Elrexfio

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: L01FX32 Mechanism of action Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T cells and B-cell maturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells.‍‍‍‍‍‍​​​‍​​​​​​ Binding of elranatamab to BCMA on tumour cells and CD3 on T cells is independent of native T cell receptor (TCR) specificity or reliance on major histocompatibility (MHC) Class 1 molecules. Elranatamab activated T cells, led to proinflammatory cytokine release, and resulted in multiple myeloma cell lysis. Pharmacodynamic effects Immunogenicity During treatment with elranatamab at the recommended dose in the MagnetisMM-3 study, anti-drug antibodies (ADA) were detected in 9.5% participants. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed; however, data are still limited. Clinical efficacy and safety Relapsed or refractory multiple myeloma The efficacy of ELREXFIO monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, non-randomised, multi-centre, Phase 2 study (MagnetisMM-3). The study included patients who were refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD) and one anti-CD38 monoclonal antibody. MagnetisMM-3 included 123 patients naïve to prior BCMA-directed therapy (pivotal Cohort A). Patients had measurable disease by international myeloma working group (IMWG) criteria at enrolment. The study included patients with an ECOG score of ≤ 2, adequate baseline bone marrow (absolute neutrophil count ≥ 1.0 × 10 9 /L, platelet count ≥ 25 × 10 9 /L, haemoglobin level ≥ 8 g/dL), renal (CrCL ≥ 30 mL/min), and hepatic [aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN)], total bilirubin ≤ 2 × ULN] function, and left‑ventricular ejection fraction ≥ 40%. Patients with smouldering multiple myeloma, active plasma cell leukaemia, amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes) syndrome, stem cell transplant within 12 weeks prior to enrolment, active infections, and clinically significant neuropathies and cardiovascular disease, were excluded from the study. Patients received subcutaneous administration of ELREXFIO at step-up doses of 12 mg on Day 1 and 32 mg on Day 4 of treatment, followed by the first full treatment dose of ELREXFIO (76 mg) on Day 8 of treatment. Thereafter, patients received 76 mg once weekly. After 24 weeks, in patients who achieved an IMWG response category of partial response or better with responses persisting for at least 2 months, the dosing interval was changed from every week to every 2 weeks, and from every 2 weeks to every 4 weeks after at least 24 weeks of 76 mg every 2 weeks dosing (see section 4.2). Among the 123 patients treated in pivotal Cohort A, the median age was 68 (range: 36 to 89) years with 19.5% of patients ≥ 75 years of age. 44.7% were female; 58.5% were White, 13.0% were Asian, 8.9% were Hispanic/Latino, and 7.3% were Black. Disease stage (R-ISS) at study entry was 22.8% in Stage I, 55.3% in Stage II, and 15.4% in Stage III. The median time since initial diagnosis of multiple myeloma to enrolment was 72.9 (range: 16 to 228) months. Patients had received a median of 5 prior lines of therapy (range: 2 to 22); with 96.0% who received ≥ 3 prior lines of therapy. 96.7% were triple-class refractory and 95.9% refractory to their last line of therapy. 68.3% received prior autologous stem cell transplantation, and 5.7% received prior allogenic stem cell transplantation. High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] were present in 25.2% of patients. 31.7% of patients had extramedullary disease [presence of any plasmacytoma (extramedullary and/or paramedullary) with a soft-tissue component] by blinded independent central review (BICR) at baseline. Efficacy results were based on response rate and duration of response (DOR), as assessed by BICR based on the IMWG criteria. Efficacy results from pivotal Cohort A are shown in Table 7. The median (range) follow-up from initial dose for responders was 27.9 (3.6, 36.8) months. Table 7. Efficacy results for MagnetisMM-3 in pivotal Cohort A BCMA-directed therapy naïve patients (pivotal Cohort A) All treated (N=123) Objective response rate (ORR: sCR+CR+VGPR+PR), n (%) (95% CI) 75 (61.0%) (51.8, 69.6) Stringent complete response (sCR) 20 (16.3%) Complete response (CR) 26 (21.1%) Very good partial response (VGPR) 23 (18.7%) Partial response (PR) 6 (4.9%) Complete response rate (sCR+CR), n (%) (95% CI) 46 (37.4%) (28.8, 46.6) Time to first response (months) Number of responders Median Range 75 1.22 (0.9, 7.4) Duration of response (DOR) (months) Number of responders Median (95% CI) Rate at 12 months (95% CI) Rate at 24 months (95% CI) 75 NE (NE, NE) 73.4 (61.4, 82.1) 66.9 (54.4, 76.7) MRD-negativity rate a in patients achieving CR or sCR and evaluable for MRD (31 of the 46 patients who reached CR/sCR were evaluable for MRD) n (%) 95% CI (%) 28 (90.3%) (74.2, 98.0) Abbreviations: CI=confidence interval; NE=not estimable; MRD=minimal residual disease. a. By threshold 10 -5 , next generation sequencing clonoSEQ assay (Adaptive Biotechnologies). Paediatric population The licensing authority has waived the obligation to submit the results of studies with ELREXFIO in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use). This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The licensing authority will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.