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

Pharmacotherapeutic group: other antineoplastic agents
ATC code: not yet assigned

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 antitumour 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 with relapsed or refractory (r/r) B-cell ALL were evaluated in one pivotal (B2202) and two supportive (B2205J and B2101J) open-label, single-arm studies (160 patients in total, up to 25 years of age). All patients had leukapheresis products collected and cryopreserved prior to or during study entry.

The pivotal study (B2202) is a multicentre, single-arm phase II study in paediatric and young adult patients with r/r B-cell acute lymphoblastic leukaemia. Of 92 patients enrolled, 75 received infusion with Kymriah; for 7 patients (8%) Kymriah could not be manufactured; reasons for discontinuation prior to Kymriah infusion included death (n=7; 8%) or adverse events (n=3; 3%) while awaiting Kymriah manufacturing in the clinical study.

Key baseline information for enrolled and infused patients is presented in Table 3. A total of 72 out of 75 patients 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) within 3 months post infusion, as determined by Independent Review Committee (IRC) assessment, duration of remission (DOR) and the proportion of patients who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) with minimal residual disease (MRD) <0.01% by flow cytometry (MRD-negative). ORR included CR and CRi. See Table 4 for efficacy results from this study. ORR was consistent across all subgroups. Seven patients who achieved CR/CRi after Kymriah infusion went to transplant while in remission. Kymriah was administered in a qualified Kymriah treatment centre in an inpatient and outpatient setting.

Health-related quality of life (HRQoL) was evaluated by PedsQLTM and EQ-5D questionnaires completed by patients aged 8 years and above (n=58). Among patients responding (n=48), the mean (SD) change from baseline in the PedsQL total score was 13.5 (13.5) at month 3, 16.9 (17.6) at month 6 and 27.2 (21.7) at month 12, and the mean (SD) change from baseline in the EQ-5D VAS score was 16.5 (17.5) at month 3, 15.9 (20.1) at month 6 and 24.7 (18.6) at month 12, indicating overall clinically meaningful improvement in HRQoL following Kymriah infusion.

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. CNS-3) included in study B2101J, three experienced cytokine release syndrome (Grade 2-4) and transient neurological abnormalities (Grade 1-3) that resolved within 1-3 months of infusion. One patient died due to disease progression and the remaining three patients achieved a CR or CRi and remain alive 1.5-2 years after infusion.

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.
² 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=61).
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.

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 an open-label, pivotal, single-arm study. 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.

The pivotal study (C2201) is a multicentre, single-arm phase II study in adult patients with relapsed or refractory DLBCL. Of 165 patients enrolled, 111 patients received infusion with Kymriah (4 infusions were pending at the time of analysis); for 12 patients (7%) Kymriah could not be manufactured. Approximately 30% of patients discontinued the study prior to Kymriah administration. Reasons for discontinuation prior to Kymriah infusion included death (n=16; 10%), physician decision/primary disease progression (n=16; 10%), patient decision (n=3; 2%) or adverse events (n=2; 1%) while awaiting Kymriah manufacturing in the clinical study.

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 (101/111, 91%) received bridging therapy for disease stabilisation. The type and duration of bridging therapy was left to the discretion of the physician. 103/111 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). ORR was consistent across subgroups.

Table 6. Study C2201: Efficacy results in adult patients with relapsed or refractory diffuse:

¹ 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).
² DOR was defined as time from achievement of CR or PR, whichever occurs first, to relapse or death due to DLBCL.
³ OS was defined as time from date of Kymriah infusion to the date of death due to any cause on FAS (N=111) and time from date of enrolment to the date of death due to any cause for enrolled patients (N=165).
⁴ Not estimable.
⁵ Efficacy analysis set (EAS) includes patients infused with Kymriah at least 3 months prior to data cutoff date.
⁶ The primary endpoint was analysed on all patients whose Kymriah was manufactured at the Novartis US facility.
⁷ The full analysis set (FAS) includes all patients infused with Kymriah.

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 above the age of 65 years (23% of the study population) were comparable to the overall population.

Paediatric population

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 following conditions: a) treatment of B-cell lymphoblastic lymphoma, and b) treatment of mature B-cell neoplasms (see section 4.2 for information on paediatric use).