Summary of medicine characteristics - Yescarta
1. NAME OF THE MEDICINAL PRODUCT
Yescarta 0.4 – 2 × 108 cells dispersion for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description
Yescarta (axicabtagene ciloleucel) is a CD19-directed genetically modified autologous T cell immunotherapy. To prepare Yescarta, patient’s own T cells are harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment linked to CD28 co-stimulatory domain and CD3-zeta signalling domain. The anti-CD19 CAR-positive viable T cells are expanded and infused back into the patient, where they can recognise and eliminate CD19-expressing target cells.
2.2 Qualitative and quantitative composition
Each patient specific single infusion bag of Yescarta contains a dispersion of anti-CD19 CAR T cells in approximately 68 mL for a target dose of 2 × 106 anti-CD19 CAR-positive viable T cells/kg body weight (range: 1 × 106 – 2 × 106 cells/kg), with a maximum of 2 × 108 anti-CD19 CAR T cells.
Excipients with known effect
Each bag of Yescarta contains 300 mg sodium.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Dispersion for infusion.
A clear to opaque, white to red dispersion.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Yescarta is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL), after two or more lines of systemic therapy.
4.2 Posology and method of administration
Yescarta must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with Yescarta. At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion. The treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose.
Posology
Yescarta is intended for autologous use only (see section 4.4).
A single dose of Yescarta contains 2 × 106 CAR-positive viable T cells per kg of body weight (or maximum of 2 × 108 CAR-positive viable T cells for patients 100 kg and above) in approximately 68 mL dispersion in an infusion bag.
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/m2
intravenous and fludarabine 30 mg/m2 intravenous should be administered on the 5th, 4th, and 3rd day before infusion of Yescarta.
Pre-medication
- • Paracetamol 500–1,000 mg given orally and diphenhydramine 12.5 to 25 mg intravenous or oral
(or equivalent) approximately 1 hour before Yescarta infusion is recommended.
- • Prophylactic use of systemic corticosteroids is not recommended as it may interfere with the
activity of Yescarta.
Monitoring
- • Patients should be monitored daily for the first 10 days following infusion for signs and
symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs or symptoms of CRS and/or neurologic events.
- • After the first 10 days following the infusion, the patient should be monitored at the physician’s
discretion.
- • Patients should be instructed to remain within proximity of a qualified clinical facility for at
least 4 weeks following infusion.
Special populations
Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection
There is no clinical experience in patients with active HIV, HBV or HCV infection.
Paediatric population
The safety and efficacy of Yescarta in children and adolescents below 18 years of age have not yet been established. No data are available.
Elderly
No dose adjustment is required in patients > 65 years of age. Efficacy was consistent with the overall treated patient population.
Method of administration
Yescarta is to be administered via intravenous infusion.
Yescarta must not be irradiated. Do NOT use a leukodepleting filter.
Precautions to be taken before handling or administering the medicinal product
This medicinal product contains genetically modified human blood cells. Healthcare professionals handling Yescarta should take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases.
Preparation for infusion
- • Verify that the patient’s identity (ID) matches the patient identifiers on the Yescarta cassette.
- • The Yescarta bag must not be removed from the metal cassette if the information on the patient
specific label does not match the intended patient.
- • Once the patient ID is confirmed, remove the Yescarta bag from the metal cassette.
- • Check that the patient information on the metal cassette label matches that on the bag label.
- • Inspect the product bag for any breaches of container integrity before thawing. If the bag is
compromised, follow the local guidelines for the handling of waste of human-derived material (or immediately contact Kite).
- • Place the infusion bag inside a second bag.
- • Thaw Yescarta at approximately 37 °C using either a water bath or dry thaw method until there
is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Yescarta should not be washed, spun down, and/or re-suspended in new media prior to infusion. Thawing should take 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 should begin within 30 minutes of thaw completion.
Administration
- • For autologous use only.
- • Tocilizumab and emergency equipment should be available prior to infusion and during the
monitoring period.
- • A leukodepleting filter must not be used.
- • Central venous access is recommended for the administration of Yescarta.
- • Verify the patient ID again to match the patient identifiers on the Yescarta bag.
- • Prime the tubing with 0.9% sodium chloride solution (0.154 mmol sodium per mL) prior to
infusion.
- • Infuse the entire content of the Yescarta bag within 30 minutes by either gravity or a peristaltic
pump.
- • Gently agitate the bag during Yescarta infusion to prevent cell clumping.
- • After the entire content of the bag is infused, rinse the tubing at the same infusion rate with
0.9% sodium chloride solution (0.154 mmol sodium per mL) to ensure all Yescarta is delivered.
For instructions on the handling, accidental exposure to and disposal of the medicinal product, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Contraindications of the lymphodepleting chemotherapy must be considered.
4.4 Special warnings and precautions for use
Traceability
The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient should be kept for a period of 30 years after expiry date of the product.
General
Yescarta is intended solely for autologous use and must not be administered to other patients. Before infusion, the patient’s identity must match the patient identifiers on the Yescarta infusion bag and cassette. Do not infuse Yescarta if the information on the patient-specific label does not match the intended patient.
Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurologic events. After the first 10 days following infusion, the patient should be monitored at the physician’s discretion.
Counsel patients to remain within the proximity of a qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS or neurological adverse reactions occur. Monitoring of vital signs and organ functions should be considered depending on the severity of the reaction.
Reasons to delay treatment
Due to the risks associated with Yescarta treatment, infusion should be delayed if a patient has any of the following conditions:
- • Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) including from preceding chemotherapies.
- • Active uncontrolled infection.
- • Active graft-versus-host disease (GVHD).
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with Yescarta.
Live vaccines
The safety of immunisation 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 with Yescarta.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception
The pregnancy status of women of child bearing potential must be verified before starting Yescarta treatment.
See the prescribing information for lymphodepleting chemotherapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.
There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Yescarta.
Pregnancy
There are no available data with Yescarta use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with Yescarta to assess whether it can cause foetal harm when 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 of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, Yescarta is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Yescarta therapy should be discussed with the treating physician.
Assessment of immunoglobulin levels and B-cells in newborns of mothers treated with Yescarta should be considered.
Breast-feeding
It is unknown whether Yescarta is excreted in human milk or transferred to the breast-feeding child. Breast-feeding women should be advised of the potential risk to the breast-fed child.
Fertility
No clinical data on the effect of Yescarta on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.
4.7 Effects on ability to drive and use machines
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 should refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.
4.8 Undesirable effects
Summary of the safety profile
The safety data described in this section reflect exposure to Yescarta in ZUMA-1, a Phase 1/2 study in which 108 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) received CAR-positive T cells based on a recommended dose which was weight-based. The median duration of follow up was 27.4 months.
The most significant and frequently occurring adverse reactions were CRS (93%), encephalopathy (58%), and infections (39%).
Serious adverse reactions occurred in 56% of patients. The most common serious adverse reactions included encephalopathy (22%), unspecified pathogen infections (16%), bacterial infections (6%), febrile neutropenia (6%), viral infections (5%), and pyrexia (5%).
The most common Grade 3 or higher adverse reactions included encephalopathy (31%), unspecified pathogen infections (19%), CRS (11%), bacterial infection (9%), aphasia (7%), viral infection (6%), delirium (6%), hypotension (6%), and hypertension (6%).
Tabulated list of adverse reactions
Adverse reactions reported from clinical trials and post-marketing setting are presented below. These reactions are 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); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, 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 |
| Infections and infestations | ||
| Very common | Unspecified pathogen infections Viral infections Bacterial infections | |
| Common | Fungal infections | |
| Blood and lymphatic system disorders | ||
| Very common | Leukopenia Neutropenia Anaemia Thrombocytopenia | |
| Common | Coagulopathy | |
| Immune system disorders | ||
| Very common | Cytokine Release Syndrome Hypogammaglobulinaemia | |
| Common | Hypersensitivity Histiocytosis Haematophagic | |
| Metabolism and nutrition disorders | ||
| Very common | Dehydration Decreased appetite Hypophosphataemia Hyponatraemia Weight decrease | |
| Common | Hypocalcaemia Hypoalbuminaemia | |
| Psychiatric disorders | ||
| Very common | Delirium Anxiety | |
| Common | Insomnia | |
| Nervous system disorders | ||
| System Organ Class (SOC) | Frequency | Adverse reactions |
| Very common | Encephalopathy Headache Tremor Dizziness Aphasia | |
| Common | Ataxia Neuropathy Seizure Dyscalculia Myoclonus | |
| Uncommon | Spinal cord oedema Myelitis Quadriplegia | |
| Cardiac disorders | ||
| Very common | Tachycardia Arrhythmia | |
| Common | Cardiac arrest Cardiac failure | |
| Vascular disorders | ||
| Very common | Hypotension Hypertension | |
| Common | Thrombosis Capillary leak syndrome | |
| Respiratory, thoracic and mediastinal disorders | ||
| Very common | Cough Dyspnoea Hypoxia Pleural effusion | |
| Common | Pulmonary oedema | |
| Gastrointestinal disorders | ||
| Very common | Diarrhoea Nausea Vomiting Constipation Abdominal pain Dry mouth | |
| Common | Dysphagia* | |
| Skin and subcutaneous tissue disorders | ||
| Common | Rash | |
| Musculoskeletal and connective tissue disorders | ||
| Very common | Motor dysfunction Pain in extremity Back pain Arthralgia Muscle pain | |
| Renal and urinary disorders | ||
| Common | Renal insufficiency | |
| General disorders and administration site conditions | ||
| Very common | Fatigue Pyrexia Oedema Chills | |
| Investigations | ||
| Very common | Alanine aminotransferase increased Aspartate aminotransferase increased | |
| Common | Bilirubin increased | |
Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment in current therapy are included in table 3.
* Dysphagia has been reported in the setting of neurologic toxicity and encephalopathy
Description of selected adverse reactions
Cytokine release syndrome
CRS occurred in 93% of patients. Eleven percent (11%) of patients experienced Grade 3 or higher (severe, life-threatening, and fatal) CRS. The median time to onset was 2 days (range: 1 to 12 days) and the median duration was 7 days (range: 2 to 29 days). Ninety-eight percent (98%) of patients recovered from CRS.
The most common signs or symptoms associated with CRS included pyrexia (83%), hypotension (44%), tachycardia (24%), hypoxia (23%), and chills (20%). Serious adverse reactions that may be associated with CRS included acute kidney injury, atrial fibrillation, ventricular tachycardia, cardiac arrest, cardiac failure, capillary leak syndrome, hypotension, hypoxia, and HLH/MAS. See section 4.4 for monitoring and management guidance.
Neurologic adverse reactions
Neurologic adverse reactions occurred in 67% of patients. Thirty-two percent (32%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onset was 5 days (range: 1 to 17 days). The median duration was 13 days (range: 1 to 191 days). Most patients recovered from neurologic adverse reactions, with the exception of 4 patients who had ongoing neurologic adverse reactions at the time of death; the deaths were due to other causes.
The most common signs or symptoms associated with neurologic adverse reactions included encephalopathy (58%), headache (40%), tremor (31%), dizziness (21%), aphasia (18%), and delirium (17%). Serious adverse reactions including encephalopathy (22%), aphasia (4%), delirium (4%), and seizures (1%) have been reported in patients administered Yescarta.
Other neurologic adverse reactions have been reported less frequently in clinical trials and included dysphagia (5%), myelitis (0.2%), and quadriplegia (0.2%).
Spinal cord oedema was reported, in the context of neurologic toxicity in the post-marketing setting.
See section 4.4 for monitoring and management guidance.
Febrile neutropenia and infections
Febrile neutropenia was observed in 36% of patients after Yescarta infusion. Infections occurred in 39% of patients in ZUMA-1. Grade 3 or higher (severe, life-threatening, or fatal) infections occurred in 26% of patients. Grade 3 or higher unspecified pathogen, bacterial, and viral infections occurred in 19%, 9%, and 6% of patients respectively. The most common site of infection was in the respiratory tract. See section 4.4 for monitoring and management guidance.
Prolonged cytopenias
Grade 3 or higher neutropenia (including febrile neutropenia), anaemia, and thrombocytopenia occurred in 80%, 45%, and 40% of patients, respectively. Prolonged (still present at Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher neutropenia, thrombocytopenia, and anaemia occurred in 26%, 24%, and 10% of patients, respectively. Grade 3 or higher neutropenia, thrombocytopenia, and anaemia present after Day 93 occurred in 11%, 7%, and 3% of patients, respectively. See section 4.4 for management guidance.
Hypogammaglobulinaemia
In ZUMA-1, hypogammaglobulinaemia occurred in 16% of patients. Cumulatively, 33 (31%) of 108 subjects received intravenous immunoglobulin therapy at the time of the 24-month analysis. See section 4.4 for management guidance.
Immunogenicity
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 the anti-CD19 CAR. Three patients tested positive for anti-FMC63 prior to being treated with Yescarta. An impact of these antibodies on efficacy or safety was not discernible.
Special population
There is limited experience with Yescarta in patients > 75 years of age. Generally, safety and efficacy were 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 0 and 1 and by sex.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in
4.9 Overdose
There are no data regarding the signs of overdose with Yescarta.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: not yet assigned
Mechanism of action
Yescarta, an engineered autologous T-cell immunotherapy product, binds to CD19 expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19 expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signalling cascades that lead to T-cell activation, proliferation, acquisition of effector functions, and secretion of inflammatory cytokines and chemokines. This sequence of events leads to apoptosis and necrosis of CD19-expressing target cells.
Pharmacodynamic effects
In phase 2 of ZUMA-1, after Yescarta infusion, pharmacodynamic responses were evaluated over a 4-week interval by measuring transient elevation of cytokines, chemokines, and other molecules in blood. Levels of cytokines and chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-a, IFN-y, and IL2Ra were analyzed. Peak elevation was observed within the first 14 days after infusion, and levels generally returned to baseline within 28 days.
Due to the on-target, off-tumour effect of Yescarta, a period of B-cell aplasia is expected following treatment. Among 73 patients 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% had detectable B-cells at Month 3, and 22% had detectable B-cells at Month 6. The initiation of B-cell recovery was first noted at Month 9, when 56% of patients 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 77% of patients had detectable B-cells at Month 24. Patients were not required to be followed after they progressed; thus, the majority of patients with evaluable samples were responders.
Analyses performed to identify associations between cytokine levels and incidence of CRS or neurologic events showed that higher levels (peak and AUC at 1 month) of IL-15, as well as IL-6, were associated with Grade 3 or higher neurologic adverse reactions and Grade 3 or higher CRS.
Clinical efficacy and safety
DLBCL, PMBCL and DLBCL arising from follicular lymphoma (ZUMA-1)
A total of 108 patients were treated with Yescarta in a phase 1/2 open-label, multicentre, single-arm study in patients with relapsed or refractory aggressive B-cell NHL. Efficacy was based on 101 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. DLBCL in ZUMA-1 included patients with DLBCL NOS, other DLBCL subtypes, and high-grade B-cell lymphoma (HGBCL) 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 of both MYC and BCL-2 protein); 5 were found to have HGBCL with MYC, BCL-2 or BCL-6 gene rearrangement (double- and triple-hit); and 2 were found to have HGBCL 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) or stable disease (SD) as best response to last line of therapy, or disease progression within 12 months after autologous stem cell transplant (ASCT). Patients who were refractory to chemotherapy or who relapsed after two or more lines of systemic therapy were generally ineligible for haematopoietic stem cell transplantation. Patients must have received at least prior anti-CD20 antibody therapy and an anthracycline containing regimen. Patients with CNS lymphoma, a history of allogeneic stem cell transplantation (SCT) or prior anti-CD19 CAR or other genetically modified T-cell therapy were excluded. 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%, or autoimmune disease requiring systemic immunosuppression were ineligible. The median duration of follow up was 51.1 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 (ITT) Cohort 1 + 2 (N = 111) | All treated (mITT) Cohort 1 + 2 (N = 101) |
| Age (years) | ||
| Median (min, max) | 58 (23, 76) | 58 (23, 76) |
| > 65 | 23% | 24% |
| Male gender | 69% | 67% |
| Race | ||
| 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% |
Yescarta was administered as a single infusion at a target dose of 2 × 106 anti-CD19 CAR T cells/kg after lymphodepleting chemotherapy regimen of 500 mg/m2 intravenous cyclophosphamide and 30 mg/m2 intravenous fludarabine on the 5th, 4th, and 3rd day before Yescarta. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. All patients were hospitalized 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 cell delivery. One out of 111 patients did not receive the product due to manufacturing failure. The median time from leukapheresis to product delivery was 17 days (range: 14 to 51 days), and the median time from leukapheresis to infusion was 24 days (range: 16 to 73 days). The median dose was 2.0 × 106 anti-CD19 CAR T cells/kg. ITT was defined as all patients who underwent leukapheresis; mITT was defined as all patients who received Yescarta.
The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR), overall survival (OS), and severity of adverse events. The ORR was prespecified to be 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 ORR was 72% and the complete response (CR) rate was 51%, as determined by an independent review committee. In the 12-month follow-up analysis (Table 5), the ORR was 72% and the CR rate was 51%. The median time to response was 1.0 months (range: 0.8 to 6.3 months). The DOR was longer in patients who achieved CR, as compared to patients with a best response of partial response (PR). Of the 52 patients who achieved CR, 7 patients had SD and 9 had PR at their initial tumour assessment and converted to CR as late as 6.5 months. The ORR results within PMBCL and DLBCL arising from follicular lymphoma were both 88%. CR rates were 75% and 56%, respectively. Of the 111 patients in the ITT population, the ORR was 66% and the CR was 47%. Other outcomes were consistent with those of the mITT population.
In the 24-month follow-up analysis, based on the mITT population (results from an independent review committee), the ORR and the CR rate were 74% and 54%, respectively. The median time to response 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, 7 patients had SD and 10 had PR at their initial tumour assessment and converted to CR as late as 12 months after Yescarta infusion. Median duration of response and median overall survival had not been reached (Table 5). In a 36-month analysis (median study follow-up of 39.1 months) the median overall survival was 25.8 months with 47 patients (47*%) still alive. In a 48-month analysis (median study follow-up of 51.1 months) the median overall survival was 25.8 months with 43 patients (44*%) still alive.
*The Kaplan-Meier estimates of the 3-year and 4-year OS rates were 47% and 44% respectively.
In the phase 1 part of ZUMA-1, 7 patients were treated. Five patients responded, including 4 CRs. At the 12-month follow-up analysis, 3 patients remained in CR 24 months after Yescarta infusion. At the 24-month follow-up analysis, these 3 patients remained in CR at 30 to 35 months after Yescarta infusion.
Table 5. Summary of efficacy results for ZUMA-1 phase 2
| Category | All leukapheresed (ITT) Cohort 1 + 2 (N = 111) | All treated (mITT) Cohort 1 + 2 (N = 101) | ||
| 12-month analysis | 24-month analysis | 12-month analysis | 24-month analysis | |
| ORR (%) [95% CI] | 66 (56, 75) | 68 (58, 76) | 72 (62, 81) | 74 (65, 82) |
| CR (%) | 47 | 50 | 51 | 54 |
| Category | All leukapheresed (ITT) Cohort 1 + 2 (N = 111) | All treated (mITT) Cohort 1 + 2 (N = 101) | ||
| 12-month analysis | 24-month analysis | 12-month analysis | 24-month analysis | |
| ORR (%) [95% CI] | 66 (56, 75) | 68 (58, 76) | 72 (62, 81) | 74 (65, 82) |
| Duration of Response3, median (range) in months | 14.0 (0.0, 17.3) | NE (0.0, 29.5) | 14.0 (0.0, 17.3) | NE (0.0, 29.5) |
| Duration of Response3, CR, median (range) in months | NE (0.4, 17.3) | NE (0.4, 29.5) | NE (0.4, 17.3) | NE (0.4, 29.5) |
| Overall Survival, 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) |
NE= Not estimable (not reached)
a Duration of response was censored at the time of SCT for subjects 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 of 27.1 months. OS relates to the time from the leukapheresis date (ITT) or Yescarta infusion (mITT) to death from any 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 rate of 20% and historical context for interpreting the ZUMA-1 results. The analysis included patients who had 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 of 6.3 months.
5.2 Pharmacokinetic properties
Peak levels of anti-CD19 CAR T cells occurred within the first 8 to 15 days after Yescarta infusion. The median peak level of anti-CD19 CAR T cells in the blood (Cmax) was 38.3 cells/pL (range: 0.8 to 1513.7 cells/pL), which decreased to a median of 2.1 cells/pL by 1 month (range: 0 to 167.4 cells/pL) and to a median of 0.4 cells/pL by 3 months (range: 0 to 28.4 cells/pL) after Yescarta infusion.
Age (range: 23 to 76 years) and sex had no significant impact on AUC and Cmax of Yescarta.
The number of anti-CD19 CAR T cells in the blood was positively associated with objective response (CR or PR). The median anti-CD19 CAR T cell Cmax level in responders (N = 71) was 216% higher compared to the corresponding level in nonresponders (N = 25) (43.6 cells/pL versus 20.2 cells/pL). Median AUCDay 0–28 in responding patients (N = 71) was 253% of the corresponding level in nonresponders (N = 25) (562.0 days x cells/pL versus 222.0 days x cells/pL).
Yescarta comprises human autologous T cells. The anticipated metabolic products are typical cellular degradation products resulting from normal cellular clearance mechanisms. Thus, the infused CAR T cells are expected to be cleared over time. Anti-CD19 CAR T cell levels decreased toward background levels by Month 3 after infusion.
Studies of Yescarta in patients with hepatic and renal impairment were not conducted.
5.3 Preclinical safety data
Yescarta comprises engineered human T cells, therefore there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human 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, and development.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Cryostor CS10
Sodium chloride
Human albumin
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
Yescarta is stable for 1 year when stored frozen in the vapour phase of liquid nitrogen (< –150 °C).
The stability of Yescarta upon completion of thawing is up to 3 hours at room temperature (20 °C to 25 °C). However, Yescarta infusion should begin within 30 minutes of thaw completion and the total Yescarta infusion time should not exceed 30 minutes. Thawed product should not be refrozen.
6.4 Special precautions for storage
Yescarta bags must be stored in the vapour phase of liquid nitrogen (< –150 °C) and Yescarta must remain frozen until the patient is ready for treatment to ensure viable live autologous cells are administered to the patient.
For storage conditions after thawing of the medicinal product, see section 6.3.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
Irradiation could lead to inactivation of the product.
Precautions to be taken for transport and disposal of the medicinal product
Yescarta should be transported within the facility in closed, break-proof, leak-proof containers.
Yescarta contains genetically-modified human blood cells. Local guidelines on handling of waste of human-derived material should be followed for unused medicinal products or waste material. All material that has been in contact with Yescarta (solid and liquid waste) should be handled and disposed of in accordance with local guidelines on handling of waste of human-derived material.
Accidental exposure to Yescarta must be avoided. Local guidelines on handling of waste of human derived-materials should be followed in case of accidental exposure, which may include washing of the contaminated skin, and removal of contaminated clothes. Work surfaces and materials which have potentially been in contact with Yescarta must be decontaminated with appropriate disinfectant.
7. MARKETING AUTHORISATION HOLDER
Kite Pharma EU B.V.
Tufsteen 1
2132 NT Hoofddorp
The Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/18/1299/001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23 August 2018