The CetuxIMAX study: a population pharmacokinetic approach to modelling the pharmacokinetics and pharmacodynamics relationships of Cetuximab in patients with head and neck cancer.

Cetuximab is a chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR) and is used to treat head and neck squamous cell carcinoma (HNSCC). Despite its clinical benefits, significant interindividual variability in efficacy and toxicity has been observed, which could be at least partly due to differences in pharmacokinetics. The CetuxIMAX study aimed to evaluate the predictive value of Cetuximab exposure levels for disease control (i.e., composite criteria including complete and partial response and stable disease). CetuxIMAX was a prospective, non-interventional, single-arm, multicenter study conducted in patients with HNSCC who were receiving Cetuximab. Plasma concentrations were measured and pharmacokinetic (PK) metrics and parameters were modelled using a two-compartment structure with linear and saturable elimination. Covariate analysis included BSA, age, and serum albumin. Significant variability in Cetuximab plasma concentrations was observed between patients (i.e., > 40%). A trough concentration threshold of 38 µg/mL was identified as predictive of disease control, aligning with prior findings, although final multivariate analysis found that skin toxicity only was associated with efficacy endpoints. However, protocol-specific thresholds varied, with upper values observed in the EXTREME and CaX protocols (i.e., cetuximab in association with cisplatin with or without 5-fluorouracil). No significant PK-toxicity relationships were found. The final PK model demonstrated robustness, with BSA and albumin influencing volume of distribution parameters. The CetuxIMAX study seems to confirm the predictive value of early Cetuximab plasma levels for disease control, but not for long-term survival or safety endpoints.