Funding obtained (400 000 euros from Ligue Nationale contre le Cancer – Clinical Research 2024) for a research project on the influence of morphological characteristics on the pharmacokinetics and toxicity of trastuzumab deruxtecan in patients with HER2-overexpressed/amplified or low-expressed metastatic breast cancer.

The aim of this project is to compare the plasma exposure to trastuzumab deruxtecan of patients with a normal BMI vs. overweight or obese patients, and to verify that the latter do not have more adverse effects due to the calculation of doses in mg/kg.

Contact : Fabienne Thomas Team DIAD

Antibody Drug Conjugates are an increasingly important therapeutic class in the treatment of many cancers. Trastuzumab-dercecan (T-DXd) is an antibody to the HER2 receptor coupled to the topoisomerase inhibitor deruxtecan (DXd), which is released after hydrolysis of the linker in intracellular lysosomes. In patients with metastatic breast cancer expressing high or low HER2 levels, T-DXd is administered at a dose of 5.4 mg/kg by intravenous infusion every 3 weeks. Weight-based dose adjustment appears justified by the pharmacokinetic (PK) studies carried out during its development, which showed a correlation between patient weight and the elimination clearance of both T-DXd and Dxd. However, as clearance does not increase as much as weight, it appears that heavier patients are more exposed. Thus, in obese patients, adapting doses to weight could entail a risk of overdosing, associated also with an increased risk of DXd release into the circulation due to the chronic inflammatory state associated with obesity.

The aim of our study is to assess whether overweight (BMI >25) or obese (BMI>30) patients treated with T-DXd for breast cancer are overexposed to the drug and develop more adverse effects. To this end, 210 patients will be included (105 of them overweight or obese) and treated according to standard practice with the usual doses of T-DXd. Blood samples will be taken during the first 4 cycles for the T-DXd pharmacokinetic study, which will involve determining each patient’s plasma exposure to T-DXd and DXd.

This will enable us to recommend specific adaptations to T-DXd doses in the future, such as taking into account corrected weight or lean body mass, or proposing a cap on doses above a certain weight (for example, administering the same dose to patients weighing over 100kg). This multi-center project is due to start in 2025 and will involve 10 cancer centers (CLCC and CHU).

 

Centre de Recherches en Cancérologie de Toulouse

Toulouse Cancer Research Center (Oncopole)

Toulouse - FR

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