SUMMARY

• MajesTEC-1 (MMY1001) is an ongoing, phase 1/2, multicohort study evaluating the safety and efficacy of TECVAYLI in patients with relapsed or refractory multiple myeloma (RRMM).^1-6
  • Cohort A (triple-class exposed) included 165 patients with RRMM who were previously treated with a proteasome inhibitor (PI), an immunomodulatory agent, and an anti-CD38 monoclonal antibody.¹
    • Moureau et al (2022)^1,3 published a pharmacokinetic (PK) analysis at a median follow-up of 14.1 months (range, 0.3-24.4) in 165 patients treated with TECVAYLI. At the recommended phase 2 dose (RP2D), serum concentrations (C_max) of TECVAYLI measured during the first 4 cycles were maintained above the upper limit of 90% of maximum TECVAYLI exposure (EC₉₀=6 μg/mL).
  • Cohort C included 40 patients with RRMM, previously treated with a PI, an immunomodulatory agent, an anti-CD38 monoclonal antibody and anti-B-cell maturation antigen (BCMA)-targeted therapies.⁷ Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
    • Touzeau et al (2024)⁷ published PK analysis at a median follow-up of 28.0 months (range, 0.7-31.1) in 40 patients treated with TECVAYLI. TECVAYLI C_trough values in patients were comparable to those observed in BCMA-treatment-naïve patients, with mean C_trough consistently above the maximal EC₉₀ value from an ex vivo assay.
  • The prophylactic tocilizumab cohort is evaluating the administration of intravenous (IV) tocilizumab (8 mg/kg) prior to TECVAYLI dosing for the reduction of cytokine release syndrome (CRS) in 24 patients with RRMM.^8,9 Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
    • van de Donk et al (2023)⁸ compared the PK profiles of 8 patients from the phase 1 exploratory prophylactic cohort with those of 40 patients from the MajesTEC-1 phase 1 population treated with TECVAYLI at the RP2D. The timing of induction of cytokines interleukin 6 (IL-6) and IL-10 were compared between the prophylactic tocilizumab cohort and the MajesTEC-1 phase 1 cohort.
• Other relevant data has been identified in addition to the data summarized above:
  • Lee et al (2024)¹⁰ conducted a correlative analysis to evaluate the impact of soluble BCMA (sBCMA) and non-T cell factors on refractoriness to BCMA-targeting T cell engagers in MM using whole genome sequencing and in vitro assays.
  • Quijano Cardé et al (2024)¹¹ evaluated the administration of subcutaneous (SC) TECVAYLI in the arm or thigh in specific cohorts in MajesTEC-1 to assess the impact of SC injection site on TECVAYLI disposition.
  • Cortes-Selva et al (2024)¹² conducted correlative analyses to evaluate the relationship between tumor characteristics and baseline immune profiles with clinical response and disease burden in 165 patients with RRMM who received ≥1 dose of TECVAYLI at the RP2D in the MajesTEC-1 study. Higher baseline total T-cell counts in the periphery were associated with better clinical outcomes for TECVAYLI. Baseline bone marrow BCMA expression or BCMA receptor density did not correlate with clinical response to TECVAYLI.
  • Miao et al (2023)¹³ investigated the population PK and exposure-relationships between efficacy/safety of TECVAYLI in MajesTEC-1. Body weight, disease state, and multiple myeloma (MM) type were found to be statistically significant covariates on the PK of TECVAYLI. Exposure-efficacy analysis supported the RP2D of TECVAYLI. Exposure-safety analysis explored the relationship of predicted TECVAYLI concentrations to select grade ≥3 treatment-emergent adverse events (TEAEs): anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection.
  • Niu et al (2023)¹⁴ developed a mechanism-based quantitative systems pharmacology (QSP) model to evaluate the dose- and exposure-response of TECVAYLI monotherapy in patients with RRMM.
  • Vishwamitra et al (2023)¹⁵conducted longitudinal immune- and tumor-correlative analyses to evaluate clinical response, resistance, and relapse in patients treated with TECVAYLI in the MajesTEC-1 study. Patients responding to TECVAYLI exhibited a differential immune profile, with greater T-cell redistribution, greater recovery of CD3 T cells, increased T-cell infiltration, and transient activation in early cycles compared with nonresponders.
  • Girgis et al (2022)¹⁶ developed a 2-compartment PK model to predict the doses of TECVAYLI with exposure in the expected therapeutic range (between C_max at 50% of maximum exposure [EC₅₀] and C_max at EC₉₀) using ex vivo cytotoxic assays. TECVAYLI intravenous (IV) doses (0.27 mg/kg and 0.72 mg/kg) QW and TECVAYLI SC doses (0.72 mg/kg and 1.5 mg/kg) QW with overall response rate (ORR) between 60-75% were included in the translational modeling analysis to support the RP2D of TECVAYLI.

CLINICAL DATA - MAJESTEC-1 STUDY

MajesTEC-1 (MMY1001; clinicaltrials.gov identifiers: NCT03145181; NCT04557098) is evaluating the safety and efficacy of TECVAYLI in patients with RRMM.^1-6

Study Design/Methods

The main objectives are as follows: Part 1 (dose escalation) to determine the RP2D for TECVAYLI; Part 2 (dose expansion) to distinguish safety and tolerability of TECVAYLI at the RP2D; Part 3 (the phase 2 component) to evaluate the efficacy of TECVAYLI at the RP2D.^1,2

• Key eligibility criteria:
  • Cohort A: ≥3 prior lines of therapy including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, no prior BCMA-targeted therapy use.¹
  • Cohort C: ≥3 prior lines of therapy, a prior PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, enrolled patients who had prior exposure to BCMA-targeted treatment (chimeric antigen receptor [CAR]-T cell and/or antibody drug conjugate [ADC]).⁷
  • Prophylactic tocilizumab cohort: ≥3 prior lines of therapy including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.⁸
• Primary endpoint for Cohort A and Cohort C: ORR.^1,7
• Key secondary endpoint for Cohort A and Cohort C: safety.^1,7
• Endpoint for prophylactic tocilizumab cohort: incidence of CRS.⁸

Cohort A

Moreau et al (2022)^1,3 published a PK analysis in 165 patients treated with TECVAYLI at a median follow-up if 14.1 months (range, 0.3-24.4).

Results

• TECVAYLI exposure remained over the target level EC₉₀ of 6 μg/mL (previously determined in an ex vivo cytotoxic assay) with a low peak-to-trough ratio.^1,3
• Serum levels of sBCMA were assessed as a potential marker of tumor burden and response. Within one month of TECVAYLI dosing, total sBCMA decreased in 68% of patients (40 of 59) with a partial response or better. Reduced sBCMA levels were observed in 88% of patients (63 of 72) with a partial response or better in cycles 1-4. Increased sBCMA levels were observed in 96% of patients (27 of 28) with no response to TECVAYLI in cycle 1. Additionally, increased sBCMA levels were observed in 9 patients without a response.
• TECVAYLI treatment induced cytokines and activated T cells, but the response was not correlated to changes in levels of cytokine or T-cell activation. Patients with a response had higher levels of IFN-γ, IL-6, IL-10, IL-2 receptor alfa than those without a response.

Cohort C

Touzeau et al (2024)⁷ published a PK analysis in 40 patients treated with TECVAYLI at a median follow-up of 28.0 months (range, 0.7-31.1).

Results

Pharmacokinetics and Immunogenicity

• TECVAYLI C_trough values in patients were comparable to those observed in BCMA-treatment-naïve patients, with mean C_trough consistently above the maximal EC₉₀ value from an ex vivo assay.
• TECVAYLI serum concentrations at or within 48 hours of CRS onset (including step-up and treatment doses) ranged from 0.070 to 8.99 μg/mL.
  • At a PK data cutoff of June 7, 2023, no clear correlation was observed between CRS events or grade and TECVAYLI concentration; serum levels were comparable in patients with CRS across all grades and in patients without CRS.
  • No serum samples from CRS events were positive for antibodies to TECVAYLI.
• Antibodies to TECVAYLI were not detected in the serum of any of the 36 antidrug antibody-evaluable patients.

Soluble BCMA and Bone Marrow BCMA Expression

• Serum was collected prior to the first TECVAYLI dose, and samples were analyzed for sBCMA.
• Baseline sBCMA serum levels overlapped between Cohort C patients and BCMA-treatment-naïve patients. See Table: MajesTEC-1 Study (Cohort C): sBCMA Levels for additional details.
• On cycle 4 day 1, a total of 78.6% of responders (11 out of 14) had a decrease in sBCMA, while 75% of non-responders (3 out of 4) had an increase in sBCMA after TECVAYLI administration.
• sBCMA reduction was higher in responders to TECVAYLI, although the sample size was limited.
• BCMA expression on multiple myeloma (MM) cells in the bone marrow showed no significant difference in the percentage or level of BCMA expression between patients who had prior anti-BCMA CAR-T or ADC exposure (last prior line or any prior line).

Immune Cell Effects

• Assessments included the impact of prior anti-BCMA CAR-T therapy on the number of T cells and the activation and inhibitory receptor expression on T cells prior to TECVAYLI treatment. B-cell numbers were also evaluated.
• Baseline CD4 and CD8 T-cell numbers trended lower in patients who had received anti-BCMA CAR-T compared with those who received prior BCMA-ADC therapy.
  • Activation markers (CD25 and CD38) and inhibitory receptors (programmed cell death 1 [PD-1], T-cell immunoglobulin mucin family member 3 [TIM-3]) were not upregulated on CD4+ and CD8+ T cells from patients in the prior anti-BCMA CAR-T cohort.
• Patients with prior anti-BCMA therapy did not have lower baseline B-cell numbers compared with anti-BCMA-naive patients at any point during treatment.

Prophylactic Tocilizumab Cohort

van de Donk et al (2023)⁸ compared the PK profiles of 8 patients from the phase 1 exploratory prophylactic cohort with those of 40 patients from the MajesTEC-1 phase 1 population treated with TECVAYLI at the RP2D.

Results

• A PK profile of 8 patients from the phase 1 exploratory prophylactic cohort was compared to 40 patients from the MajesTEC-1 phase 1 population treated at TECVAYLI RP2D. See Figure: MajesTEC-1 Study: TECVAYLI Serum Concentration-Time Profile in Patients Treated with TECVAYLI with or Without Prophylactic Tocilizumab for additional details.
• The timing of induction of cytokines IL-6 and IL-10 were compared between the prophylactic tocilizumab cohort, and the MajesTEC-1 phase 1 cohort treated at RP2D. See Figure: MajesTEC-1 Study: Cytokine Induction in Patients treated with TECVAYLI with or Without Prophylactic Tocilizumab for additional details.

Population pK and Exposure-relationship - majestec-1 study

Miao et al (2023)¹³ developed a population PK model to evaluate the exposure of TECVAYLI in baseline demographic subgroups and other covariates. In addition, the exposure-efficacy and exposure-safety relationships were explored using available data from 338 patients in the phase 1/2 MajesTEC-1 study.

Methods

• A population PK model was developed using serum concentrations of TECVAYLI from patients administered either IV or SC doses of TECVAYLI. This model was used to predict average concentrations of TECVAYLI after the first treatment RP2D dose (C_ave,1stdose) across various patient baseline demographic subgroups.
• Population PK analysis: The effects of patient demographic characteristics, disease characteristics and biomarkers, clinical characteristics, prior treatment, and refractory status were tested on TECVAYLI systemic exposure (C_ave,1stdose). This analysis included all patients from the phase 1/2 portions of the MajesTEC-1 trial (Cohorts A and C) who had received at least one dose of TECVAYLI and had at least one serum concentration measurement of TECVAYLI.
• Exploratory efficacy analysis: The exposure-efficacy relationship for ORR, duration of response (DOR), PFS, and overall survival (OS) were explored in patients treated with TECVAYLI at RP2D in the MajesTEC-1 Cohort A (N=165). ORR was also assessed in patients who received phase 1 dosing in SC cohorts (n=92). This analysis used predicted average concentrations of TECVAYLI after the first treatment RP2D dose (C_ave,1stdose) and predicted trough concentration after the first four weekly treatment doses (C_{trough,4doses}) to characterize the exposure-efficacy relationship.
• Exploratory safety analysis: The exposure-safety relationship for select grade ≥3 TEAEs (anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection) were estimated in patients who received TECVAYLI SC dosing in the phase 1/2 (Cohort A) portion of the trial (n=217).The analysis used predicted maximum concentration following the first treatment dose (C_max,1stdose) and predicted maximum concentration following the first four weekly treatment doses (C_max,4doses) to characterize the exposure-safety relationship.

Results

Patient Disposition

• Among 338 patients (4840 PK observations) from the phase 1/2 MajesTEC-1 study, 83 patients (1976 PK observations) were administered TECVAYLI IV, and 255 patients (2864 PK observations) were administered TECVAYLI SC.
• Among patients who received TECVAYLI SC, 28 patients (604 PK observations) received doses <RP2D, 203 (1679 PK observations) received RP2D, 21 patients (502 PK observations) received doses >RP2D, and 3 patients (79 PK observations) received flat dosing.
• See Table: MajesTEC-1 Study: Patient Baseline Demographics and Characteristics for additional details.

Population PK Model

• The final population PK model was a 2-compartment model with parallel time-independent and time-dependent clearance pathways. The estimates for TECVAYLI PK parameters and covariates (body weight, disease state by International Staging System [ISS], and MM type [immunoglobulin G {IgG} or non-IgG]) included in the final model are summarized in Table: MajesTEC-1 Study: Parameter Estimates of TECVAYLI for the Final Population PK Model.
• The individual point estimate of C_{ave,1st dose} (95% confidence interval [CI]) at the RP2D for all covariates are summarized in the Table: MajesTEC-1 Study: Subgroup Analyses of the Predicted Average Concentration of First Treatment Dose of TECVAYLI per the RP2D Dose.

Exposure-Relationships

Efficacy analysis

• See Table: MajesTEC-1 Study: Subgroup Analysis of RP2D ORR Based on Baseline Characteristics.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 13 November 2024.