Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: 7. MARKETING AUTHORISATION HOLDER, Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium
Teclistamab is a full-size, IgG4-PAA bispecific antibody that targets the CD3 receptor expressed on the surface of T cells and B cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. With its dual binding sites, teclistamab is able to draw CD3+ T cells in close proximity to BCMA+ cells, resulting in T cell activation and subsequent lysis and death of BCMA+ cells, which is mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. This effect occurs without regard to T cell receptor specificity or reliance on major histocompatibility complex (MHC) Class 1 molecules on the surface of antigen presenting cells.
Within the first month of treatment, activation of T-cells, redistribution of T-cells, reduction of B-cells and induction of serum cytokines were observed.
Within one month of treatment with teclistamab, the majority of responders had reduction in soluble BCMA, and a greater reduction in soluble BCMA was observed in subjects with deeper responses to teclistamab.
The efficacy of TECVAYLI monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multi-centre, Phase ½ study (MajesTEC-1). The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients who experienced stroke or seizure within the past 6 months, and patients with Eastern Cooperative Oncology Group performance score (ECOG PS) ≥2, plasma cell leukaemia, known active CNS involvement or exhibited clinical signs of meningeal involvement of multiple myeloma, or active or documented history of autoimmune disease with the exception of vitiligo, Type 1 diabetes and prior autoimmune thyroiditis.
Patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg of TECVAYLI administered subcutaneously, followed by the maintenance dose of TECVAYLI 1.5 mg/kg, administered subcutaneously once weekly thereafter, until disease progression or unacceptable toxicity (see section 4.2). The median duration between Step-up Dose 1 and Step-up Dose 2 was 2.9 (Range: 2-7) days. The median duration between Step-up Dose 2 and the initial maintenance dose was 3.1 (Range: 2-9) days. Patients were hospitalised for monitoring for at least 48 hours after administration of each dose of the TECVAYLI Step-up dosing schedule.
The efficacy population included 165 patients. The median age was 64 (Range: 33-84) years with 15% of subjects ≥75 years of age; 58% were male; 81% were White, 13% were Black, 2% were Asian. The International Staging System (ISS) at study entry was 52% in Stage I, 35% in Stage II and 12% in Stage III. High-risk cytogenetics (presence of del(17p), t(4;14) or t(14;16)) were present in 26% of patients. Seventeen percent of patients had extramedullary plasmacytomas.
The median time since initial diagnosis of multiple myeloma to enrolment was 6 (Range: 0.8-22.7) years. The median number of prior therapies was 5 (Range: 2-14), with 23% of patients who received 3 prior therapies. Eighty-two percent of patients received prior autologous stem cell transplantation, and 4.8% of patients received prior allogenic transplantation. Seventy-eight percent of patients were triple-class refractory (refractory to proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody).
Efficacy results were based on overall response rate, as determined by the Independent Review Committee (IRC) assessment, using International Myeloma Working Group (IMWG) 2016 criteria (see Table 7).
Table 7. Efficacy results for MajesTEC-1:
| All Treated (N=165) | |
|---|---|
| Overall response rate (ORR: sCR, CR, VGPR, PR) n(%) | 104 (63.0%) |
| 95% CI (%) | (55.2%, 70.4%) |
| Stringent complete response (sCR) | 54 (32.7%) |
| Complete response (CR) | 11 (6.7%) |
| Very good partial response (VGPR) | 32 (19.4%) |
| Partial response (PR) | 7 (4.2%) |
| Duration of Response (DOR) (months) | |
| Number of Responders DOR (Months): Median (95% CI) | 104 18.4 (14.9, NE)1 |
| Time to First Response (months) | |
| Number of responders Median Range | 104 1.2 (0.2; 5.5) |
| MRD negativity rate2 in all treated patients, n (%) [N=165] | 44 (26.7%) |
| 95% CI (%) | (20.1%, 34.1%) |
| MRD negativity rate2,3 in patients achieving CR or sCR, n (%) [N=65] | 30 (46.2%) |
| 95% CI (%) | (33.7%, 59.0%) |
1 NE=not estimable
2 MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10-5) at any timepoint after initial dose, and prior to progressive disease (PD) or subsequent anti-myeloma therapy.
3 Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy (exclusive) are considered.
The European Medicines Agency has waived the obligation to submit the results of studies with TECVAYLI in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).
Teclistamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose range of 0.08 mg/kg to 3 mg/kg (0.05 to 2.0 times the recommended dose). The mean accumulation ratio following subcutaneous weekly dosing of teclistamab at steady state (based on the 7th weekly maintenance dose), was 2.71- and 3.05-fold for Cmax and AUCtau, respectively. The mean bioavailability following teclistamab subcutaneous administration was 69%, relative to intravenous dosing.
Pharmacokinetic parameters of teclistamab following the 1st and 7th recommended maintenance dose of 1.5 mg/kg are shown in Table 8.
Table 8. Pharmacokinetic parameters of teclistamab following the at first and seventh recommended maintenance dose (1.5 mg/kg) in patients with relapsed or refractory multiple myeloma in MajesTEC-1:
| Pharmacokinetic Parameters | 1st maintenance dose of 1.5 mg/kg | 7th maintenance dose of 1.5 mg/kg (steady-state) |
|---|---|---|
| Tmax (hours) | 72.0 (45.8–193) (n=40) | 48.9 (0.0–166) (n=15) |
| Cmax (µg/mL) | 8.74 ± 3.65 (n=40) | 25.3 ± 11.1 (n=15) |
| Ctrough (µg/mL) | 7.67 ± 3.52 (n=38) | 22.1 ± 10.9 (n=27) |
| AUCtau (µg·h/mL) | 1 169 ± 481 (n=38) | 3 905 ± 1 748 (n=13) |
Tmax = Time to reach the Cmax; Cmax = Maximum observed serum teclistamab concentration; Ctrough = Observed serum teclistamab concentration prior to next dose; AUCtau = Area under the concentration-time curve over the weekly dosing interval. Data are presented as mean ± standard deviation, except for Tmax which is presented as median (minimum, maximum).
Based on the population pharmacokinetic model, mean volume of distribution was 4.13 L (48.8% CV (coefficient of variation)) for the central compartment, and 1.34 L for the peripheral compartment.
Teclistamab exhibited both time-independent and time-dependent clearance. Based on the population pharmacokinetic model, the mean time-independent clearance of teclistamab is 0.449 L/day (53.6% CV), with the median of time-dependent clearance contributing approximately 43% of the total clearance at baseline and decreasing rapidly thereafter to less than 10% after Week 8.
Based on non-compartmental analysis, the mean half-life (SD) was 3.8 (1.7) days (individual values ranging up to 8.8 days) following the first treatment intravenous dose of teclistamab.
Population pharmacokinetic analysis (based on MajesTEC-1) showed that soluble BCMA did not impact teclistamab serum concentrations.
The pharmacokinetics of TECVAYLI in paediatric patients aged 17 years and younger have not been investigated.
Results of population pharmacokinetic analyses indicate that age (24 to 84 years) and sex did not influence the pharmacokinetics of teclistamab.
No formal studies of TECVAYLI in patients with renal impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m² ≤ estimated glomerular filtration rate (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 teclistamab. Limited data are available from patients with severe renal impairment.
No formal studies of TECVAYLI in patients with hepatic impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin >1 to 1.5 times upper limit of normal (ULN) and any aspartate aminotransferase (AST), or total bilirubin ≤ULN and AST>ULN) did not significantly influence the pharmacokinetics of teclistamab. No data are available in patients with moderate and severe hepatic impairment.
No animal studies have been performed to assess the carcinogenic or genotoxic potential of teclistamab.
No animal studies have been conducted to evaluate the effects of teclistamab on reproduction and foetal development. In the 5-week repeat-dose toxicity study in cynomolgus monkeys, there were no notable effects in the male and female reproductive organs at doses up to 30 mg/kg/week (approximately 22 times the maximum recommended human dose, based on AUC exposure) intravenously for five weeks.
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