on-target, off-tumour effect of Yescarta, a period of B-cell aplasia is expected followingtreatment.

Among 73 patients in ZUMA-1 with evaluable samples at baseline, 40% had detectable B-cells; the

B-cell aplasia observed in the majority of patients at baseline was attributed to prior therapies.

Following Yescarta treatment, the proportion of patients with detectable B-cells decreased: 20% haddetectable B-cells at Month 3, and 22% had detectable B-cells at Month 6. The initiation of B-cellrecovery was first noted at Month 9, when 56% of patients had detectable B-cells. This trend of B-cellrecovery continued over time, as 64% of patients had detectable B-cells at Month 18, and 77% ofpatients had detectable B-cells at Month 24. Among 141 patients in ZUMA-7 with evaluable samplesat baseline, 57% had detectable B-cells. Following Yescarta treatment, the proportion of patients withdetectable B-cells decreased: 38% had detectable B-cells at Month 3, and 41% had detectable B-cellsat Month 6. The initiation of B-cell recovery was apparent at Month 9, when 58% had detectable B-cells. This trend of B-cell recovery continued over time, as 64% of patients had detectable B-cells at

Month 18 and 84% of patients had detectable B-cells at Month 24. Among 113 FL patients withevaluable samples at baseline in ZUMA-5, 75% of patients had detectable B-cells. Following Yescartatreatment, the proportion of patients with detectable B-cells decreased: 40% of patients had detectable

B-cells at Month 3. B-cell recovery was observed over time, with 61% of patients having detectable B-cells at Month 24. Patients were not required to be followed after they progressed; thus, the majorityof patients with evaluable samples were responders.

Relapsed or refractory DLBCL, PMBCL and DLBCL arising from follicular lymphoma after two ormore lines of systemic therapy (ZUMA-1)

A total of 108 patients were treated with Yescarta in a phase 1/2 open-label, multicentre, single-armstudy in patients with r/r aggressive B-cell non-Hodgkin lymphoma (NHL). Efficacy was based on101 patients in phase 2, including histologically confirmed DLBCL (N = 77), PMBCL (N = 8), or

DLBCL arising from follicular lymphoma, (N = 16) based on the 2008 WHO-classification. DLBCLin ZUMA-1 included patients with DLBCL not otherwise specified (NOS), other DLBCL subtypes,and HGBL based on the 2016 WHO-classification. Forty-seven patients were evaluable for MYC,

BCL-2, and BCL-6 status. Thirty were found to have double expressor DLBCL (overexpression ofboth MYC and BCL-2 protein); 5 were found to have HGBL with MYC, BCL-2 or BCL-6 generearrangement (double- and triple-hit); and 2 were found to have HGBL not otherwise specified.

Sixty-six patients were evaluable for cell-of-origin classifications (germinal center B-cell type [GCB]or activated B-cell type [ABC]). Of these, 49 patients had GCB-type and 17 patients had ABC-type.

Eligible patients were ≥ 18 years of age with refractory disease defined as progressive disease (PD) orstable disease (SD) as best response to last line of therapy, or disease progression within 12 monthsafter autologous stem cell transplant (ASCT). Patients who were refractory to chemotherapy or whorelapsed after two or more lines of systemic therapy were generally ineligible for haematopoietic stemcell transplantation. Patients must have received at least prior anti-CD20 antibody therapy and ananthracycline containing regimen. Patients with CNS lymphoma, a history of allogeneic stem celltransplantation (SCT) or prior anti-CD19 CAR or other genetically modified T-cell therapy wereexcluded. Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia),cardiac ejection fraction of less than 50% or room air oxygen saturation of less than 92%, orautoimmune disease requiring systemic immunosuppression were ineligible. The median duration offollow-up was 63.1 months (still ongoing). A summary of the patient demographics is provided in

Table 4.

Table 4: Summary of demographics for ZUMA-1 phase 2 (12 month analysis)

Category All leukapheresed All treated(ITT) (mITT)

Cohort 1 + 2 Cohort 1 + 2(N = 111) (N = 101)

Age (years)

Median (min, max) 58 (23, 76) 58 (23, 76)≥ 65 23% 24%

Male gender 69% 67%

White 85% 86%

Asian 4% 3%

Black 4% 4%

ECOG status

ECOG 0 41% 42%

ECOG 1 59% 58%

Median number of prior therapies (min, max) 3 (1, 10) 3 (1, 10)

Patients with refractory disease to ≥ 2 prior lines of therapy 77% 76%

Patients relapsed within 1 year of ASCT 20% 21%

Patients with International Prognostic Index 3/4 46% 46%

Patients with disease stage III/IV 85% 85%

ASCT, autologous stem cell transplant; ECOG, Eastern Cooperative Oncology Group; ITT, intention-to-treat; mITT,modified intention-to-treat.

Yescarta was administered as a single infusion at a target dose of 2 × 106 anti-CD19 CAR T cells/kgafter lymphodepleting chemotherapy regimen of 500 mg/m2 intravenous cyclophosphamide and30 mg/m2 intravenous fludarabine on the 5th, 4th, and 3rd day before Yescarta. Bridging chemotherapybetween leukapheresis and lymphodepleting chemotherapy was not permitted. All patients werehospitalized for observation for a minimum of 7 days after Yescarta infusion.

Of 111 patients who underwent leukapheresis, 101 received Yescarta. Nine patients were not treated,primarily due to progressive disease or serious adverse events after enrolment and prior to celldelivery. One out of 111 patients did not receive the product due to manufacturing failure. The mediantime from leukapheresis to product delivery was 17 days (range: 14 to 51 days), and the median timefrom leukapheresis to infusion was 24 days (range: 16 to 73 days). The median dose was 2.0 × 106anti-CD19 CAR T cells/kg. ITT was defined as all patients who underwent leukapheresis; mITT wasdefined as all patients who received Yescarta.

The primary endpoint was objective response rate (ORR). Secondary endpoints included duration ofresponse (DOR), overall survival (OS), and severity of adverse events. The ORR was prespecified tobe tested in the first 92 treated patients and was significantly higher than the prespecified rate of 20%(P < 0.0001).

In the primary analysis, based on the mITT population (minimum follow-up of 6 months) the ORRwas 72% and the complete response (CR) rate was 51%, as determined by an independent reviewcommittee. In the 12 month follow-up analysis (Table 5), the ORR was 72% and the CR rate was51%. The median time to response was 1.0 months (range: 0.8 to 6.3 months). The DOR was longer inpatients who achieved CR, as compared to patients with a best response of partial response (PR). Ofthe 52 patients who achieved CR, 7 patients had SD and 9 had PR at their initial tumour assessmentand converted to CR as late as 6.5 months. The ORR results within PMBCL and DLBCL arising fromfollicular lymphoma were both 88%. CR rates were 75% and 56%, respectively. Of the 111 patients inthe ITT population, the ORR was 66% and the CR was 47%. Other outcomes were consistent withthose of the mITT population.

In the 24-month follow-up analysis, based on the mITT population (results from an independentreview committee), the ORR and the CR rate were 74% and 54%, respectively. The median time toresponse was 1.0 months (range: 0.8 to 12.2 months). The DOR was longer in patients who achieved

CR compared to patients with a best response of PR (Table 5). Of the 55 patients who achieved CR, 7patients had SD and 10 had PR at their initial tumour assessment and converted to CR as late as12 months after Yescarta infusion. Median duration of response and median OS had not been reached(Table 5). In a 36-month analysis (median study follow-up of 39.1 months) the median OS was25.8 months with 47 patients (47%*) still alive. In a 48-month analysis (median study follow-up of51.1 months) the median OS was 25.8 months with 43 patients (44%*) still alive. In a 60-monthanalysis (median study follow-up of 63.1 months) the median overall survival was 25.8 months with42 patients (43%*) still alive.

*The Kaplan-Meier estimates of the 3-year, 4-year and 5-year OS rates were 47%, 44% and 43%respectively.

In the phase 1 part of ZUMA-1, 7 patients were treated. Five patients responded, including 4 CRs. Atthe 12-month follow-up analysis, 3 patients remained in CR 24 months after Yescarta infusion. At the24-month follow-up analysis, these 3 patients remained in CR at 30 to 35 months after Yescartainfusion.

Table 5. Summary of efficacy results for ZUMA-1 phase 2

Category All leukapheresed All treated(ITT) (mITT)

Cohort 1 + 2 Cohort 1 + 2(N = 111) (N = 101)12-month 24-month 12-month 24-monthanalysis analysis analysis analysis

ORR (%) [95% CI] 66 (56, 75) 68 (58, 76) 72 (62, 81) 74 (65, 82)

CR (%) 47 50 51 54

DORa, median (range) in 14.0 (0.0, 17.3) NE (0.0, 29.5)months 14.0 (0.0, 17.3) NE (0.0, 29.5)

DORa, CR, median (range) in NE (0.4, 17.3) NE (0.4, 29.5)months NE (0.4, 17.3) NE (0.4, 29.5)

OS, median (months) [95% CI] 17.4 (11.6, NE) 17.4 (11.6, NE) NE (12.8, NE) NE (12.8, NE)6 month OS (%) [95% CI] 81.1 (72.5, 87.2) 81.1 (72.5, 87.2) 79.2 (69.9, 85.9) 79.2 (69.9, 85.9)9 month OS (%) [95% CI] 69.4 (59.9, 77.0) 69.4 (59.9, 77.0) 69.3 (59.3, 77.3) 69.3 (59.3, 77.3)12 month OS (%) [95% CI] 59.3 (49.6, 67.8) 59.5 (49.7, 67.9) 60.4 (50.2, 69.2) 60.4 (50.2, 69.2)24 month OS (%) [95% CI] Not applicable 47.7 (38.2, 56.7) Not applicable 50.5 (40.4, 59.7)

CI, confidence interval; CR, complete response; DOR, duration of response; ITT, intention-to-treat; mITT, modifiedintention-to-treat; NE= Not estimable (not reached); ORR, objective response rate; OS, overall survival.

a. Duration of response was censored at the time of SCT for patients who received SCT while in response

Note: The 12-month analysis had a median follow-up of 15.1 months. The 24-month analysis had a median follow-up of27.1 months. Overall survival relates to the time from the leukapheresis date (ITT) or Yescarta infusion (mITT) to death fromany cause.

SCHOLAR-1

A retrospective, patient-level, pooled analysis of outcomes in refractory aggressive NHL (N = 636)was conducted (Crump et al., 2017) to provide confirmation of the prespecified control response rateof 20% and historical context for interpreting the ZUMA-1 results. The analysis included patients whohad not responded (SD or PD) to their last line of therapy or had relapsed within 12 months after

ASCT. Response and survival after treatment with available standard-of-care therapy was evaluated.

The ORR was 26% [95% CI (21, 31)] and the CR rate was 7% [95% CI (3, 15)], with a median OS of6.3 months.

DLBCL and HGBL that relapses within 12 months from completion of, or is refractory to, first-linechemoimmunotherapy (ZUMA-7)

The efficacy and safety of Yescarta in adult patients with r/r large B-cell lymphoma (LBCL) wasdemonstrated in a Phase 3 randomised, open-label, multicenter study (ZUMA-7). Enrolled patientswere predominantly diagnosed with DLBCL and HGBL disease subtypes based on the 2016

WHO-classification and all patients had received first-line rituximab and anthracycline-basedchemotherapy. In total, 359 patients were randomised in a 1:1 ratio to receive a single infusion of

Yescarta or to receive SOCT (defined as 2 to 3 cycles of standard chemoimmunotherapy [R-ICE, R-

DHAP or R-DHAX, R-ESHAP, or R-GDP] followed by high-dose therapy [HDT] and ASCT in thosewith disease response). Randomisation was stratified by response to first-line therapy (primaryrefractory, vs relapse ≤ 6 months of first-line therapy vs relapse > 6 and ≤ 12 months of first-linetherapy) and second-line age-adjusted International Prognostic Index (IPI) (0 to 1 vs 2 to 3) asassessed at the time of screening. The study excluded prior HSCT, detectable cerebrospinal fluidmalignant cells or brain metastases, Eastern Cooperative Oncology Group (ECOG) performance statusof 2 or greater, and any history of central nervous system lymphoma. Patients with active or seriousinfections were excluded, however patients with simple urinary tract infection and uncomplicatedbacterial pharyngitis were permitted if responding to active treatment.

Following lymphodepleting chemotherapy, Yescarta was administered as a single intravenous infusionat a target dose of 2 × 106 anti-CD19 CAR T cells/kg (maximum dose: 2 × 108 cells). Thelymphodepleting regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine30 mg/m2 intravenously, both given on the 5th, 4th, and 3rd day before Yescarta. Nondisease modifyingbridging therapy limited to corticosteroids, could be administered between leukapheresis andlymphodepleting chemotherapy for patients with high disease burden at screening.

In the overall study population, the median age was 59 years (range: 21 to 81 years); 66% were male,and 83% were white. Seventy-four percent of patients had primary refractory LBCL and 26% ofpatients had relapsed within 12 months of first-line therapy. Patients had a second-line age-adjusted

IPI score of 0-1 (55%) or 2-3 (45%) and an ECOG performance status of 0 (54%) or 1 (46%).

Patients in the Yescarta and SOCT arms were categorized as DLBCL NOS/without furtherclassification possible (126 patients and 120 patients, respectively); DLBCL arising from follicularlymphoma (19 patients and 27 patients, respectively); HGBL with MYC, BCL2, and/or BCL6 (double-and triple-hit) rearrangements (31 patients and 25 patients, respectively) or HGBL NOS, (1 patient inthe SOCT arm); the remaining subjects were categorized under not confirmed, missing, or other.

Of the 180 patients randomised to receive Yescarta, 178 underwent leukapheresis and 170 weretreated with Yescarta. Of the patients treated, 60 (33%) received bridging corticosteroid therapy. Therewere no manufacturing failures. Eight patients (4%) were not treated following leukapheresis,primarily due to progressive disease, serious adverse events, or death. The median time fromleukapheresis to product release was 13 days (range: 10 to 24 days), and leukapheresis to Yescartainfusion was 26 days (range: 16 to 52 days). The median dose was 2.0 × 106 anti-CD19 CAR Tcells/kg. All 170 patients who received Yescarta were monitored at a healthcare facility for aminimum of 7 days. Of the 179 patients randomised to receive SOCT, 64 patients (36%) received

HDT-ASCT.

The primary endpoint was event-free survival (EFS) as determined by blinded central review. Keysecondary endpoints were ORR and OS. The summary of efficacy results in the overall population isshown in Table 6 and the Kaplan-Meier curves for EFS and OS are shown in Figure 1 and Figure 2,respectively. The 24-month EFS was 40.5% [95% CI: 33.2, 47.7] in the Yescarta arm and 16.3% [95%

CI: 11.1, 22.2] in the SOCT arm. At the time of the primary EFS analysis, the median progression freesurvival (PFS) per central assessment in the Yescarta arm was 14.7 months (95% CI: 5.4, NE)compared with 3.7 months (95% CI: 2.9, 5.3) in the SOCT arm (HR: 0.490 [95% CI: 0.368, 0.652]).

The median study duration was 24.9 months at the time of the primary EFS analysis and 47.2 monthsat the time of the primary OS analysis. The primary analysis of OS was performed at the protocol-specified timepoint of 5 years from the first subject enrolled. A statistically significant improvement in

OS in favour of Yescarta was demonstrated (see Table 6). The estimated 48-month OS rates were54.6% in the Yescarta arm and 46.0% in the SOCT arm. Fifty-seven percent of patients receivedcellular immunotherapy after no response to or relapse after randomisation to SOCT.

Consistent efficacy favouring Yescarta was generally observed across selected subgroups includingresponse to first-line therapy, second-line age-adjusted IPI score, ECOG performance status, age,double expressor lymphoma status and HGBL disease subtype (see Figure 3). Among patients with

HGBL per central laboratory, Yescarta demonstrated an improvement in EFS compared to SOCT(HR: 0.285 [95% CI: 0.137, 0.594]). The ORR was 81% (95% CI: 62.5%, 92.5%) and CR rate was68% (95% CI: 48.6%, 83.3%) in patients treated with Yescarta compared with 42% (95% CI: 23.4%,63.1%) and 23% (95% CI: 9.0%, 43.6%) respectively in the SOCT arm. The OS HR for Yescartaversus SOCT was 0.735 [95% CI: 0.338, 1.600] for patients with HGBL per central laboratory.

Table 6. Summary of Efficacy Results for ZUMA-7

Yescarta Standard of Care Therapy

N = 180 N = 179

EFSa

Number of events (%) 108 (60) 144 (80)

Median, months [95% CI]b 8.3 [4.5, 15.8] 2.0 [1.6, 2.8]

Stratified hazard ratio [95% CI] 0.398 [0.308, 0.514]

Stratified log-rank p-valuec <0.0001

ORR (%) [95% CI]a 83 [77.1, 88.5] 50 [42.7, 57.8]

Odds ratio [95% CI] 5.31 [3.08, 8.90]

Stratified CMH test p-valuec <0.0001

Complete Response Rate (%) 65 [57.6, 71.9] 32 [25.6, 39.8]

Partial Response Rate (%) 18 [13.0, 24.8] 18 [12.6, 24.3]

OSd

Number of events (%) 82 (46) 95 (53)

Median OS, months [95% CI]b NR (28.6, NE) 31.1 (17.1, NE)

Stratified hazard ratio [95% CI] 0.726 (0.540, 0.977)

Stratified log-rank p-valuec,e 0.0335

CI, confidence interval; CMH, Cochran-Mantel-Haenszel; EFS, event-free survival; NE, not estimable; NR, not reached;

ORR, objective response rate; OS, overall survival.

a. Per central assessment performed at the time of primary EFS analysis

b. Kaplan-Meier method

c. The p values are two-sided. Stratified log-rank test or stratified CMH adjusted for response to first-line therapy (primaryrefractory versus relapse ≤ 6 months of first-line therapy versus relapse > 6 and ≤ 12 months of first-line therapy) andsecond-line age-adjusted International Prognostic Index (0 to 1 versus 2 to 3)

d. Per assessment performed at the time of primary analysis of OS (five years from the first subject enrolled)

e. p-value is compared with 0.0482, the two-sided efficacy boundary (significance level) for the primary OS analysis

Figure 1. Kaplan-Meier Plot of Event-Free Survival in ZUMA-7

Censored ○ Axi-Cel + SOCT Median [95 % Cl] Stratified HR [95 % Cl] Stratified P-value

Axi-Cel (N = 180): 8.3 (4.5, 15.8) 0.398 (0.308, 0.514) < 0.0001

SOCT (N = 179): 2.0 (1.6, 2.8)

Time Since Randomization (months)—————— Axi-Cel ------------------ SOCT

Subjects at Risk

Axi-Cel 180 174 163 145 106 98 92 92 91 89 87 85 85 83 82 77 74 74 67 57 52 46 40 36 26 14 12 12 12 10 6 0

SOCT 179 151 86 70 54 50 45 42 38 32 32 30 29 27 27 25 25 25 24 21 20 18 12 10 9 7 7 6 6 6 3 1 1 1 0

CI, confidence interval; HR, hazard ratio; SOCT, standard of care treatment.

Probability of Event-free (%)

Figure 2. Kaplan-Meier Plot of Overall Survival in ZUMA-7

Censored ○ Axi-Cel + SOCT Median (95% Cl) Stratified HR (95% Cl) Stratified P-value

Axi-Cel (N= 180): NR (28.6, NE) 0.726 (0.540, 0.977) 0.0335

SOCT (N= 179): 31.1 (17.1, NE)

Time Since Randomization (months)

Axi-Cel SOCT

Subjects at Risk

Axi-Cel

SOCT

CI, confidence interval; HR, hazard ratio; NE, not estimable; SOCT, standard of care treatment.

Note: Subjects who did not respond to SOCT could receive subsequent treatment for lymphoma including anti-CD19 CAR

T-cell therapy outside the requirement of the protocol.

Figure 3. Forest Plot of Event-Free Survival in Selected Subgroups in ZUMA-7

Axicabtagene Standard of

Ciloleucel Care

Subgroup Event/N (%) Event/N (%) HR (95 % CI)

Overall 108/180 (60) 144/179 (80) 0.398 (0.308, 0.514)

Age< 65 81/129 (63) 96/121 (79) 0.490 (0.361, 0.666)≥ 65 27/51 (53) 48/58 (83) 0.276 (0.164, 0.465)

ECOG performance status0 59/95 (62) 76/100 (76) 0.504 (0.356, 0.713)1 49/85 (58) 68/79 (86) 0.292 (0.195, 0.436)

Second-line age-adjusted IPI score per IXRS0-1 54/98 (55) 73/100 (73) 0.407 (0.285, 0.582)2-3 54/82 (66) 71/79 (90) 0.388 (0.269, 0.561)

Response to first-line therapy per IXRS

Primary refractory 85/133 (64) 106/131 (81) 0.426 (0.319, 0.570)

Relapse ≤ 12 months of first line therapy 23/47 (49) 38/48 (79) 0.342 (0.202, 0.579)

Central Laboratory Double Expressor Status

Double expressor lymphoma 35/57 (61) 50/62 (81) 0.424 (0.268, 0.671)

Central Laboratory Disease Type

DLBCL NOS/without further classification possible 79/126 (63) 95/120 (79) 0.443 (0.325, 0.603)

HGBL with or without MYC and BCL2 and/or BLCL6 rearrangement 15/31 (48) 21/26 (81) 0.285 (0.137, 0.594)

Axicabtagene Ciloleucel Better SOCT Better0.01 0.1 0.2 0.5 1 2 5

CI, confidence interval; HR, hazard ratio; IxRS, interactive voice/web response system; SOCT, standard of care.

Note: At the time of the primary EFS analysis, disease type by central laboratory was confirmed in 303 of 359 patients, theremaining patients were categorised by the central laboratory as not confirmed, missing or other.

The OS benefit with Yescarta is consistent across clinically relevant subgroups.

Relapsed or refractory FL after three or more lines of systemic therapy (ZUMA-5)

The efficacy and safety of Yescarta in adult patients with FL, were evaluated in a phase 2 single-arm,open-label, multicentre study in patients with r/r FL based on 2016 WHO-classification.

Eligible patients were ≥ 18 years of age with refractory disease after 2 or more prior lines of therapy.

Prior therapy must have included an anti-CD20 monoclonal antibody combined with an alkylatingagent (single-agent anti-CD20 antibody did not count as line of therapy for eligibility). Patients with

SD (without relapse) > 1 year from completion of last therapy were not considered eligible. Patientswith CNS lymphoma, a history of allogeneic SCT or prior anti-CD19 CAR or other genetically

SSuurrvviivvaall PPrroobbaabbiilliittyy ((%%))modified T-cell therapy were excluded. Patients with a history of CNS disorders (such as seizures orcerebrovascular ischemia), left ventricular ejection fraction of less than 50% or room air oxygensaturation of less than 92%, or autoimmune disease requiring systemic immunosuppression wereineligible. The study excluded patients with active or serious infections and patients with FL Grade 3b.

The actual duration of follow-up was 25.9 months (range: 0.3 to 44.3 months, still ongoing). Asummary of the patient demographics is provided in Table 7.

At the time of the primary analysis, a total of 122 FL patients were enrolled (i.e. leukapheresed),including 75 patients who had received 3 or more lines of previous therapy. In the period between theprimary analysis data cut-off date and the 24-month follow-up analysis data cut-off date, no additionalpatients with FL were enrolled or treated with Yescarta.

Table 7: Summary of demographics for ZUMA-5 FL patients (24-month analysis)

Category All leukapheresed All leukapheresed with ≥ 3(N = 122) lines of therapy(N = 75*)

Age (years)

Median (min, max) 60 (34, 79) 60 (34, 79)≥ 65 30% 31%

Male gender 60% 63%

White 93% 93%

Asian 2% 4%

Black 2% 1%

ECOG status0 63% 59%1 37% 41%

High tumour bulk as defined by GELFcriteria 52% 57%

Median number of prior therapies (min,max) 3 (1, 10) 4 (3, 10)

Patients with refractory disease to ≥ 2prior lines of therapy 30% 24%

Patients with disease stage III/IV 86% 86%

Patients with prior autologous stem celltransplant 25% 29%

Prior PI3K inhibitor 26% 40%

Time to relapse from first anti-CD20chemotherapy combination therapy 54% 51%< 24 months

ECOG, Eastern Cooperative Oncology Group; GELF, Groupe d’Etude des Lymphomes Folliculaires.

* All patients with locally confirmed diagnosis, including 60 patients with centralised confirmed diagnosis. Number ofleukapheresed (n=75) and treated (n=73) patients.

Yescarta was administered as a single intravenous infusion at a target dose of 2 × 106 anti-CD19 CAR

T cells/kg after lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2intravenously and fludarabine 30 mg/m2 intravenously, both given on the 5th, 4th, and 3rd day before

Yescarta. All patients were hospitalized for observation for a minimum of 7 days after Yescartainfusion. The administration and monitoring of Yescarta is consistent between ZUMA-5 and

ZUMA-1.

The primary analysis was performed, when at least 80 consecutively enrolled FL patients had aminimum follow-up of 12 months from first response assessment. The primary endpoint was ORR.

Secondary endpoints included CR rate, ORR and CR in patients who received 3 or more lines of priortherapy, DOR, OS and PFS and incidence of adverse events. Three out of the 122 FL patients enrolledat the time of the primary analysis were not treated, primarily due to ineligibility, experiencing CRprior or death prior to the treatment.

A 24-month follow-up analysis was performed, when at least 80 FL patients had a minimum follow-upof 24 months after infusion.

As of the 24-month follow-up analysis, no additional patients underwent leukapheresis nor weretreated with Yescarta. No manufacturing failures occurred. The median time from leukapheresis toproduct release was 12 days (range: 10 to 37 days), leukapheresis to product delivery was 17 days(range: 13 to 72 days) and leukapheresis to Yescarta infusion was 27 days (range: 19 to 330 days). Themedian dose was 2.0 × 106 anti-CD19 CAR T cells/kg.

At the time of the primary analysis data cut, 122 FL patients were enrolled. Among the 75 enrolled FLpatients who had 3 or more lines of prior therapy, the ORR was 91% and the CR rate was 77%.

The 24-month follow-up analysis was performed on the 122 enrolled FL patients, and 119 of thesepatients were treated with Yescarta. Among the 122 enrolled FL patients, 75 had 3 or more lines ofprior therapy, resulting in an ORR of 91% and CR rate of 77%. The median time to response was1 month (range: 0.8 to 3.1 months), the median DOR was 38.6 months and the proportion ofresponders who remained in response was 62% at Month 24. Twenty nine out of 75 FL patients whohad 3 or more prior lines of therapy initially achieved a PR, 19 of whom later achieved CR. Subgroupanalysis included ORR in patients who were refractory (88%), FLIPI score ≥ 3 (94%), high tumourburden (91%), progression of disease within 24 months of first immunotherapy (89%) and priortreatment with PI3K inhibitor (90%). Key efficacy results for FL patients with 3 or more prior lines oftherapy are summarized in Table 8.

Table 8. Summary of Efficacy Results for all enrolled ZUMA-5 FL patients with 3 or moreprior lines of therapy (24-month analysis)

Category All leukapheresed (ITT)

N = 75*

ORRa, (%) 91%[95% CI] (82, 96)

CR, (%) 77%

PR, (%) 13%

DORb, median in months 38.6[95% CI] (24.7, NE)(range) (0.0, 38.6)

Ongoing Response (n) 42

Rate of Continued Remissionb % [95% CI]12 Month 79.5(67.2, 87.6)18 Month 75.5 (62.5, 84.6)24 Month 67.6 (52.7, 78.7)

CI, confidence interval; CR, complete response; DOR, duration of response; ITT, intention-to-treat; NE, not estimable; ORR,objective response; PR, partial response

a. Per the International Working Group Lugano Classification (Cheson 2014), as assessed by the Independent Radiology

Review Committee

b. Measured from the date of first objective response to the date of progression or death

* All patients with locally confirmed diagnosis, including 60 patients with centralized confirmed diagnosis. Number ofleukapheresed (n=75) and treated (n=73) patients.

Figure 4. Kaplan Meier DOR in the all leukapheresed set, patients with objective response(FL patients with 3 or more lines of prior therapy, 24-month analysis, independentreview committee)

CENSORED ∆ FL Median [95% Cl]

FL (N = 68): 38.6 [24.7, NE]

Time (Months)—————— FL

Subjects at Risk

FL 68 66 65 60 60 56 53 53 53 51 51 50 46 45 45 45 45 44 34 32 30 29 28 17 10 9 9 8 8 8 8 8 8 8 8 6 1 1 1 0

CI, confidence interval; NE, not estimable.

The European Medicines Agency has waived the obligation to submit the results of studies with

Yescarta in all subsets of the paediatric population in the treatment of mature B-cell neoplasms (seesection 4.2 for information on paediatric use).

Yescarta comprises human autologous T cells. The anticipated residual products are typical cellulardegradation products resulting from normal cellular clearance mechanisms. Thus, the infused CAR Tcells are expected to be cleared over time.

Cellular kinetics

Following infusion of Yescarta anti-CD19 CAR T cells exhibited an initial rapid expansion followedby a decline to near baseline levels by 3 months. Peak levels of anti-CD19 CAR T cells occurredwithin the first 7 to 14 days after the day of Yescarta infusion. Age (range: 21 to 80 years) and sex hadno significant impact on AUC and peak levels of Yescarta.

Among patients in ZUMA-1, the median peak level of anti-CD19 CAR T cells in the blood was38.3 cells/µL (range: 0.8 to 1513.7 cells/μL), which decreased to a median of 2.1 cells/µL by 1 month(range: 0 to 167.4 cells/μL) and to a median of 0.4 cells/µL by 3 months (range: 0 to 28.4 cells/μL)after Yescarta infusion. Among patients in ZUMA-7 the median peak level of anti-CD19 CAR T cellsin the blood was 25.84 cells/μL (range: 0.04 to 1173.25 cells/μL), which decreased towards baseline inevaluable patients by 3 months (0.35 cells/μL; range: 0.00 to 28.44 cells/μL), but were still detectablein 12 out of 30 evaluable patients until 24 months post-treatment.

Probability of Event-free (%)

Among patients in ZUMA-5 with FL, the median peak level of anti-CD19 CAR T cells in the bloodwas 37.6 cells/µL (range: 0.5 to 1415.4 cells/μL). The median time to peak of anti-CD19 CAR T cellsin the blood was 8 days after infusion (range: 8 to 371 days). By 3 months, anti-CD19 CAR T celllevels decreased to near baseline levels to a median of 0.3 cells/µL (range: 0 to 15.8 cells/μL).

Among patients in ZUMA-1, the number of anti-CD19 CAR T cells in the blood was positivelyassociated with objective response (CR or PR). The median anti-CD19 CAR T cell peak level inresponders (N = 71) was 216% higher compared to the corresponding level in nonresponders (N = 25)(43.6 cells/μL versus 20.2 cells/μL). Median AUC0-28 in responding patients (N = 71) was 253% of thecorresponding level in nonresponders (N = 25) (562 days × cells/μL versus 222 days × cells/μL).

Among patients in ZUMA-7 the number of anti-CD19 CAR T cells in the blood was positivelyassociated with objective response (CR or PR). The median anti-CD19 CAR T cell peak levels inresponders (n=142) were about 275% higher compared to the corresponding level in nonresponders(n=20) (28.9 cells/μL versus 10.5 cells/μL). Median AUC0 - 28 in responding patients (n=142) wasabout 417% higher compared to the corresponding level in nonresponders (n=20)(292.9 days × cells/μL versus 70.1 days × cells/μL).

Among patients with FL in ZUMA-5, the median peak anti-CD19 CAR T-cell levels in responders(n=112) versus nonresponders (n=5) were 38.0 cells/μL and 31.3 cells/μL, respectively. The median

AUC0-28 in responders versus nonresponders were 454.8 cells/μL*days and 247.1 cells/μL*days,respectively.

Studies of Yescarta in patients with hepatic and renal impairment were not conducted.

Yescarta comprises engineered human T cells, therefore there are no representative in vitro assays, exvivo models, or in vivo models that can accurately address the toxicological characteristics of thehuman product. Hence, traditional toxicology studies used for drug development were not performed.

No carcinogenicity or genotoxicity studies have been conducted with Yescarta.

No studies have been conducted to evaluate the effects of Yescarta on fertility, reproduction, anddevelopment.

Cryostor CS10 (contains DMSO)

Sodium chloride

Human albumin

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

1 year.

The stability of Yescarta upon completion of thawing is up to 3 hours at room temperature (20 ˚C to25 °C). However, Yescarta infusion must begin within 30 minutes of thaw completion and the totalinfusion time should not exceed 30 minutes.

Yescarta must be stored in the vapour phase of liquid nitrogen (≤ -150 ˚C) and must remain frozenuntil the patient is ready for treatment to ensure viable live autologous cells are available for patientadministration. Thawed medicinal product should not be refrozen.

For storage conditions after thawing of the medicinal product, see section 6.3.

Ethylene-vinyl acetate cryostorage bag with sealed addition tube and two available spike ports,containing approximately 68 mL of cell dispersion.

One cryostorage bag is individually packed in a shipping cassette.

Irradiation could lead to inactivation of the product.

Yescarta must be transported within the facility in closed, break-proof, leak-proof containers.

This medicinal product contains human blood cells. Healthcare professionals handling Yescarta musttake appropriate precautions (wearing gloves and eye protection) to avoid potential transmission ofinfectious diseases.

Preparation prior to administration

* Verify that the patient’s identity (ID) matches the patient identifiers on the Yescarta cassette.

* The Yescarta infusion bag must not be removed from the metal cassette if the information onthe patient-specific label does not match the intended patient.

* Once the patient ID is confirmed, remove the Yescarta infusion bag from the metal cassette.

* Check that the patient information on the metal cassette label matches that on the infusion baglabel.

* Inspect the infusion bag for any breaches of container integrity before thawing. If the infusionbag is compromised, follow the local guidelines for the handling of waste of human-derivedmaterial (or immediately contact Kite).

Thawing

* Place the infusion bag inside a second bag.

* Thaw Yescarta at approximately 37 °C using either a water bath or dry thaw method until thereis no visible ice in the infusion bag. Gently mix the contents of the infusion bag to disperseclumps of cellular material. If visible cell clumps remain, continue to gently mix the contents ofthe infusion bag. Small clumps of cellular material should disperse with gentle manual mixing.

Yescarta must not be washed, spun down, and/or re-suspended in new medium prior to infusion.

Thawing takes approximately 3 to 5 minutes.

* Once thawed, Yescarta is stable at room temperature (20 °C-25 °C) for up to 3 hours.

However, Yescarta infusion must begin within 30 minutes of thaw completion.

* A leukodepleting filter must not be used.

* Tocilizumab and emergency equipment must be available prior to infusion and during themonitoring period. In the exceptional case where tocilizumab is not available due to a shortagethat is listed in the European Medicines Agency shortage catalogue, suitable alternativemeasures to treat CRS instead of tocilizumab must be available prior to infusion.

* Yescarta is for autologous use only.

* The patient’s identity must be matched with the patient identifiers on the Yescarta infusion bag.

* Central venous access is recommended for the administration of Yescarta.

* The tubing must be primed with sterile sodium chloride 9 mg/mL (0.9%) (0.154 mmol sodiumper mL) solution for injection prior to infusion.

* The entire content of the Yescarta infusion bag must be infused within 30 minutes by eithergravity or a peristaltic pump.

* Gently agitate the infusion bag during Yescarta infusion to prevent cell clumping.

* After the entire content of the infusion bag is infused, the infusion bag and the tubing must berinsed at the same infusion rate with 10 to 30 mL sodium chloride 9 mg/mL (0.9%) solution forinjection by back priming to ensure all Yescarta is delivered.

Measures to take in case of accidental exposure

In case of accidental exposure local guidelines on handling of human-derived materials must befollowed. Work surfaces and materials which have potentially been in contact with Yescarta must bedecontaminated with appropriate disinfectant.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Yescarta (solid and liquidwaste) must be handled and disposed of as potentially infectious waste in accordance with localguidelines on the handling of waste of human-derived material.

Kite Pharma EU B.V.

Tufsteen 12132 NT Hoofddorp

The Netherlands

EU/1/18/1299/001

Date of first authorisation: 23 August 2018

Date of latest renewal: 24 July 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.