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Clinical Studies

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

British Journal of Cancer volume 130, pages 961–969 (2024)Cite this article

Subjects

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.

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Fig. 1
Fig. 2
Fig. 3: Survival in patients treated in the second-line or later-line (n = 71) according to cabaozantinib plasma exposure.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Author information

Authors and Affiliations

  1. Université de Paris, CNRS, INSERM, CiTCoM, U1268, F-75006, Paris, France

    Benoit Blanchet & Michel Vidal

  2. Biologie du Médicament – Toxicologie, Institut du Cancer Paris CARPEM, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

    Benoit Blanchet, Alicja Puszkiel, Xavier Decleves & Michel Vidal

  3. Groupe de Pharmacologie Clinique Oncologique GPCO-Unicancer, Paris, France

    Benoit Blanchet, Florent Puisset, David Combarel, Félicien Le Louedec, Fabienne Thomas, Alicja Puszkiel, Etienne Chatelut & Xavier Decleves

  4. Department of Medical Oncology, Institut du Cancer Paris CARPEM, Assistance Publique Hôpitaux de Paris, Hôpital Georges Pompidou, Paris, France

    Alexandre Xu-Vuilard, Stéphane Oudard, Jacques Medioni & Yann-Alexandre Vano

  5. Department of Medical Oncology, ARIANE, Institut du Cancer Paris CARPEM, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France

    Anne Jouinot, Olivier Huillard & François Goldwasser

  6. Université Paris Cité, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France

    Anne Jouinot

  7. Oncopole Claudius-Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, 31059, Toulouse, France

    Florent Puisset, Félicien Le Louedec, Fabienne Thomas, Loic Mourey & Etienne Chatelut

  8. Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France

    David Combarel

  9. Faculté de pharmacie, Université Paris Saclay, Orsay, France

    David Combarel

  10. Medical School, University of Paris XI, Saclay, France

    David Combarel

  11. CRCT, Cancer Research Center of Toulouse, Inserm U1037, Université Paul Sabatier, 31037, Toulouse, France

    Fabienne Thomas & Etienne Chatelut

  12. Department of Oncological Medicine, Gustave Roussy, Villejuif, France

    Marcus Teixeira, Ronan Flippot & Laurence Albiges

  13. Medical School, University of Paris XI Saclay, Saclay, France

    Marcus Teixeira, Ronan Flippot & Laurence Albiges

  14. Laboratoire d’immunomonitoring en oncologie, CNRS3655 & INSERM US23, Université Paris Saclay, Paris, France

    Ronan Flippot

  15. Department of Medical Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Saint Antoine, Paris, France

    Thomas Pudlarz

  16. Department of Medical Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor, Université de Paris Est, Créteil, France

    Charlotte Joly & Christophe Tournigand

  17. Lixoft, 92160, Antony, France

    Jonathan Chauvin

  18. Université Paris Cité, Inserm, UMR-S1144, Paris, France

    Alicja Puszkiel & Xavier Decleves

  19. Université de Paris Cité, INSERM U970, PARCC, Paris, France

    Stéphane Oudard

  20. Université de Paris Cité, UMR_S1138-INSERM, Paris, France

    Yann-Alexandre Vano

Authors
  1. Benoit Blanchet
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  2. Alexandre Xu-Vuilard
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  4. Florent Puisset
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  6. Olivier Huillard
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  7. Félicien Le Louedec
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  8. Fabienne Thomas
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  11. Loic Mourey
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  12. Laurence Albiges
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  14. Charlotte Joly
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  15. Christophe Tournigand
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  18. Etienne Chatelut
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  19. Xavier Decleves
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  20. Michel Vidal
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  21. François Goldwasser
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  22. Stéphane Oudard
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  23. Jacques Medioni
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  24. Yann-Alexandre Vano
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Contributions

BB, AJ, JM, and YV designed the study. All authors participated in the collection and assembly of data. AJ performed the statistical analysis. BB, AJ, and YV drafted the manuscript. All authors revised the work, approved its final version, and agreed to be accountable for all its aspects.

Corresponding author

Correspondence to Benoit Blanchet.

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Competing interests

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.

Ethics approval and consent to participate

The study was approved by the local ethics committee in oncology (CLEP number: AAA-2022–08055). Informed consent was obtained from all patients prior to inclusion.

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Blanchet, B., Xu-Vuilard, A., Jouinot, A. et al. Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care. Br J Cancer 130, 961–969 (2024). https://doi.org/10.1038/s41416-024-02585-y

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