073: Clinical Pharmacology of Bemarituzumab in Gastric & Gastroesophageal Junction Cancer Patients Supports the Interchangeability of Q2W & Q3W Dosing Regimens

Bemarituzumab (Bema) is an antibody-dependent cell-mediated cytotoxicity (ADCC) enhanced monoclonal antibody that blocks fibroblast growth factor receptor 2b (FGFR2b), which inhibits downstream pro-tumor signaling pathways. In the phase 1/2 FIGHT study, Bema in combination with mFOLFOX was explored as a first-line treatment for FGFR2b overexpressing gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Bema was administered 15 mg/kg every two weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8 (C1D8). The same Q2W dosing regimen is being implemented in two ongoing registrational trials to synchronize with mFOLFOX dosing frequency. However, in Asian countries, CAPOX every three weeks (Q3W) is favored over mFOLFOX Q2W per local standards of care. This study aims to establish the interchangeability between a 22 mg/kg Q3W with an additional 11 mg/kg dose on C1D8 and the Q2W regimen, offering flexibility and convenience to investigators and patients.   

Description of Methods & Materials:

Bema PK and exposures were predicted using the PopPK model developed based on FIGHT data. Steady-state peak (C_max,ss), trough (C_trough,ss) and time-averaged (C_ave,ss) concentrations were predicted and compared for patients receiving the Q2W and Q3W dosing regimens. Exposure-response (E-R) analysis was performed to support the interchangeability between the Q2W and Q3W dosing regimens. Objective response rate (ORR) was assessed as the efficacy endpoint. The probability of grade ≥ 2 corneal adverse events (AEs) was the primary safety endpoint because corneal AEs were identified as events of interest for Bema in FIGHT. Observed PK and safety data from ongoing studies along with Mechanistic(M)-PBPK modeling approach to predict Bema cornea exposure as toxicity-target tissue were also leveraged to support interchangeability.

Data & Results:

C_trough,ss was identified as the most sensitive parameter to bridge efficacy and safety. E-R relationships based on data from FIGHT demonstrated that the median (95% CI) C_trough,ss of the current Q2W regimen is predicted to yield a median (95% CI) probability of 41% (38%, 44%) for ORR, and a 40% (37%, 43%) probability for grade ≥ 2 corneal AEs, respectively. The Q3W dosing regimen is projected to match the C_trough,ss of the Q2W dosing regimen, with no major difference expected in ORR and probability of grade ≥ 2 corneal AEs. Observed exposures from the registrational study FORTITUDE 102 (Q2W) and a Phase 1b study FORTITUDE 103 (Q3W) are as expected with values within 95% confidence interval of predictions. Compared with the Q2W dosing regimen, the Q3W dosing regimen demonstrated similar C_trough but higher C_max. However, both regimens exhibited favorable safety profiles without any new safety signals. The M-PBPK model predicted a delayed achievement of peak steady-state exposure in the cornea, which was consistent with observed delayed ocular toxicity. Additionally, no major differences in corneal exposures were predicted between Q2W and Q3W dosing regimens at steady-state, providing supportive evidence for interchangeability based on predicted similarities in corneal exposures.

Interpretation, Conclusion or Significance:

Clinical Pharmacology, modeling & simulations analyses indicate lack of major differences between the Bema Q3W and Q2W regimens. The Q3W represents a new dosing schedule option, providing convenience and flexibility for investigators and patient care.

Disclosures:

All authors are or were employed by Amgen, Inc. during the time this work was conducted. All authors own or have owned stock in Amgen, Inc. during the time this work was conducted.

Citations/References:

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