Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates
ATC code: not yet assigned
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.
During treatment with elranatamab at the recommended dose, anti-drug antibodies (ADA) were detected in 8.3% participants. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed; however, data are still limited.
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 × 109/L, platelet count ≥25 × 109/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 (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 15.2 (2.4, 24.2) 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) | 19 (15.4%) |
| Complete response (CR) | 25 (20.3%) |
| Very good partial response (VGPR) | 25 (20.3%) |
| Partial response (PR) | 6 (4.9%) |
| Complete response rate (sCR+CR), n (%) (95% CI) | 44 (35.8%) (27.3, 44.9) |
| 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 6 months (95% CI) Rate at 9 months (95% CI) Rate at 12 months (95% CI) Rate at 15 months (95% CI) | 75 NE (NE, NE) 89.1 (79.5, 94.4) 80.7 (69.5, 88.1) 74.3 (62.3, 83.0) 70.8 (58.2, 80.2) |
| MRD-negativity ratea in patients achieving CR or sCR and evaluable for MRD (29 of the 44 patients who reached CR/CRs were evaluable for MRD) n (%) 95% CI (%) | 26 (89.7%) (72.7, 97.8) |
Abbreviations: CI=confidence interval; NE=not estimable; MRD=minimal residual disease.
a By threshold 10-5, next generation sequencing clonoSEQ assay (Adaptive Biotechnologies).
The European Medicines Agency 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 European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Pharmacokinetic parameters are presented as geometric mean (coefficient of variation [CV]%) for unbound elranatamab unless otherwise specified. The Cmax and AUCtau of elranatamab after the first subcutaneous dose increased in a dose proportional manner over the evaluated dose range via subcutaneous administration (~6 to 76 mg). The median accumulation ratio after 24 weeks of weekly dosing relative to the first subcutaneous dose of elranatamab 76 mg for Cmax and AUCtau was 6.6-fold and 11.2-fold, respectively. The predicted Cavg, Cmax, and Ctrough of elranatamab are presented in Table 8.
Table 8. Predicted pharmacokinetic parameters of elranatamab following the recommended dose:
| Timepoint | Parameters | ||
|---|---|---|---|
| Cavg (mcg/mL) | Cmax (mcg/mL) | Ctrough (mcg/mL) | |
| End of weekly dose (week 24) | 32.7 (49%) | 33.6 (48%) | 31.2 (50%) |
| Steady state (every two weeks dosing)a,b | 18.4 (57%) | 20.1 (55%) | 15.9 (64%) |
a In patients who have achieved a response.
b Steady state exposure of elranatamab every two weeks dose is approximated at week 48.
The predicted mean bioavailability of elranatamab was 56.2% when administered subcutaneously. The median Tmax after elranatamab SC administration across all dose levels ranged from 3 to 7 days.
Based on the population pharmacokinetic model, the predicted mean volume of distribution of unbound elranatamab was 4.78 L, 69% (CV) for the central compartment, and 2.83 L for the peripheral compartment.
The predicted geometric mean half-life of elranatamab is 22, 64% (CV) days at week 24 following doses of 76 mg weekly. Based on the population pharmacokinetic model, the predicted mean elranatamab clearance was 0.324 L/day, 69% (CV).
No clinically relevant differences in the pharmacokinetics of elranatamab were observed based on age (36 to 89 years), sex (167 male, 154 female), race (193 White, 49 Asian, 29 Black), and body weight (37 to 160 kg).
No studies of elranatamab in patients with renal impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m² ≤ eGFR < 90 mL/min/1.73 m²) or moderate renal impairment (30 mL/min/1.73 m² ≤ eGFR < 60 mL/min/1.73 m²) did not significantly influence the pharmacokinetics of elranatamab. Limited data are available from patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).
No studies of elranatamab in patients with hepatic impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin >1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN) did not significantly influence the pharmacokinetics of elranatamab. No data are available in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe (total bilirubin >3.0 × ULN and any AST) hepatic impairment.
No animal studies have been performed to assess the carcinogenic or genotoxic potential of elranatamab.
No animal studies have been performed to evaluate the effects of elranatamab on fertility or reproduction and foetal development.
In a 13-week repeat-dose toxicity study in sexually mature cynomolgus monkeys, there were no notable effects on male and female reproductive organs following subcutaneous doses up to 6 mg/kg/week (approximately 6.5 times the maximum recommended human dose, based on AUC exposure).
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