Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
Formerly of Eisai Inc., Woodcliff Lake, NJ, USA.
Breast Cancer Res. 2021 Mar 18;23(1):33. doi: 10.1186/s13058-021-01407-w.
The recommended starting dose of eribulin in patients with hepatic impairment is based on the Child-Pugh score, largely informed by a pharmacokinetic study of 18 patients. In the pivotal studies of eribulin in metastatic breast cancer (Study 301 and Study 305 [EMBRACE]), entry criteria and dose modifications were based on liver-function test (LFT) results rather than Child-Pugh score. In populations such as patients with metastatic breast cancer, in which metastatic infiltration is the predominant cause of hepatic impairment, using Child-Pugh score may be problematic; in clinical practice, it has been more common for oncologists to make dosing decisions based on LFTs. To address this, the effects of abnormal baseline LFT results on eribulin efficacy and safety were investigated.
In this pooled post hoc analysis, 1062 patients who were randomized to receive eribulin in Studies 301 and 305 were divided into 4 groups: (A) no elevated LFT results (no liver impairment); (B) increased levels of aspartate aminotransferase and/or alanine aminotransferase; (C) decreased albumin and/or increased levels of aspartate aminotransferase and/or alanine aminotransferase but not increased bilirubin; and (D) increased bilirubin. Patients were subcategorized by presence of liver metastasis. Drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs) were analyzed.
Eribulin mesylate mean dosage was 0.82 (group A)-0.65 mg/m/week (group D). Group D had shorter treatment, more dose reductions/delays, more TEAEs leading to dose modifications, and numerically lower objective response rates and clinical benefit rates versus groups A-C. TEAE rates leading to dose modification were similar between group D (45.5%) and groups A-C (range, 43.5-54.9%) in the absence of liver metastases, but higher in group D (91.3%) compared with groups A-C (range, 41.7-54.3%) if liver metastases were present.
Mild elevations in bilirubin levels were associated with increased toxicity and a greater requirement for dose modifications. Based both on these study data and existing recommendations, we propose a novel scheme to guide initial dose selection in patients with metastatic breast cancer and hepatic impairment that is based on LFTs rather than Child-Pugh score.
肝功能损伤患者推荐的艾立布林起始剂量基于 Child-Pugh 评分，主要来自于对 18 例患者的药代动力学研究。在转移性乳腺癌的关键性艾立布林研究（研究 301 和研究 305[EMBRACE]）中，入组标准和剂量调整基于肝功能检测（LFT）结果，而不是 Child-Pugh 评分。在转移性乳腺癌等患者人群中，肝转移是导致肝功能损伤的主要原因，此时使用 Child-Pugh 评分可能会存在问题；在临床实践中，肿瘤医生更倾向于根据 LFT 来做出剂量决策。为解决这一问题，本研究评估了基线 LFT 异常结果对艾立布林疗效和安全性的影响。
本研究为两项研究 301 和 305 的汇总事后分析，共纳入 1062 例随机接受艾立布林治疗的患者，将其分为 4 组：（A）无升高的 LFT 结果（无肝损伤）；（B）天门冬氨酸氨基转移酶和（或）丙氨酸氨基转移酶水平升高；（C）白蛋白降低和（或）天门冬氨酸氨基转移酶和（或）丙氨酸氨基转移酶水平升高但胆红素未升高；（D）胆红素升高。根据是否存在肝转移对患者进行亚组分类。分析药物暴露量、剂量强度和治疗期间出现的不良事件（TEAEs）。
艾立布林甲磺酸酯的平均剂量为 0.82（A 组）-0.65mg/m/周（D 组）。与 A-C 组相比，D 组的治疗时间更短，剂量减少/延迟更多，因 TEAEs 而导致剂量调整的比例更高，客观缓解率和临床获益率更低，数值更低。在无肝转移的情况下，D 组（45.5%）与 A-C 组（范围为 43.5%-54.9%）因 TEAEs 导致剂量调整的发生率相似，但如果存在肝转移，D 组（91.3%）的发生率高于 A-C 组（范围为 41.7%-54.3%）。
胆红素水平轻度升高与毒性增加及更大的剂量调整需求相关。基于这些研究数据和现有推荐，我们提出了一种新的方案，基于 LFT 而不是 Child-Pugh 评分来指导肝功能损伤的转移性乳腺癌患者的初始剂量选择。
