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.

Results of the first international quality control programme for oral targeted oncolytics

“…This might have led to contrary dose recommendations, as was also described in the treatment algorithm based on measured exposure and clinical response proposed by Krens et al 30 In contrast to pazopanib, however, no clear exposure-response relationship has been established for cabozantinib thus far and TDM is not yet routinely used for this drug. 31,32 The overall performances seem to largely depend on the drug being analysed. This was to be expected for some of the oral targeted oncolytics of the QC programme due to their drug-specific properties.…”

“…The reference concentration was spiked at 800 μg/L, while the results ranged from 486 to 916 μg/L. This might have led to contrary dose recommendations, as was also described in the treatment algorithm based on measured exposure and clinical response proposed by Krens et al 30 In contrast to pazopanib, however, no clear exposure–response relationship has been established for cabozantinib thus far and TDM is not yet routinely used for this drug 31,32 …”