EBVALLO Dispersion for injection Ref.[50629] Active ingredients: Tabelecleucel

Pharmacotherapeutic group: not yet assigned
ATC code: not yet assigned

Mechanism of action

Ebvallo is an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates EBV-infected cells in an HLA-restricted manner. Ebvallo has an equivalent mechanism of action to that demonstrated by endogenous circulating T cells in the donors from which the medicinal product is derived. The T-cell receptor of each clonal population within Ebvallo recognises an EBV peptide in complex with a specific HLA molecule on the surface of target cells (the restricting HLA allele) and allows the medicinal product to exert cytotoxic activity against the EBV-infected cells.

Pharmacodynamic effects

Across multiple clinical studies, systemic cytokine levels of IL-1β, IL-2, IL-6 and TNFα did not meaningfully change from baseline after administration of Ebvallo.

Clinical efficacy and safety

ALLELE is an ongoing, multicentre, open-label, single-arm, Phase 3 study in 43 adult and paediatric patients with EBV+ PTLD following solid organ transplant (SOT) or haematopoietic cell transplant (HCT) after failure of previous therapy. Patients were assigned to prespecified cohorts based on transplant type and treatment failure of prior therapy for EBV+ PTLD. The SOT cohort (29 patients) consisted of SOT patients who had failed rituximab monotherapy (13 patients) and SOT patients who had failed rituximab plus chemotherapy (SOT-R+C, 16 patients). The HCT cohort (14 patients) consisted of HCT patients who had failed rituximab. Eligible patients had a prior HCT or SOT (kidney, liver, heart, lung, pancreas, small bowel or any combination), a diagnosis of biopsy-proven EBV+ PTLD with radiographic measurable disease, and failure of rituximab monotherapy or rituximab plus any concurrent or sequentially administered chemotherapy regimen for treatment of EBV+ PTLD. The most commonly administered chemotherapy combination was cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone. Patients with Grade ≥ 2 graft-versus-host disease (GvHD), active central nervous system (CNS) PTLD, Burkitt lymphoma, classical Hodgkin lymphoma, or any T-cell lymphoma were excluded. Patients received standard prophylactic anti-viral therapy until 30 days after the last dose of Ebvallo. Table 3 summarises the demographics and baseline characteristics from the SOT-R+C and HCT indicated cohorts.

Table 3. Summary of demographics and baseline characteristics in ALLELE from cohorts SOTR+C and HCT:

DLBCL = diffuse large B-cell lymphoma; EBV+ PTLD = Epstein-Barr virus positive post-transplant lymphoproliferative disease; ECOG = Eastern Cooperative Oncology Group; HCT = haematopoietic cell transplant; LDH = lactate dehydrogenase; max = maximum; min = minimum; SOT = solid organ transplant; SOT-R+C = SOT patients who had failed rituximab plus chemotherapy
^a Patients received at least one dose of Ebvallo.
^b SOT types included kidney, heart, liver, lung, pancreas, bowel and multiviscera.
^c Percentages for ECOG and Lansky scores were based on the number of patients in the corresponding age group.
^d Disease risk for PTLD patients was assessed at baseline using the PTLD-adapted prognostic index (based on age, ECOG score and serum LDH level).
^e Morphologies not clearly DLBCL or plasmablastic lymphoma were categorized as Other and were consistent with PTLD. f Chemotherapy regimens could have also been combined with rituximab or other immunotherapy agents.

The primary efficacy endpoint was objective response rate (ORR) per evaluation by independent oncologic response adjudication (IORA), using Lugano classification criteria with lymphoma response to immunomodulatory therapy criteria (LYRIC) modification. ORR was obtained following administration of Ebvallo with up to 2 different HLA restrictions (one restriction switch). Ebvallo was selected for each patient from an existing product inventory based on an appropriate HLA restriction. The treatment plan consisted of administration of Ebvallo by intravenous injection at 2 × 10⁶ viable T cells/kg on days 1, 8 and 15 followed by observation through day 35, during which a response was assessed at approximately day 28. The number of cycles of Ebvallo administered to patients was determined by the response to treatment as shown in Table 1 (see section 4.2). Seventeen (39.5%) patients required treatment with an Ebvallo lot that had a different HLA restriction (restriction switch). Of these 17 patients, 15 received one restriction switch, 2 received 2 restriction switches and 5 (29.4%) patients achieved a first response following the first restriction switch. Table 4 summarises efficacy results from the SOT-R+C and HCT indicated cohorts.

Table 4. Summary of efficacy results in ALLELE from cohorts SOT-R+C and HCT:

CI = confidence interval; DOR = duration of response; EBV+ PTLD = Epstein-Barr virus positive post-transplant lymphoproliferative disease; HCT = haematopoietic cell transplant; KM = Kaplan-Meier; max = maximum; min = minimum; NE = not estimable; SOT = solid organ transplant; SOT-R+C = SOT patients who had failed rituximab plus chemotherapy
^a Patients received at least one dose of Ebvallo.
^b Objective response rate was the proportion of patients who achieved a response (complete response or partial response).
^c Independent oncologic response adjudication (IORA)-assessed response.

Special populations

Elderly

Based on limited data, no overall differences in efficacy were observed between patients ≥65 years of age and younger. Seventeen patients were ≥65 to <75 years of age, 3 patients were ≥75 to <85 years of age, no patients were ≥85 years of age.

Paediatric population

Paediatric patients with EBV+ PTLD 2 years of age and older were treated with Ebvallo. Eight patients were ≥2 to <6 years of age, 16 patients were ≥6 to <12 years of age, 17 patients were ≥12 to <18 years of age. Based on limited data, the efficacy and safety results in paediatric patients were consistent with those in adults.

The European Medicines Agency has deferred the obligation to submit the results of studies with Ebvallo in one or more subsets of the paediatric population in the treatment of Epstein-Barr virus associated post-transplant lymphoproliferative disorder (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.