727P - Cabozantinib (Cabo) concentration (Cmin) association with toxicity (tox) and treatment failure in metastatic renal cell carcinoma (mRCC) patients: The MONICA study

Background

Cabozantinib is a novel TKI used in mRCC with a narrow therapeutic index (all grade (G) tox occurring in almost 100% pts and G3-4 tox occurring in 60%). No data are available about CABO PK monitoring and association with tox and efficacy.

Methods

We performed a routine PK monitoring study (INDS MR 5612140520). Blood plasma samples were collected from Cabo treated pts and analyzed using a validated Liquid Chromatography Tandem Mass Spectroscopy method. All blood draws were obtained at least 7h from the last dose, (i.e when the distribution phase was over) and Cmin was estimated using measured concentration of cabo (Cmeas) as follows: Cmin=Cmeas*0,5dosing interval-24/t1/2. G3-4 or G2 tox leading to drug discontinuation or dose reduction were considered as limiting tox and recorded per CTCAE criteria v 5.0, response per RECIST v 1.1. Statistical analysis was performed using SPSS v 25.0.

Results

Overall, 50 pts were enrolled to the study. Pts’ characteristics are resumed in the table. With a median f-up of 3.6 months, 17 tox and 20 progressions occurred. Median Cmin for the whole cohort was 491.6 ng/ml (25-75 IQR 365.3-779.9) Median Cmin for pts experiencing intolerable tox was 623 ng/ml (25-75 IQR 462.2-981.8) and was 452 ng/ml (IQR 304.9-588.9) (p 0,006) in patients without limiting tox. Median Cmin for pts experiencing PD was 405 ng/ml (IQR 287.5-523.9) and 521 ng/(25-75 IQR 380.2-832.9.9) ml in patients with SD/PR (p 0,017). Three pts were treated at a CABO daily dose of 20 mg, 26 at 40 mg and 21 at 60 mg. There was no difference in term of daily dose between the tox/non tox and PD/non PD groups.

Conclusions

A higher median CABO Cmin is associated with relevant toxicity, while a lower CABO Cmin seems associated with PD under Cabo. CABO PK assay should be considered both in case of CABO toxicity and in case of PD. Table: 727P

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Institut Gustave Roussy.

Funding

Has not received any funding.

Disclosure

A. Geraud: Principal/sub-Investigator of Clinical Trials: Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Astra Zeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Bristol-Myers Squibb International Corporation, Ca, Celgene Corporation, Cephalon, Chugai Pharmaceutical Co., Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm S.A., Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Gilead Sciences, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Philogen S.P.A., Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharmaceuticals France, Xencor, Y's Therapeutics, Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-financial support (drug supplied): Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. E. Colomba-Blameble: Honoraria (self), Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses: GSK; Travel/Accommodation/Expenses: Novartis. O. Mir: Stock and other ownership interests: Amplitude Surgical; Ipsen; Transgene; Honoraria (self): Roche; Advisory/Consultancy: Janssen/ Lilly/Lundbeck/Pfizer/Roche; Speakers' Bureau: Lilly/Pfizer/Roche; Travel/Accommodation/Expenses: Pfizer/Roche. B. Escudier: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy: EUSApharma; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Advisory/Consultancy: Novartis; Advisory/Consultancy: AVEO; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche/Genentech; Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. L. Albiges: Honoraria (institution), Travel/Accommodation/Expenses: BMS; Honoraria (institution), Travel/Accommodation/Expenses: MSD; Honoraria (institution): Amgen; Honoraria (institution): Astellas Pharma; Honoraria (institution): AstraZeneca; Honoraria (institution), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (institution): Corvus Pharmaceutical; Honoraria (institution): Exelixis; Honoraria (institution): Ipsen; Honoraria (institution): Novartis; Honoraria (institution): Peloton therapeutics; Honoraria (institution): Pfizer; Honoraria (institution): Roche. ll other authors have declared no conflicts of interest.