PMID- 33554383 OWN - NLM STAT- MEDLINE DCOM- 20210705 LR - 20210705 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 26 IP - 5 DP - 2021 May TI - The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma. PG - 389-396 LID - 10.1002/onco.13711 [doi] AB - INTRODUCTION: Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. MATERIALS AND METHODS: This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method. RESULTS: We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. CONCLUSION: In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. IMPLICATIONS FOR PRACTICE: Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context. CI - (c) 2021 AlphaMed Press. FAU - Rassy, Elie AU - Rassy E AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Cerbone, Luigi AU - Cerbone L AUID- ORCID: 0000-0003-0663-244X AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Auclin, Edouard AU - Auclin E AD - Medical Oncology Department, Hopital Europeen Georges Pompidou, AP-HP, Paris, France. FAU - Benchimoll-Zouari, Axelle AU - Benchimoll-Zouari A AD - Early Drug Development Department, Gustave Roussy, Villejuif, France. FAU - Flippot, Ronan AU - Flippot R AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Alves Costa Silva, Carolina AU - Alves Costa Silva C AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Colomba, Emeline AU - Colomba E AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Geraud, Arthur AU - Geraud A AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. AD - Early Drug Development Department, Gustave Roussy, Villejuif, France. FAU - Guida, Annalisa AU - Guida A AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. AD - Department of Oncology, Azienda Ospedaliera Santa Maria, Terni, Italy. FAU - Mir, Olivier AU - Mir O AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Combarel, David AU - Combarel D AD - Medical biology and Pathology Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Paci, Angelo AU - Paci A AD - Medical biology and Pathology Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Escudier, Bernard AU - Escudier B AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. FAU - Albiges, Laurence AU - Albiges L AD - Cancer Medicine Department, Gustave Roussy, Universite Paris-Saclay, Villejuif, France. LA - eng PT - Journal Article DEP - 20210225 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Anilides) RN - 0 (Proton Pump Inhibitors) RN - 0 (Pyridines) RN - 1C39JW444G (cabozantinib) SB - IM MH - Anilides MH - *Carcinoma, Renal Cell/drug therapy MH - Humans MH - *Kidney Neoplasms/drug therapy MH - Proton Pump Inhibitors/therapeutic use MH - Pyridines MH - Retrospective Studies PMC - PMC8100573 OTO - NOTNLM OT - Cabozantinib OT - Overall survival OT - Pharmacology OT - Proton pump inhibitors OT - Renal cell carcinoma OT - Toxicity COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2021/02/09 06:00 MHDA- 2021/07/06 06:00 PMCR- 2021/05/01 CRDT- 2021/02/08 06:01 PHST- 2020/08/10 00:00 [received] PHST- 2021/01/15 00:00 [accepted] PHST- 2021/02/09 06:00 [pubmed] PHST- 2021/07/06 06:00 [medline] PHST- 2021/02/08 06:01 [entrez] PHST- 2021/05/01 00:00 [pmc-release] AID - ONCO13711 [pii] AID - 10.1002/onco.13711 [doi] PST - ppublish SO - Oncologist. 2021 May;26(5):389-396. doi: 10.1002/onco.13711. Epub 2021 Feb 25.