KYMRIAH Dispersion for infusion Ref.[8681] Active ingredients: Tisagenlecleucel

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents
ATC code: L01XL04

Mechanism of action

Tisagenlecleucel is an autologous, immunocellular cancer therapy which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19 expressing cells. The CAR is comprised of a murine single chain antibody fragment which recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and anti-tumour activity, while 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19-expressing cells, the CAR transmits a signal promoting T-cell expansion and persistence of tisagenlecleucel.

Clinical efficacy and safety

Acute lymphoblastic leukaemia (ALL)

The safety and efficacy of Kymriah treatment in paediatric and young adult patients up to and including 25 years of age, with relapsed or refractory (r/r) B-cell ALL were evaluated in a total of 203 patients in one pivotal (B2202, N=79) and two supportive (B2205J, N=64, and B2101J, N=60) open-label, single-arm phase I/II studies. All patients had leukapheresis products collected and cryopreserved prior to or during study entry.

The pivotal study B2202 (ELIANA) is a multicentre, single-arm phase II study in paediatric and young adult patients with r/r B-cell ALL. Of 97 patients enrolled in the main cohort, 79 received infusion with Kymriah; for 8 patients (8%) Kymriah could not be manufactured; reasons for discontinuation prior to Kymriah infusion included death (n=7; 7%) or adverse events (n=3; 3%) while awaiting Kymriah manufacturing in the clinical study. The median duration of study follow-up defined as the time from Kymriah infusion to the date of completion or discontinuation from follow-up prior to the data cut-off date was 28.5 months (range: 0.4-65.5). The median time from Kymriah infusion to the data cut-off date was 79.4 months (range: 59.7-90.3).

Key baseline information for enrolled and infused patients is presented in Table 3. The majority of patients (69/79, 87%) received bridging therapy while waiting for Kymriah. A total of 76 out of 79 patients (96%) who received Kymriah infusion also received lymphodepleting chemotherapy after enrolment and prior to infusion of a single dose of Kymriah (see section 4.2 for condition of lymphodepleting chemotherapy).

Table 3. Study B2202: Baseline information across the enrolled and the infused patient population:

¹ Primary refractory: Never had a morphologic complete remission (CR) prior to the study;
² Relapsed disease: Had at least one relapse prior to the study

Efficacy was established through the primary endpoint of overall remission rate (ORR), which includes best overall response as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) within 3 months post infusion, as determined by Independent Review Committee (IRC) assessment, as well as secondary endpoints including duration of remission (DOR) and the proportion of patients who achieved CR or CRi with minimal residual disease (MRD) <0.01% by flow cytometry (MRD-negative). See Table 4 for efficacy results from this study. ORR was consistent across all subgroups. Eight patients (10.1%) who achieved CR/CRi after Kymriah infusion went to haematopoietic stem cell transplant while in remission of which 6 of the patients (7.6%) proceeded to transplant within the first 6 months post-infusion while in remission. Kymriah was administered in a qualified Kymriah treatment centre in an inpatient and outpatient setting.

Table 4. Study B2202: Efficacy results in paediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL):

¹ Requires remission status to be maintained for at least 28 days without clinical evidence of relapse.
62^ Nominal one-sided exact p-value based on H0: ORR ≤20% vs. Ha: ORR >20%
³ CR (complete remission) was defined as <5% of blasts in the bone marrow, circulating blasts in blood should be <1%, no evidence of extramedullary disease, and full recovery of peripheral blood counts (platelets >100,000/μL and absolute neutrophil counts [ANC] >1,000/μL) without blood transfusion.
⁴ CRi (complete remission with incomplete blood count recovery) was defined as <5% of blasts in the bone marrow, circulating blasts in blood should be <1%, no evidence of extramedullary disease, and without full recovery of peripheral blood counts with or without blood transfusion.
⁵ MRD (minimal residual disease) negative was defined as MRD by flow cytometry <0.01%.
⁶ Nominal one-sided exact p-value based on H0: Rate of MRD negative remission ≤15% vs. Ha: >15%.
⁷ DOR was defined as time since onset of CR or CRi to relapse or death due to underlying indication, whichever is earlier (N=66). One patient achieved remission after month 3.
⁸ OS was defined as time from date of Kymriah infusion to the date of death due to any cause for infused patients and from time of date of enrolment to the date of death due to any cause for enrolled patients.
⁹ Not estimable.

The supportive study B2205J (ENSIGN) was a multicentre single-arm phase II study in paediatric and young adult patients with r/r B‑cell ALL. The study had similar study design and enrolled comparable patient populations as the pivotal study B2202. The main difference between the two studies was the definition of the primary efficacy endpoint ORR, which was measured within 6 months after Kymriah infusion in study B2205J compared to 3 months in the pivotal study. Of 75 patients enrolled, 64 received infusion of Kymriah; for 5 patients (6.7%), Kymriah could not be manufactured and 6 patients (8.0%) died while awaiting Kymriah manufacturing in the clinical study. The median duration of study follow-up defined as the time from Kymriah infusion to the date of completion or discontinuation from follow-up prior to the data cut-off date in the final analyses was 12.2 months (range: 0.4-49.3). The median time from Kymriah infusion to the data cut-off date was 31.7 months (range: 17.6-56.0).

Among the patients infused, the median age was 12.5 years (range: 3 to 25), 34 (53.1%) were female and 30 (46.9%) were male, 10.9% had primary refractory disease, 89.1% had relapsed disease, and 43.8% of patients had at least one prior haematopoietic stem cell transplant. Baseline disease characteristics were similar in the enrolled patients with regard to age (median age 13.0 years, range: 3 to 25), gender (46.7% female and 53.3% male), primary refractoriness (10.7%), and prior transplant history (42.7%). The majority of infused patients (57/64, 89.1%) received bridging chemotherapy while waiting for Kymriah. A total of 60 out of 64 patients (93.8%) who received Kymriah infusion also received lymphodepleting chemotherapy after enrolment and prior to infusion of a single dose of Kymriah.

Efficacy was established through the primary endpoint of ORR, which included best overall response as CR or CRi that were maintained for at least 28 days within 6 months post-infusion, as determined by IRC assessment, as well as secondary endpoints including DOR, proportion of patients who achieved CR or CRi with MRD-negative disease status, and OS. Among the patients infused, ORR was demonstrated in 45 patients (70.3%; 59.4% CR and 10.9% CRi). CR/CRi with MRD-negative bone marrow was reported in 43 patients (67.2%). The median DOR was not reached and the event-free probability at 12 months was 70.5%. The survival probability at 24 months was 54.7%, and the median OS was estimated as 29.9 months (95% CI: 15.1, 42.4). The OS results were confirmed in an updated OS analyses (i.e. median OS 29.9 months [95% CI: 15.2, NE] with 57.6% survival probability at 24 months; with a median follow-up for OS of 25.9 months), which included patients transitioned to a separate long-term follow-up study. Seven patients (10.9%) who achieved CR/CRi after Kymriah infusion proceeded to haematopoietic stem cell transplant while in remission during the study, of which 5 of the patients (7.8%) proceeded to transplant within the first 6 months post-infusion. Efficacy results reported for the enrolled patients (n=75) demonstrate an ORR of 60.0% (50.7% CR and 9.3% CRi; 57.3% with MRD-negative bone marrow). The reported overall survival in the enrolled population is in accordance with the infused population.

Special populations

No differences in efficacy or safety were observed between different age subgroups.

Patients with active CNS leukaemia

Of four patients with active CNS leukaemia (i.e. CNS3) included in study B2101J, three experienced cytokine release syndrome (Grade 24) and transient neurological abnormalities (Grade 13) that resolved within 13 months of infusion. One patient died due to disease progression and the remaining three patients achieved a CR or CRi and remain alive 1.52 years after infusion.

Diffuse large B-cell lymphoma (DLBCL)

The safety and efficacy of Kymriah treatment in adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) who received ≥2 lines of chemotherapy, including rituximab and anthracycline, or relapsed following autologous haematopoietic stem cell transplantation (HSCT), was evaluated in the multicentre, open-label, pivotal, single-arm phase II study C2201 (JULIET). Patients with T-cell rich/histiocyte-rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV-positive DLBCL of the elderly, Richter’s transformation, and Burkitt lymphoma were not enrolled in study C2201.

Of 167 patients enrolled in study C2201, 115 patients received infusion with Kymriah. Approximately 31% of patients discontinued the study prior to Kymriah infusion. For 13 patients (8%) Kymriah could not be manufactured. Other reasons for discontinuation prior to Kymriah infusion included death (n=16; 10%), physician decision/primary disease progression (n=16; 10%), patient decision (n=2; 1%), protocol deviation (n=1; 1%) or adverse events (n=4; 2%) while awaiting Kymriah manufacturing in the clinical study. The median duration of study follow-up defined as the time from Kymriah infusion to date of completion or discontinuation from follow-up prior to the data cut-off date in the final analysis was 7.7 months (range: 0.4-61.0). The median time from Kymriah infusion to the data cut-off date in the final analysis was 74.3 months (range: 58.1-86.6).

Key baseline information for enrolled and infused patients is presented in Table 5. All patients had leukapheresis starting material collected and cryopreserved prior to or during study entry. The majority of patients (103/115, 90%) received bridging therapy for disease stabilisation. The type and duration of bridging therapy was left to the discretion of the physician. 107/115 patients (93%) received lymphodepleting chemotherapy prior to Kymriah infusion. Kymriah was given as a single-dose (0.6-6.0 × 108 CAR-positive viable T cells) intravenous infusion in a qualified Kymriah treatment centre in an inpatient and outpatient setting.

Table 5. Study C2201: Baseline information across the enrolled and the infused patient populations:

The efficacy of Kymriah was evaluated through the primary endpoint of best overall response rate (ORR), which includes complete response (CR) and partial response (PR) as determined by Independent Review Committee (IRC) assessment as well as secondary endpoints including duration of response (Table 6).

Table 6. Study C2201: Efficacy results in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy:

¹ The primary endpoint was analysed on all patients whose Kymriah was manufactured at the Novartis US facility.
² ORR is the proportion of patients with best overall response (BOR) of CR or PR based on the Lugano response criteria (Cheson 2014); non-infused patients were assigned BOR=Unknown (i.e. non-responders).
³ DOR was defined as time from achievement of CR or PR to relapse or death due to DLBCL, whichever occurs first.
⁴ OS was defined as time from date of Kymriah infusion to the date of death due to any cause (N=115) and time from date of enrolment to the date of death due to any cause for enrolled patients (N=167).
⁵ Not estimable.

Among 41 patients who achieved CR, 16 patients initially had an overall disease response of PR which improved to CR over time; most patients (13/16) achieved PR to CR conversion within 6 months post-tisagenlecleucel infusion. ORR was consistent across subgroups.

Follicular lymphoma (FL)

The safety and efficacy of Kymriah treatment in adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) were evaluated in an open label, multicentre, single-arm, phase II study (E2202, N=97).

The pivotal study E2202 (ELARA) included patients who were refractory to or relapsed within 6 months after completion of a second or later line of systemic therapy (including an anti-CD20 antibody and an alkylating agent), relapsed during or within 6 months after completion of anti-CD20 antibody maintenance therapy following at least two lines of therapy, or relapsed after autologous haematopoietic stem cell transplant (HSCT). The study excluded patients with active or serious infections, transformed lymphoma or other aggressive lymphomas, including patients with FL Grade 3b, those who had received prior allogeneic HSCT, or who had disease with active CNS involvement.

Of 98 patients who were enrolled and underwent leukapheresis, 97 patients received infusion with Kymriah. One patient achieved a complete response prior to infusion which was attributed to their prior last line of therapy and was subsequently discontinued from the study due to physician decision prior to infusion. All patients had leukapheresis products collected and cryopreserved prior to or during study entry. Kymriah was delivered for all enrolled patients. The median duration of study follow-up defined as the time from Kymriah infusion to date of completion or discontinuation from follow-up prior to the data cut-off date was 18.6 months (range: 1.8-29.9). The median time from Kymriah infusion to the data cut-off date was 20.8 months (range: 14.4-29.9). The study is still ongoing.

Of the 97 patients infused with Kymriah, 94 patients had measurable disease at baseline per Independent Review Committee (IRC) and are included in the efficacy analysis set (EAS).

Key baseline information for the enrolled set and EAS is presented in Table 7. Approximately half of the patients (44/94; 47%) received bridging therapy for disease stabilisation between leukapheresis and administration of Kymriah and all patients received lymphodepleting chemotherapy. For all infused patients, Kymriah was administered as a single dose intravenous infusion in a qualified treatment centre in an inpatient or outpatient (18%) setting.

Table 7. Study E2202: Baseline information across the enrolled and the EAS patient populations:

^* Infused patients who had measurable disease at baseline per Independent Review Committee (IRC) and are included in the efficacy analysis set.
¹ FLIPI includes 5 labelled prognostic factors; FLIPI = sum (where prognostic factor = ‘Yes’); Low: 0-1 criteria met; intermediate: 2 criteria met; high: 3 or more met.
² Bulky disease defined per IRC as imaging showing any nodal or extra nodal tumour mass that is >7 cm in diameter or involvement of at least 3 nodal sites, each with a diameter >3 cm.
³ Double refractory is defined as patients who failed to respond or relapsed within 6 months following therapy with anti-CD20 and alkylating agents, any regimen
⁴ POD24: subjects with primary refractory or experiencing progression of disease within 24 months from initiation of a first-line anti-CD20 mAb containing treatment.

Efficacy was evaluated through the primary endpoint of complete response rate (CRR), recorded from infusion until progressive disease or start of new therapy. CRR was determined by IRC based on Lugano classification criteria (Cheson 2014). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Median time from enrolment to infusion was 46 days (range: 23 to 127). The first disease assessment was scheduled to be performed at month 3 post-infusion.

Table 8. Study E2202: Efficacy results in adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of therapy:

CI=Confidence interval, NE=Not estimable
^* Infused patients who had measurable disease at baseline per Independent Review Committee (IRC) and are included in the efficacy analysis set.
¹ The primary endpoint was CRR per IRC based on Lugano response criteria (Cheson 2014) and defined as the proportion of patients with a best overall response (BOR) of complete response (CR). The non-infused patient was treated as a non-responder.
² ORR was defined as the proportion of patients with a BOR of CR or partial response (PR). The non-infused patient was treated as a non-responder.
³ DOR was defined as time from achievement of CR or PR to relapse or death due to FL, whichever occurs first.

All responders achieved their first response (CR or PR) at the first disease assessment performed post-infusion, at 3 months. Of the 65 patients who eventually achieved a CR, 15 patients (16%) initially had a PR. The majority of patients converted from PR to CR within 6 months post-infusion. No patient who received Kymriah infusion went to transplant while in response (CR or PR).

The probability for a patient to remain in response (DOR) ≥9 months was 76% (95% CI: 64.9, 84.3), while the probability for a patient who achieved a CR to remain in response ≥9 months was 87% (95% CI: 75.6, 93.3).

Subgroup analyses demonstrated a generally consistent CRR across all subgroups, including the following high-risk prognostic subgroups: high FLIPI score (CRR of 63%), prior HSCT (CRR of 66%), POD24 (CRR of 59%), and double refractoriness (CRR of 66%).

Special populations

There are not enough data to determine whether there are any differences in efficacy or safety between different age subgroups, although the clinical benefit and safety experience in elderly patients with DLBCL and FL above the age of 65 years (23% and 24.7% of the study population for DLBCL and FL, respectively) were comparable to the overall population.

Paediatric population

Study B2401

An observational study (B2401) was conducted to collect long-term safety and efficacy data in patients infused with tisagenlecleucel from the Center for International Blood and Marrow Transplant Research (CIBMTR) and European Society for Blood and Marrow Transplantation (EBMT) registries. The study included 617 (CIBMTR: 570; EBMT: 47) paediatric and young adult patients with r/r B-cell ALL at time of the data cut-off. Kymriah manufacture for patients below 3 years of age and with low weight was feasible; 43 patients (CIBMTR: 40, EBMT: 3) were below 3 years of age at time of infusion. The median time from Kymriah infusion to the data cut-off date of the paediatric and young adult patients with r/r B-cell ALL was 11.8 months for CIBMTR and 9.0 months for EBMT.

Among the patients below 3 years of age included in the efficacy set (n=33), CR (including CRi) as BOR was reported for 26 patients (78.8%) (95% CI: 61.1, 91.0) and all 15 patients in CR (including CRi) and with reported MRD data were MRD-negative during follow-up. The estimated DOR rate at month 12 was 62.7% (95% CI: 35.0, 81.3).

The overall safety experience in patients below 3 years of age with r/r B-cell ALL was generally consistent with the known safety profile of tisagenlecleucel.

Study C2202

A phase II study of tisagenlecleucel (C2202, BIANCA) was conducted in 33 infused patients with relapsed or refractory mature B-cell non-Hodgkin lymphoma (NHL) in children and young adults. Of the 33 patients infused with tisagenlecleucel, 28 patients (24 patients, aged 3-17 years old and 4 patients, aged 20-22 years old) had measurable disease prior to infusion and are included in the efficacy analysis set (EAS).

The EAS included patients with Burkitt lymphoma (n=15), diffuse large B-cell lymphoma (n=8), primary mediastinal B-cell lymphoma (n=3), grey zone lymphoma (n=1) and high-grade lymphoma with MYC and BCL2 rearrangements (n=1). Among these patients, the median age was 14.0 years (range: 3 to 22), 9 (32.1%) were female and 19 (67.9%) were male. The median number of prior lines of therapy was 1 (range:1-3), 17.9% of patients had one prior haematopoietic stem cell transplant. All patients except one (96.4%) received bridging chemotherapy while waiting for tisagenlecleucel. Patients received the approved tisagenlecleucel dose for the paediatric ALL indication.

Results in the EAS showed an ORR of 32.1% (95% CI: 15.9, 52.4), with a CR of 7.1%. Subgroup analysis indicated a lower ORR in patients with Burkitt lymphoma (20%, 95% CI 4.3, 48.1) compared to patients with diffuse large B-cell lymphoma (37.5%, 95% CI: 8.5, 75.5) or other diagnoses included in the study (60.0%, 95% CI: 14.7, 94.7).

The overall safety experience in paediatric and young adult patients with CD19+ r/r mature B-cell NHL infused with tisagenlecleucel in Study C2202 was consistent with the known safety profile of tisagenlecleucel. No new safety signals were observed.

The European Medicines Agency has deferred the obligation to submit the results of studies with Kymriah in one or more subsets of the paediatric population in the treatment of B-cell lymphoblastic lymphoma (see section 4.2 for information on paediatric use).