1363:卡博赞替尼在涎腺癌和肾细胞癌患者中的暴露毒性分析

Stefanie D. Krens, W. V. Boxtel, M. Uijen, F. Jansman, I. Desar, S. Mulder, C. V. Herpen, N. P. Erp
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Methods Clinical data and cabozantinib trough concentrations (Cmin) were collected from all patients treated with cabozantinib with at least one measured Cmin at steady state in our clinic between Jan 2018 - Aug 2020. We included salivary gland cancer (SGC) patients treated in a phase II study and RCC patients from our outpatient clinic. Geometric mean (GM) Cmin at the start dose, at 40 mg and at best tolerated dose (BTD) were compared between the two tumour types. Results In total 47 patients were included. All patients with SGC (n=22) started with 60 mg, while 13 of 25 patients with RCC started with 40 mg. GM Cmin level at the start dose was 1350 µg/L (95% CI 1182-1781) vs. 689 µg/L (95% CI 576-823) (P 750 ug/L. Conclusion Unexpectedly, cabozantinib levels were significantly higher in patients with SGC compared to those with RCC at the dose of 40 mg. However, cabozantinib levels at BTD were comparable between patients with SGC and RCC. 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引用次数: 1

摘要

Cabozantinib被批准用于治疗肾细胞癌(RCC),起始剂量为60mg。然而,在登记研究中,由于毒性,46-62%的患者需要减少剂量。在平均暴露量> 750 ug/L的RCC患者中,卡博桑替尼的临床疗效得到改善。常规使用卡博赞替尼治疗的患者的药代动力学数据很少,而由于其毒性,治疗具有挑战性。因此,我们在我们的临床中探讨了两种不同肿瘤类型患者的卡博赞替尼暴露。方法收集2018年1月至2020年8月在我院接受卡博赞替尼治疗且至少有一项Cmin处于稳态的患者的临床数据和卡博赞替尼谷浓度(Cmin)。我们纳入了在II期研究中治疗的唾液腺癌(SGC)患者和门诊诊所的RCC患者。比较两种肿瘤类型在起始剂量、40mg和最佳耐受剂量(BTD)时的几何平均(GM) Cmin。结果共纳入47例患者。所有SGC患者(n=22)起始剂量为60mg,而25例RCC患者中有13例起始剂量为40mg。起始剂量时GM Cmin水平分别为1350µg/L (95% CI 1182 ~ 1781)和689µg/L (95% CI 576 ~ 823) (P 750 ug/L)。出乎意料的是,在40mg剂量下,SGC患者的卡博赞替尼水平明显高于RCC患者。然而,在SGC和RCC患者中,BTD的卡博赞替尼水平是相当的。在BTD时,大多数患者未达到>750µg/L的目标。对于大多数RCC患者,BTD时的卡博赞替尼水平相当于40mg的剂量。因此,RCC患者首选40mg而不是60mg作为起始剂量,然后根据暴露和耐受性进行剂量调整。虽然卡博赞替尼没有注册用于SGC,但基于BTD时卡博赞替尼的水平,这些患者可能需要更低的起始剂量20mg /天。未来的研究应侧重于确定卡博赞替尼的最佳和可耐受的暴露-反应目标值,并阐明导致暴露差异的因素,以便个性化和改善治疗。引用格式:Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp。卡博赞替尼在涎腺癌和肾细胞癌患者中的暴露毒性分析[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):1363。
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Abstract 1363: Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer
Background Cabozantinib is approved for treatment of renal cell cancer (RCC) in a starting dose of 60 mg. However, in the registration studies dose reductions were needed in 46-62% of patients due to toxicity. Improved clinical efficacy of cabozantinib was observed in RCC patients with an average exposure of > 750 ug/L. Data about cabozantinib pharmacokinetics in patients routinely treated with this drug is scarce, while treatment is challenging due to toxicity. Therefore, we explored the cabozantinib exposure in patients with two different tumour types in our clinic. Methods Clinical data and cabozantinib trough concentrations (Cmin) were collected from all patients treated with cabozantinib with at least one measured Cmin at steady state in our clinic between Jan 2018 - Aug 2020. We included salivary gland cancer (SGC) patients treated in a phase II study and RCC patients from our outpatient clinic. Geometric mean (GM) Cmin at the start dose, at 40 mg and at best tolerated dose (BTD) were compared between the two tumour types. Results In total 47 patients were included. All patients with SGC (n=22) started with 60 mg, while 13 of 25 patients with RCC started with 40 mg. GM Cmin level at the start dose was 1350 µg/L (95% CI 1182-1781) vs. 689 µg/L (95% CI 576-823) (P 750 ug/L. Conclusion Unexpectedly, cabozantinib levels were significantly higher in patients with SGC compared to those with RCC at the dose of 40 mg. However, cabozantinib levels at BTD were comparable between patients with SGC and RCC. At BTD, the majority of patients did not reach the target of >750 µg/L. For most patients with RCC, the cabozantinib level at BTD corresponded to a dose of 40 mg. Therefore, 40 mg instead of 60 mg as a starting dose followed by dose-adjustment based on exposure and tolerability may be preferred in patients with RCC. Although cabozantinib is not registered for SGC, an even lower starting dose of 20 mg/day may be required in these patients based on cabozantinib levels at BTD. Future studies should focus on identifying an optimal and tolerable exposure-response target value for cabozantinib and elucidate factors that contribute to the differences in exposure, in order to individualise and improve treatment. Citation Format: Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp. Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1363.
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