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
. 2022 Jan 15;150(2):308-316.
doi: 10.1002/ijc.33797. Epub 2021 Sep 16.

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

Stefanie D Krens  1 , Wim van Boxtel  2 , Maike J M Uijen  2 , Frank G A Jansman  3   4 , Ingrid M E Desar  2 , Sasja F Mulder  2 , Carla M L van Herpen  2 , Nielka P van Erp  1
Affiliations

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

Stefanie D Krens et al. Int J Cancer. .

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 Cmin at steady-state. The geometric mean (GM) Cmin 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 Cmin 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 (Cmin 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 Cmin 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.

Keywords: cabozantinib; pharmacokinetics; renal cell carcinoma; salivary gland neoplasms; toxicity.

PubMed Disclaimer

Conflict of interest statement

All mentioned relationships are outside the submitted work. FGAJ has been on an advisory board for Amgen and Genzyme. IMED received a research grant from Novartis. NPvE has received research grants from Novartis, Astellas, Janssen‐Cilag, Pfizer, Ipsen, has been on an advisory board for Pfizer, and received honoraria from Bayer and Sanofi. CMLvH has received research grants form AstraZeneca, Bristol Meyers Squibb, Merck Sharp and Dohme, Merck, Ipsen, Sanofi, and Novartis, has been on an advisory board for Bayer, Bristol‐Meyers Squibb, Ipsen, Merck Sharp and Dohme and Regeneron. SFM received honoraria from Pfizer, Roche and Merck Sharp and Dohme and Bristol Meyers Squibb. The other authors declare no conflicts of interest. (SDK, MU, WvB).

Figures

FIGURE 1
FIGURE 1
Scatter plots of the individual cabozantinib C min levels at start, 40 mg and at BTD for patients with SGC and RCC. Data are presented with geometric mean (95% CI). BTD, best tolerated dose; CI, confidence interval; C min, trough concentration, RCC, metastatic renal cell carcinoma; SGC, salivary gland cancer
See this image and copyright information in PMC

References

    1. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298‐2308. - PubMed
    1. Bergerot P, Lamb P, Wang E, Pal SK. Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol Cancer Ther. 2019;18(12):2185‐2193. - PubMed
    1. FDA . Cabometyx prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208692s008lbl.pdf. Accessed December 1, 2020.
    1. Choueiri TK, Powles T, Burotto M, et al. 696O_PR Nivolumab + cabozantinib vs sunitinib in first‐line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31:S1159.
    1. Agarwal N, Vaishampayan U, Green M, et al. 872P: phase Ib study (COSMIC‐021) of cabozantinib in combination with atezolizumab: results of the dose escalation stage in patients (pts) with treatment‐naïve advanced renal cell carcinoma (RCC). Ann Oncol. 2018;29:viii308.

MeSH terms