Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study
Luigi Cerbone, David Combarel, Arthur Géraud, Édouard Auclin, Stéphanie Foulon, C. Alves Costa Silva, Émeline Colomba, Lucia Carril, Lisa Derosa, Ronan Flippot, Olivier Mir, Nihel Khoudour, Benoı̂t Blanchet, Bernard Escudier, Angélo Paci, Laurence Albigès
Abstract
BACKGROUND: Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown. PATIENTS AND METHODS: , AUC and Cl/F. RESULTS: (693 versus 521 ng/ml, P = 0.005) and AUC (21 versus 16 μg h/ml, P = 0.046) compared with patients who did not experience any grade relevant toxicity. Receiver operating characteristic curves obtained from our study defined a threshold for drug efficacy of 536.8 ng/ml and of 617.7 ng/ml for toxicity. CONCLUSION: We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.