SUMMARY

• Janssen does not recommend any practices, procedures or usage that deviate from the product labeling or are not approved by the regulatory agencies.
• MajesTEC-2 (MMY1004) is an ongoing, phase 1b, multicohort study evaluating TECVAYLI in combination with other anticancer therapies in patients with multiple myeloma (MM). Cohort C is evaluating the efficacy and safety of TECVAYLI in combination with nirogacestat in patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM) who received ≥3 prior lines of treatment.^1,2
  • Offner et al (2023)² presented the efficacy and safety of TECVAYLI in combination with nirogacestat in 28 patients at a median follow-up of 14.7 months (range, 0.5-22.9).

CLINICAL DATA - Majestec-2 study - cohort c

MajesTEC-2 (MMY1004; clinicaltrials.gov identifier: NCT04722146) is an ongoing, phase 1b, multicohort study evaluating the efficacy and safety of TECVAYLI in combination with other anticancer treatments in patients with MM.^1,2

• Cohort C is evaluating the efficacy and safety of TECVAYLI in combination with nirogacestat in 28 patients with triple-class exposed RRMM who received ≥3 prior lines of treatment.²

Study Design/Methods

• Key eligibility criteria: ≥18 years of age; measurable MM per International Myeloma Working Group (IMWG) criteria; disease progression within 12 months of last line of therapy; ≥3 prior lines of treatment or double refractory to a proteasome inhibitor (PI), and an immunomodulatory drug and triple-class exposed to a PI, an immunomodulatory drug and an anti-CD38 monoclonal antibody. Patients with prior exposure to BCMA-targeted therapy were permitted.^1,2
• Dosing: Eligible patients received oral (PO) doses of nirogacestat and subcutaneous (SC) doses of TECVAYLI which included step-up dosing followed by once weekly (QW) full doses at three different dose levels. The step-up doses for TECVAYLI were administered 2-4 days apart and completed 2-4 days prior to the first full dose.²
  • Dose level 1:
    • TECVAYLI: step-up SC doses (0.06 mg/kg and 0.24 mg/kg), and full dose of 0.72 mg/kg SC QW.²
    • Nirogacestat: 100 mg PO twice daily initiated on day 1 with TECVAYLI step-up dose 1 (concurrent nirogacestat).²
  • Dose level 2:
    • TECVAYLI: step-up SC doses (0.06 mg/kg and 0.24 mg/kg), and full dose of 0.72 mg/kg SC QW.²
    • Nirogacestat: 100 mg PO once daily (QD) initiated after the first full dose of TECVAYLI without CRS (delayed nirogacestat administration).²
  • Dose level 3:
    • TECVAYLI: step-up SC doses (0.06 mg/kg and 0.30 mg/kg), and full dose of 1.5 mg/kg SC QW.²
    • Nirogacestat: 100 mg PO QD initiated after the first full dose of TECVAYLI without CRS (delayed nirogacestat administration).²
• Primary endpoints: safety, tolerability, and optimal doses.²
• Key secondary endpoints: overall response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), duration of response (DOR), time to response, and pharmacokinetics.²

Offner et al (2023)² presented the efficacy and safety of TECVAYLI in combination with nirogacestat) in 28 patients at a median follow-up of 14.7 months (range, 0.5-22.9). Note that the lower range limit accounts for a patient's death.

Results

Treatment Disposition

• A total of 28 patients were treated with TECVAYLI and nirogacestat.
  • At dose level 1, 8 patients received TECVAYLI and concurrent nirogacestat.
  • At dose level 2, 7 patients received TECVAYLI and delayed nirogacestat administration.
  • At dose level 3, 13 patients received TECVAYLI and delayed nirogacestat administration.
• Patient characteristics are summarized in table: MajesTEC-2 (Cohort C: TECVAYLI + nirogacestat): Baseline Characteristics.
• Patients received TECVAYLI for a median duration of 9.4 months (range, 0.03-22.9), and nirogacestat for a median duration of 4.7 months (range, 0.16-15.6).
• At the data cut-off date of March 16, 2023, 12 patients (42.8%) remained on TECVAYLI and 4 patients (14.3%) remained on nirogacestat.

Efficacy

• The median time to first response was 1.18 months (range, 1.1-2.7) in patients with a confirmed partial response or better (≥PR).
• The ORR was 74.1% (n=20) among the 27 response-evaluable patients. See table: MajesTEC-2 (Cohort C: TECVAYLI + nirogacestat): Response Summary for additional details.
• Among responders, 87.2% maintained response for ≥12 months. At data cut-off, the median DOR has not been reached.

Safety

• Any grade adverse events (AEs) were reported in 28 patients (100%) and grade 3/4 AEs were reported in 26 patients (92.9%).
• The incidence of hematologic AEs is outlined in table: MajesTEC-2 (Cohort C: TECVAYLI + nirogacestat): Hematologic AEs (≥20% Overall).
  • Across all dose levels, febrile neutropenia occurred in 1 patient (3.6%).
• The incidence of nonhematologic AEs is outlined in table: MajesTEC-2 (Cohort C: TECVAYLI + nirogacestat): Nonhematologic AEs (≥25% Overall).
• Five deaths were reported due to treatment-emergent AEs (sepsis, septic shock, COVID-19, Pneumocystis jirovecii pneumonia, and cardiac arrest).
• Treatment discontinuations related to AEs:
  • TECVAYLI: 2 patients (7.1%). AEs leading to discontinuation were confusional state (n=1), and neutropenia and pneumonia (n=1).
  • Nirogacestat: 17 patients (60.7%). AEs leading to discontinuation were diarrhea (n=3), increased alanine aminotransferase (n=2), increased aspartate aminotransferase (n=2), fatigue (n=2), and cholecystitis, confusional state, COVID-19, general physical health deterioration, hyperamylasemia, malaise, meningitis, mental disorder, muscular weakness, nausea, Pneumocystis jirovecii pneumonia, pneumonia, septic shock, upper gastrointestinal hemorrhage, and vomiting (n=1 each). A patient could have >1 AE leading to discontinuation.
• Dose reductions due to AEs were reported in 3 TECVAYLI patients (10.7%) and 11 nirogacestat patients (39.3%).
  • Dose reductions were patient-specific and not related to the dose levels described in the study design.

Dose-Limiting Toxicities

• Three dose-limiting toxicities (DLTs) were reported in 2 patients.
  • Dose level 1: 3 DLTs were reported in 2 patients: 1 patient with Grade 3 gastrointestinal bleeding and Grade 3 diarrhea; and 1 patient with Grade 3 immune effector cell-associated syndrome (ICANS).
  • Dose level 2 and 3: No DLTs or Grade 3 CRS events were reported.

Cytokine Release Syndrome

• The incidence and management of CRS events are summarized in table: MajesTEC-2 (Cohort C: TECVAYLI + nirogacestat): Incidence and Management of CRS.
• Any grade CRS events occurred in 75.0% of patients (n=21). One Grade 3 CRS event was reported at dose level 1 (concurrent nirogacestat). Most CRS events occurred during step-up dosing or cycle 1.
• The median time to onset of CRS (relative to the most recent dose) was 2 days (range, 1-3). The median duration of CRS was 2 days (range, 1-33). All CRS events had resolved at the time of data cut-off.

Neurotoxicity

• Two ICANS events occurred; one at dose level 1 (Grade 3) and one at dose level 2 (Grade 2).

Infections

• Infections reported in ≥20% of patients in the safety analysis set are presented in Table: MajesTEC-2 (Cohort C: TECVAYLI + nirogacestat): Incidence of Infections (≥20% Overall).
• No DLTs related to infections occurred.
• A total of 78.6% of patients reported either a hypogammaglobulinemia TEAE or ≥1 postbaseline IgG value of <500 mg/dL. Of these, 42.9% of patients were administered intravenous immunoglobulin (IVIG) treatment.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 11 June 2024.