Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer

Stefanie D. Krens*, Wim van Boxtel, Maike J. M. Uijen, Frank G. A. Jansman, Ingrid M. E. Desar, Sasja F. Mulder, Carla M. L. van Herpen, Nielka P. van Erp

*Corresponding author for this work

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Abstract

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C min at steady-state. The geometric mean (GM) C min at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C min at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P <.001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (C min 971 μg/L [95% CI: 790-1193] vs 669 μg/L [95% CI: 568-788]) (P =.005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM C min at BTD were comparable between the SGC and the RCC group, 694 μg/L (95% CI: 584-824) vs 583 μg/L (95% CI: 496-671) (P =.1). The observed cabozantinib exposure at BTD of approximately 600 μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity.

Original languageEnglish
Pages (from-to)308-316
Number of pages9
JournalInternational Journal of Cancer
Volume150
Issue number2
Early online date16-Sep-2021
DOIs
Publication statusPublished - 15-Jan-2022

Keywords

  • cabozantinib
  • pharmacokinetics
  • renal cell carcinoma
  • salivary gland neoplasms
  • toxicity
  • CARCINOMA
  • SORAFENIB
  • SUNITINIB
  • PHARMACOKINETICS
  • EVEROLIMUS
  • PAZOPANIB
  • EFFICACY
  • THERAPY
  • MET

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