Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2024 Apr;130(6):961-969.
doi: 10.1038/s41416-024-02585-y. Epub 2024 Jan 25.

Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care

Benoit Blanchet  1   2   3 , Alexandre Xu-Vuilard  4 , Anne Jouinot  5   6 , Florent Puisset  7   8 , David Combarel  7   9   10   11 , Olivier Huillard  5 , Félicien Le Louedec  7   8 , Fabienne Thomas  7   8   12 , Marcus Teixeira  13   14 , Ronan Flippot  13   14   15 , Loic Mourey  8 , Laurence Albiges  13   14 , Thomas Pudlarz  16 , Charlotte Joly  17 , Christophe Tournigand  17 , Jonathan Chauvin  18 , Alicja Puszkiel  19   7   20 , Etienne Chatelut  7   8   12 , Xavier Decleves  19   7   20 , Michel Vidal  21   19 , François Goldwasser  5 , Stéphane Oudard  4   22 , Jacques Medioni  4 , Yann-Alexandre Vano  4   23
Affiliations
Multicenter Study

Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care

Benoit Blanchet et al. Br J Cancer. 2024 Apr.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

BB has received consulting and speaking fees (Bristol Myers Squibb, Clovis Oncology, Janssen, Pierre Fabre, Pfizer and Promise). SO has received honoraria (Sanofi, Pfizer, Bristol Myers Squibb, Eisai, Merck, Novartis, Ipsen, Astellas, Janssen and Bayer), travel and accommodation expenses (Sanofi, Pfizer, Bristol Myers Squibb, Eisai, Merck, Novartis, Ipsen, Astellas, Janssen and Bayer) and research grants (Sanofi, Astra Zeneca, Pfizer, Novartis, Janssen, Bayer and Roche). YV has received honoraria (Bristol Myers Squibb, Merck, Ipsen, Pfizer and Eisai) and research grants (Bristol Myers Squibb and Ipsen). CJ has received honoraria (Ipsen, Astellas, Bayer and Janssen). RF has received honoraria (Bayer, Astellas, Janssen, Ipsen, Merck, Bristol Myers Squibb, Pfizer and Merck). AP has received speaking fees (Bristol Myers Squibb and Pierre Fabre). LM has received honoraria (Sanofi, Astellas, Janssen, MSD, Bristol Myers Squibb, Ipsen, Astra Zeneca and Merck, Novartis) and travel and accommodation expenses (Sanofi, Astellas, Janssen, Bristol Myers, Ipsen, Astra Zeneca, Pfizer, MSD). LA has received honoraria (Novartis, Astellas, Janssen, MSD, Bristol Myers Squibb, Ipsen, Eisai, Pfizer and Merck, Roche) and travel and accommodation expenses (Bristol Myers Squibb, Ipsen, Pfizer, MSD). OH has received honoraria (Sanofi, Bayer, MSD, Bristol Myers Squibb, Ipsen, Pfizer, Eisai, Janssen, Astra Zeneca and Merck). XD has received consulting honoraria (Inflectis Biosciences, MedDay Pharmaceuticals, MAPREG and Merck). JM has received consulting honoraria (Daiichi Sankyo, Gilead, Lilly Eli, MSD and Pfizer) and travel and accommodation expenses (Lilly Eli, Gilead and Seattle Genetics).AXV, AJ, FP, DC, FLL, FT, MT, TP, CT, JC, EC, MV and FG declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Steady-state plasma trough concentration (Cmin,ss) of cabozantinib according to the daily dose.
Fig. 2
Fig. 2
Frequency of dose-limiting toxicity (DLT) according to the threshold value of 750 ng/mL for steady-state plasma trough concentration (Cav,ss) within the first 3 months of treatment.
Fig. 3
Fig. 3. Survival in patients treated in the second-line or later-line (n = 71) according to cabaozantinib plasma exposure.
Progression-free survival (a) and overall survival (b) according to the threshold value of 336 ng/mL (first decile) for steady-state plasma trough concentration (Cmin,ss).
See this image and copyright information in PMC

References

    1. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3:17009. doi: 10.1038/nrdp.2017.9. - DOI - PMC - PubMed
    1. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl J Med. 2015;373:1814–23. doi: 10.1056/NEJMoa1510016. - DOI - PMC - PubMed
    1. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl J Med. 2021;384:829–41. doi: 10.1056/NEJMoa2026982. - DOI - PMC - PubMed
    1. Buil-Bruna N, López-Picazo J-M, Martín-Algarra S, Trocóniz IF. Bringing model-based prediction to oncology clinical practice: a review of pharmacometrics principles and applications. Oncologist. 2016;21:220–32. doi: 10.1634/theoncologist.2015-0322. - DOI - PMC - PubMed
    1. Schmidinger M, Danesi R, Jones R, McDermott R, Pyle L, Rini B, et al. Individualized dosing with axitinib: rationale and practical guidance. Future Oncol Lond Engl. 2018;14:861–75. doi: 10.2217/fon-2017-0455. - DOI - PubMed

Publication types

LinkOut - more resources