Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKI) for optimized outcome in patients with metastatic renal cell carcinoma. The TKI-TDM Trial. Study protocol.

Background: Metastatic renal cell carcinoma (mRCC) is notably resistant to chemotherapy and radiotherapy. However, tyrosine kinase inhibitors (TKIs) and checkpoint immunotherapy have significantly improved outcomes. Still, about 20% of patients experience disease progression as their best response to TKIs, and 16-63% endure severe toxicities, reducing quality of life. Optimizing dosing is therefore essential. Therapeutic drug monitoring (TDM) is a promising strategy for individualizing treatment. The TKI-TDM trial aims to identify a therapeutic plasma concentration range for six TKIs (axitinib, cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib) in mRCC patients.

Material and methods: This prospective observational study will enroll mRCC patients with at least 6 months of stable disease or regression on TKI therapy. Blood samples will be collected during routine care. Plasma concentrations of TKIs and metabolites will be measured using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. These levels will be correlated with clinical outcomes including objective response rate, progression-free survival, overall survival, and toxicity. Genetic analysis of UGT1A1 polymorphisms will explore their influence on pazopanib metabolism and response.

Interpretation: Identifying plasma TKI levels associated with efficacy and reduced toxicity could minimize under- or overdosing, improving outcomes and quality of life. TDM may allow dose adjustments early in therapy, improving therapeutic management and reducing healthcare costs. Findings may also inform treatment of other cancers using TKIs or TKI-immunotherapy combinations. The trial (clinicaltrials.gov NCT04659343) is expected to conclude in 2028, with results in 2029.