Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care
2 CiTCoM - UMR 8038 - Cibles Thérapeutiques et conception de médicaments
3 SIRIC CARPEM - Cancer Research and Personalized Medicine - CARPEM [Paris]
4 Hôpital Cochin [AP-HP]
5 HEGP - Hôpital Européen Georges Pompidou [APHP]
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
8 Oncopole Claudius Regaud
9 IGR - Institut Gustave Roussy
10 Université Paris-Saclay
11 UP11 - Université Paris-Sud - Paris 11
12 Service de Cancérologie Médicale [AP-HP Cochin]
13 CRCT - Centre de Recherches en Cancérologie de Toulouse
14 DMO - Département de médecine oncologique [Gustave Roussy]
15 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
16 CHU Saint-Antoine [AP-HP]
17 CHU Henri Mondor [Créteil]
18 UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12
19 Lixoft
20 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
21 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
22 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
- Fonction : Auteur
- PersonId : 753239
- IdHAL : anne-jouinot
- ORCID : 0000-0002-7922-2065
- Fonction : Auteur
- PersonId : 1443946
- IdHAL : florent-puisset
- Fonction : Auteur
- PersonId : 779102
- ORCID : 0000-0001-9764-0845
- IdRef : 227894529
- Fonction : Auteur
- PersonId : 768671
- IdHAL : fabienne-thomas
- ORCID : 0000-0001-9886-412X
- IdRef : 120706377
- Fonction : Auteur
- PersonId : 837185
- IdHAL : etienne-chatelut
- ORCID : 0000-0002-7740-9096
Résumé
Background: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. Methods: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. Results: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. Conclusion: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.