Chen Ling, Jiang Hong, Rao Jun-Jie, Wang Liu-Sheng, Yan Wei, Ye Jian, Lou Jiang
Department of Pharmacy, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Oncol. 2023 Mar 3;13:1146362. doi: 10.3389/fonc.2023.1146362. eCollection 2023.
Efficacy and toxicities of anlotinib (ANL) show large inter-patient variation, which may partly be explained by differences in ANL exposure. Exposure-response/toxicities relationship have not been investigated for ANL. Therefore, the aim of the present study was to explore the association between the trough plasma concentration (C) of ANL and treatment outcomes in Chinese patients with advanced non-small cell lung cancer (NSCLC).
Patients with advanced NSCLC who started third-line or further ANL alone therapy between January 2021 and October 2022. This study examined the ANL C and clinical response evaluation at day 43 after initiation of ANL treatment. We evaluated the association between the ANL C and clinical efficacy and toxicities. Additionally, this study defined patients with complete response (CR), partial response (PR) and stable disease (SD) as responder. The receiver-operating characteristic (ROC) curve combined with Youden index was identify the potential threshold value of ANL C for the responder.
52 patients were evaluated for analyses. The median ANL C was 11.45ng/ml (range, 3.69-26.36 ng/ml). The ANL C values in the PR group (n=6, 15.51 ng/ml (range, 8.19-17.37 ng/ml)) was significantly higher than in the PD group (n=8, 7.44 ng/ml (range, 5.41-14.69 ng/ml), =0.001). The area under the ROC curve (AUC) was 0.76 (95% confidence interval (CI), 0.58-0.93; =0.022) and threshold value of ANL C predicting responder was 10.29 ng/ml (sensitivity 65.9% and specificity 87.5%, the best Youden index was 0.53). The disease control rate (DCR) was 84.6%, and DCR was significantly higher in the high-exposure group (≥10.29ng/ml) than low-exposure group (<10.29ng/ml) (96.67% vs 68.18%, =0.005). Although there was no significant difference in ANL C between grade ≥ 3 and grade ≤2 toxicities, the incidence of any grade hand-foot syndrome (70.0% vs 36.36%, =0.016) and thyroid-stimulating hormone elevation (53.33% vs 22.73%, =0.026) was significantly higher in the high-exposure group compared with the low-exposure group.
Considering these results, we propose that maintaining ANL C ≥ 10.29ng/ml was important for achieving the response in advanced NSCLC patients treated with ANL.
安罗替尼（ANL）的疗效和毒性在患者间存在较大差异，这可能部分归因于ANL暴露量的不同。目前尚未对ANL的暴露-反应/毒性关系进行研究。因此，本研究旨在探讨中国晚期非小细胞肺癌（NSCLC）患者中ANL的血药谷浓度（C）与治疗结果之间的关联。
纳入2021年1月至2022年10月期间开始接受三线或更后线单药ANL治疗的晚期NSCLC患者。本研究检测了ANL治疗开始后第43天的ANL血药浓度C及临床反应评估情况。我们评估了ANL血药浓度C与临床疗效和毒性之间的关联。此外，本研究将完全缓解（CR）、部分缓解（PR）和疾病稳定（SD）的患者定义为有反应者。采用受试者工作特征（ROC）曲线结合约登指数来确定ANL血药浓度C对有反应者的潜在阈值。
共纳入52例患者进行分析。ANL血药浓度C的中位数为11.45ng/ml（范围：3.69 - 26.36 ng/ml）。PR组（n = 6，15.51 ng/ml（范围：8.19 - 17.37 ng/ml））的ANL血药浓度C值显著高于疾病进展（PD）组（n = 8，7.44 ng/ml（范围：5.41 - 14.69 ng/ml），P = 0.001）。ROC曲线下面积（AUC）为0.76（95%置信区间（CI），0.58 - 0.93；P = 0.022），预测有反应者的ANL血药浓度C阈值为10.29 ng/ml（敏感性65.9%，特异性87.5%，最佳约登指数为0.53）。疾病控制率（DCR）为84.6%，高暴露组（≥10.29ng/ml）的DCR显著高于低暴露组（<10.29ng/ml）（96.67% vs 68. 18%，P = 0.005）。虽然≥3级毒性和≤2级毒性患者的ANL血药浓度C无显著差异，但高暴露组任何级别手足综合征的发生率（70.0% vs 36.36%，P = 0.016）和促甲状腺激素升高的发生率（53.33% vs 22.73%，P = 0.026）均显著高于低暴露组。
基于这些结果，我们提出对于接受ANL治疗的晚期NSCLC患者，维持ANL血药浓度C≥10.29ng/ml对于实现反应很重要。
