126: Evaluation of Talquetamab Drug-Drug Interaction Potential as a Result of Cytokine Release Syndrome in Patients With Relapsed/Refractory Multiple Myeloma in MonumenTAL-1, Using a Physiologically Based Pharmacokinetic Model

Statement of Purpose: Talquetamab, a G protein–coupled receptor family C group 5 member D × CD3 bispecific antibody, yielded responses in >70% of patients with relapsed/refractory multiple myeloma in MonumenTAL-1 (NCT03399799/NCT04634552). Cytokine release syndrome (CRS) is observed with initial step-up and first treatment doses of talquetamab, leading to elevated IL-6 levels, which can suppress cytochrome P450 (CYP) enzymes. We present a physiologically based pharmacokinetic (PBPK) modeling framework to evaluate the potential impact of IL-6 serum level on the exposure of co-administered CYP substrates in patients treated with talquetamab in MonumenTAL-1 on the exposure of co-administered CYP substrates.

Description of Methods & Materials: PBPK modeling and simulations were performed using SimCYP v21, and the ability of the model to capture DDIs was verified using literature data. Observed DDIs from literature with CYP substrates at steady state concentrations of IL-6 (50 pg/mL) were well predicted, giving confidence in the model. Prospective simulations were then performed on systemic IL-6 concentrations in patients in MonumenTAL-1 who received the recommended phase 2 doses of subcutaneous talquetamab (0.4 mg/kg QW and 0.8 mg/kg Q2W, with step-up doses). Time to reach maximum change in CYP activity due to IL-6 and to return to 80% baseline enzymatic activity was assessed. Two scenarios were envisioned: the observed IL-6 median serum profile and a profile based on a patient with the highest observed concentration of IL-6 (C_max).

Data & Results: At 0.4 mg/kg QW and 0.8 mg/kg Q2W, respectively, observed median IL-6 C_max were 18.4 and 7.1 pg/mL and highest IL-6 C_max were 213 and 3,503 pg/mL. For the median IL-6 profile, no interaction between IL-6 and CYP1A2, 2C9, 2C19, 3A4 or 3A5 substrates was predicted at either dose. For the IL-6 profile with the highest C_max, the impact on exposure was predicted to be weak to moderate for CYP2C19, 3A4 and 3A5 substrates and minimal for CYP1A2 substrates at both doses. Impact on the exposure of CYP2C9 substrates was predicted to be minimal at 0.4 mg/kg QW and minimal to weak at 0.8 mg/kg Q2W. Time to return to 80% baseline enzymatic activity was predicted as 7 and 9 days after start of cycle 1 for 0.4 mg/kg QW and 0.8 mg/kg Q2W, respectively.

Interpretation, Conclusion or Significance: IL-6 release as a consequence of talquetamab-induced CRS has a limited impact on potential DDIs. PBPK modeling suggests the highest risk of DDI is from initiation of talquetamab step-up dose up to 7 days (0.4 mg/kg QW) or 9 days (0.8 mg/kg Q2W) after start of cycle 1 based on the scenario of highest IL-6 C_max. During this time, toxicity or concentration of drugs that are CYP450 substrates should be monitored, where minimal changes in concentration may cause serious adverse reactions. The dose of the concomitant CYP450 substrate should be adjusted as needed.

Disclosures: