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.
We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (Cmeas) to determine the area under the curve (AUC), apparent clearance (Cl/F) and residual blood concentration (Ctrough). Best overall response according to RECIST 1.1 and relevant toxicity (adverse event grade 3-4 or grade 2 requiring dose reduction or discontinuation) were assessed according to Cmeas, Ctrough, AUC and Cl/F.
We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median Ctrough (406 versus 634 ng/ml, P = 0.001), Cl/F (2 versus 2.9 l/h, P = 0.002) and AUC (16 versus 20 μg h/ml, P = 0.037) compared with patients who had disease control as best response. Patients with relevant toxicity had a significantly higher Cmeas (732 versus 531 ng/ml, P = 0.006), Ctrough (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.
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.
ESMO open. 2021 Dec 01 [Epub ahead of print]
L Cerbone, D Combarel, A Geraud, E Auclin, S Foulon, C Alves Costa Silva, E Colomba, L Carril, L Derosa, R Flippot, O Mir, N Khoudour, B Blanchet, B Escudier, A Paci, L Albiges
Department of Oncological Medicine, Gustave Roussy, Villejuif, France., Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France; Medical School, University of Paris XI Sacly, Saclay, France., Medical School, University of Paris XI Sacly, Saclay, France; Department of Therapeutic Innovations and Early Trials, Gustave Roussy, Villejuif, France., Medical Oncology Hopital Europeen Georges Pompidou, Paris, France., Department of Biostatistics and Epidemiology, Gustave Roussy, Paris, France., Functional Unity (UF) Drug Biology and Toxicology Department, Hopital Cochin, Paris, France., Functional Unity (UF) Drug Biology and Toxicology Department, Hopital Cochin, Paris, France; UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University of Paris, Paris, France., Department of Oncological Medicine, Gustave Roussy, Villejuif, France; Medical School, University of Paris XI Sacly, Saclay, France. Electronic address: .