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

• Authors: 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
• Journal: International journal of cancer (Int J Cancer) Vol. 150 Issue 2 Pg. 308-316 (01 15 2022) ISSN: 1097-0215 [Electronic] United States
• PMID: 34494665 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• Anilides
• Pyridines
• cabozantinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Anilides (administration & dosage, adverse effects)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Drug-Related Side Effects and Adverse Reactions (etiology, pathology)
• Female
• Follow-Up Studies
• Humans
• Kidney Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Prognosis
• Pyridines (administration & dosage, adverse effects)
• Retrospective Studies
• Salivary Gland Neoplasms (drug therapy, pathology)