SUMMARY

• No drug interaction studies have been performed with TALVEY.¹
• MonumenTAL-1 (MMY1001) is an ongoing, open-label, phase 1/2 study evaluating the efficacy and safety of TALVEY in patients with relapsed or refractory multiple myeloma (RRMM) after ≥3 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug, and anti-CD38 monoclonal antibody.^2-4
  • Per protocol, cytochrome P450 (CYP450) substrates with narrow therapeutic index should be used with caution when administered concomitantly with TALVEY.⁴
• Willemin et al (2023)⁵ conducted a physiologically based pharmacokinetic (PBPK) modelling study to evaluate the potential impact of elevated interleukin-6 (IL-6) levels during cytokine release syndrome (CRS) on the exposure of CYP450 substrates coadministered with TALVEY. Drug-drug interaction (DDI) liability was predicted based on simulations of CYP450 substrate interaction at observed median and highest IL-6 levels in patients administered TALVEY at the recommended phase 2 doses (RP2Ds; 0.4 mg/kg weekly [QW] and 0.8 mg/kg every other week [Q2W]) in the MonumenTAL-1 study.

BACKGROUND

• CRS occurs with TALVEY, consistent with its mechanism of action.⁵ Elevated IL-6 levels that occur during CRS can suppress CYP450 enzymes, potentially resulting in increased exposure of CYP substrates.^1,5
• Monitor for toxicity of concentrations of drugs that are CYP (eg, CYP2C9, CYP2C19, CYP3A4/5) substrates where minimal concentration changes may lead to serious adverse reactions. Adjust the dose of the concomitant CYP (eg, CYP2C9, CYP2C19, CYP3A4/5) substrate drugs as needed.¹

CLINICAL DATA - Monumental-1 STUDY

MonumenTAL-1 (MMY1001; NCT03399799, NCT04634552) is a phase 1/2 study of TALVEY in patients with RRMM.^6,7

The study was conducted in 3 parts; the primary objectives are listed below²:

• Part 1 (phase 1; dose escalation): to characterize the safety of TALVEY and determine the RP2Ds and schedule.
• Part 2 (phase 1; dose expansion): to further characterize the safety of TALVEY at the RP2Ds.
• Part 3 (phase 2): to evaluate the efficacy of TALVEY at the RP2Ds.

Shown below is the summary of the study design and results from part 3 of the phase-2 portion of the MonumenTAL-1 study.

Study Design/Methods (Phase 2)

Patients were enrolled into 1 of the following 3 cohorts^2,8:

• T-cell redirection (TCR) therapy naive: 0.4 mg/kg subcutaneous (SC) QW, not previously exposed to TCR such as chimeric antigen receptor T-cell therapy (CAR-T) or bispecific antibodies (BsAbs; prior B-cell maturation antigen [BCMA] antibody-drug conjugate [ADC] allowed).
• TCR naive: 0.8 mg/kg SC Q2W, not previously exposed to TCRs (prior BCMA ADC allowed).
• Prior TCR: 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W, have been previously exposed to TCRs.
  • Among the prior TCR-exposed cohort, patients were divided based on type of TCR (CAR-T, BsAb or CAR-T and BsAb).
• Key eligibility criteria (Part 3; Phase 2):
  • Measurable multiple myeloma (MM).⁸
  • ≥3 prior lines of therapy including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.⁸
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.⁸
• Key exclusion criteria (Part 3; Phase 2):
  • Prior grade 3 or higher CRS; per Lee criteria 2014⁹ related to any TCR or any prior G protein-coupled receptor class C group 5 member D (GPRC5D)-targeting therapy.⁴
  • Received cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within 14 days prior to study drug (not including premedication).⁴
• Primary endpoint: overall response rate (ORR).²
• Key secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival, safety, immunogenicity, and pharmacodynamics.²
• Dosing
  • TALVEY 0.4 mg/kg SC QW and 0.8 mg/kg SC Q2W treatment dose schedule is based on a 28-day cycle.⁴
  • Step-up dosing for 0.4 mg/kg SC QW⁴:
    • Week 1: step-up doses of TALVEY (0.01 mg/kg and 0.06 mg/kg SC).
    • Cycles 1+: TALVEY 0.4 mg/kg SC QW until progressive disease or unacceptable toxicity.
  • Step-up dosing for 0.8 mg/kg SC Q2W⁴:
    • Week 1: step-up doses of TALVEY (0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg SC).
    • Cycles 1+: TALVEY 0.8 mg/kg SC Q2W until progressive disease or unacceptable toxicity.
  • Premedications: dexamethasone, acetaminophen, and diphenhydramine were required to be administered for each step-up dose, and for the first full treatment dose of TALVEY.⁴
  • Patients were required to be hospitalized for at least 48 hours from the start of the injection, for each step-up dose and the first full treatment dose of TALVEY.⁴

MonumenTAL-1 Study Protocol (Phase 2, Part 3) - Key Exclusion Criteria

• Prior antitumor therapy prior to the first dose of study drug as follows⁴:
  • Gene modified adoptive cell therapy (eg, CAR-T, natural killer [NK] cells) within 3 months
  • Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or at least 5 half-lives, whichever is less
  • Monoclonal antibody treatment for MM within 21 days
  • Cytotoxic therapy within 21 days
  • Proteasome inhibitor therapy within 14 days
  • Immunomodulatory agent therapy within 7 days
  • Radiotherapy within 14 days. However, if palliative focal radiation is used, the patient is eligible irrespective of the end date of radiotherapy.
  • 0.4 mg/kg or 0.8 mg/kg dosing, not previously exposed to TCR therapies: exposed to a CAR-T or TCR at any time
  • 0.4 mg/kg or 0.8 mg/kg dosing, previously exposed to TCR therapies: TCR within 3 months

MonumenTAL-1 Study Protocol (Phase 2, Part 3) - Key Prohibited Medications Related to Drug Interactions

• CYP substrates with narrow therapeutic index should be used with caution for the first 48 hours after administration of the first TALVEY dose and during any events of CRS.⁴
• For patients receiving warfarin, investigators should consider switching from warfarin to a different anticoagulant. For patients who cannot switch to a different anticoagulant and who experience CRS, coagulation parameters should be monitored closely during a CRS event and until CRS symptoms resolve.⁴
• The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CF), should be avoided during CRS.¹

physiologically based pharmacokinetic model - Monumental-1

Willemin et al (2023)⁵ applied PBPK modelling and simulations to analyze DDIs between TALVEY and other drugs that are substrates of CYP450.

Methods

• SimCYP v21 was used to perform simulations and assess DDIs, which were verified using in vitro and in vivo literature data.
• Selected CYP450 substrates were evaluated for the potential of DDIs based on the administration of a single dose of substrate and when minimum (or maximum for CYP1A2) enzymatic activity was reached.
• Prospective simulations were performed using IL-6 profiles from patients administered TALVEY at the RP2Ds of 0.4 mg/kg QW and 0.8 mg/kg Q2W in the MonumenTAL-1 study either without or prior to administration of tocilizumab (anti-IL-6 receptor) or siltuximab (anti-IL-6).
• The exposure of substrates of CYP450 enzymes were predicted for 2 IL-6 kinetic profiles by the model: one with a median observed IL-6 serum profile and the second with the highest IL-6 serum concentration (C_max; to predict the highest DDI risk) measured in patients.
• Additionally, the time to reach maximum change in CYP450 activity (due to elevated IL6) and return to 80% of CYP450 activity was evaluated using the start of cycle 1 (first full treatment dose) as reference. A cutoff of 80% baseline enzymatic activity was chosen due to low risk of DDI.

Results

PBPK Model Verification

• The model successfully predicted the transient peak concentration and steady state IL-6 concentration (50 pg/mL). DDIs for CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 substrates observed from literature in the presence of 50 pg/mL IL-6 concentration were well predicted, which provided confidence in the application of the model to assess IL-6 as the perpetrator of these substrates.

PBPK Model Application to Talquetamab RP2Ds

• In patients who experienced CRS after TALVEY administration, the observed median IL-6 C_max was 18.4 pg/mL and highest IL-6 C_max was 213 pg/mL for 0.4 mg/kg QW dosing, and 7.1 pg/mL and 3503 pg/mL for 0.8 mg/kg Q2W dosing, respectively.
• Predicted exposures of CYP450 substrates at median and highest IL-6 levels are presented in the Table: MonumenTAL-1 Study: Simulated Changes in CYP450 Substrate Exposure and DDI Liability at Observed Systemic Median and Highest C_max IL-6 Profiles.
  • The model predicted no interaction between IL-6 and CYP1A2, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 substrates at the median IL-6 C_max for both RP2Ds.
  • The model predicted minimal interaction between IL-6 and CYP1A2 and weak-to-moderate inhibition of CYP2C19, CYP3A4, and CYP3A5 substrates at the highest IL-6 C_max for both RP2Ds.
• At median IL-6 concentrations, maximum change in exposure of CYP450 substrates occurred in 2-3 days (0.4 mg/kg QW) and in 3 days (0.8 mg/kg Q2W) after the first full treatment dose of TALVEY.
• The time to return to 80% of baseline CYP450 activity was predicted to be 7 days (0.4 mg/kg QW) and 9 days (0.8 mg/kg Q2W) after the first full treatment dose of TALVEY.

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 09 September 2024.