Intensified Monitoring of PhArmacology of Cabozantinib as a Tool for Toxicity Management in Patients With Renal Cell Carcinoma

Intensified Monitoring of PhArmacology of Cabozantinib as a Tool for Toxicity Management in Patients With Renal Cell Carcinoma

Adverse events (AEs) with Cabozantinib are frequent (about 40-67% of patients) and often lead to temporary treatment interruptions, dose reductions or permanent discontinuations, potentially reducing dose intensity and sustained exposure. Therefore, strategies are needed to improve tolerability without compromising antitumor activity. Therapeutic drug monitoring (TDM) is particularly suitable for drugs with high interpatient variability, narrow therapeutic windows and defined exposure-response relationships; real world data support this profile for Cabozantinib and suggest that pharmacokinetically guided dosing could help manage toxicity while maintaining efficacy. Based on this evidence, the study proposes a model of individualized pharmacological counselling integrating TDM, pharmacogenetic testing and structured evaluation of pharmacological interactions to optimize Cabozantinib exposure and minimize avoidable toxicity.

Inclusion Criteria for the intervention group:

• Patients diagnosed with histologically confirmed advanced/metastatic RCC with predominantly clear cell subtype.
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC, candidate to receive systemic treatment with nivolumab + Cabozantinib or Cabozantinib monotherapy as per clinical practice (investigators choice).
• Signed Written Informed Consent.
• Male or female subjects aged ≥18 years old.
• Women of childbearing potential must avoid pregnancy while on Cabozantinib. Female partners of male patients taking Cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as "effective methods of contraception", due to factors such as missed doses, gastrointestinal disturbances, or potential drug interactions that could reduce their effectiveness, they should be used together with another method, such as a barrier method.
• Previous nephrectomy is permitted.
• All IMDC (International Metastatic RCC Database Consortium) risk (good, intermediate, poor).
• Eastern Cooperative Oncology Group performance status 0 or 1
• Capable of understanding and complying with the protocol requirements.
• patients will be included in the study regardless of their time of treatment start with Cabozantinib and regardless of their concomitant diseases or co-medication.

Exclusion Criteria for intervention group:

• Patients with non-renal cell neoplasms of the kidney (e.g. urothelial, sarcoma, lymphoma).
• Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of the start of treatment except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or low-grade prostate cancer (≤pT2, N0; Gleason 6) with no plans for treatment intervention.
• Pregnancy status.
• Refusal of informed consent.
• Patients who could not attend periodic clinical check-ups.
• Any condition that, in the investigator's judgment, could compromise appropriate participation in the study.

Inclusion criteria for the historical control group:

• Patients diagnosed with histologically confirmed advanced/metastatic RCC with predominantly clear cell subtype.
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC, candidate to receive systemic treatment with nivolumab + Cabozantinib or Cabozantinib monotherapy as per clinical practice (investigators choice).

Exclusion criteria for the historical control group:

• Patients with non-renal cell neoplasms of the kidney (e.g. urothelial, sarcoma, lymphoma).
• Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of the start of treatment except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or low-grade prostate cancer (≤pT2, N0; Gleason 6) with no plans for treatment intervention.