Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.
Ann Arbor Pharmacometrics Group, Inc., Ann Arbor, MI, USA.
Cancer Chemother Pharmacol. 2018 Jun;81(6):1061-1070. doi: 10.1007/s00280-018-3579-7. Epub 2018 Apr 17.
In the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx™) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure.
Exposure-response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints.
Compared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (- 11.9 vs - 9.1 and - 4.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (grade ≥ 1), fatigue/asthenia (grade ≥ 3), diarrhea (grade ≥ 3), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose.
ER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs.
在 III 期 METEOR 试验中，与依维莫司相比，酪氨酸激酶抑制剂卡博替尼显著改善了晚期肾细胞癌（RCC）患者的无进展生存期（PFS）、客观缓解率（ORR）和总生存期，这些患者先前接受过血管内皮生长因子受体抑制剂治疗。在 METEOR 中，RCC 患者起始每日 60mg 卡博替尼片剂（Cabometyx™）剂量，但可减少至 40 或 20mg 以实现可耐受的暴露。
开发暴露-反应（ER）模型以描述 METEOR 中入组的 RCC 患者中卡博替尼的临床相关暴露与疗效（PFS 和肿瘤反应）和安全性终点之间的关系。
与 60mg 剂量的平均稳态卡博替尼浓度相比，模拟 40 和 20mg 起始剂量的暴露预计会增加疾病进展或死亡的风险[风险比（HRs）分别为 1.10 和 1.39]，最大中位肿瘤大小缩小幅度降低（分别为-11.9%、-9.1%和-4.5%），ORR 降低（分别为 19.1%、15.6%和 8.7%）。60mg 暴露还与某些不良事件（AE）的风险增加相关，包括掌跖红细胞发育不良综合征（≥1 级）、疲劳/乏力（≥3 级）、腹泻（≥3 级）和高血压（预测 HRs 分别为 2.21、2.01、1.78 和 1.85），与预测的 20mg 起始剂量的平均稳态卡博替尼浓度相关。
ER 模型预测，与模拟的 40 和 20mg 起始剂量相关的暴露相比，RCC 患者 60mg 起始剂量的卡博替尼暴露将提供更大的抗肿瘤活性，同时降低与临床相关 AE 发生率降低相关的暴露。
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