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/m2/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.

中文翻译：

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艾日布林、Child-Pugh 评分和肝功能检查：关键乳腺癌研究 301 和 305 的经验教训

肝功能不全患者推荐的艾日布林起始剂量基于 Child-Pugh 评分，主要来自对 18 名患者的药代动力学研究。在转移性乳腺癌中艾日布林的关键研究（研究 301 和研究 305 [EMBRACE]）中，进入标准和剂量修改基于肝功能测试 (LFT) 结果而不是 Child-Pugh 评分。在转移性乳腺癌患者等人群中，转移性浸润是肝功能损害的主要原因，使用 Child-Pugh 评分可能存在问题；在临床实践中，肿瘤学家更普遍地根据 LFT 做出剂量决定。为了解决这个问题，研究了异常基线 LFT 结果对艾日布林疗效和安全性的影响。在这个汇总的事后分析中，在研究 301 和 305 中随机接受艾日布林治疗的 1062 名患者分为 4 组：(A) LFT 结果无升高（无肝损伤）；(B) 天冬氨酸转氨酶和/或丙氨酸转氨酶水平升高；(C) 白蛋白降低和/或天冬氨酸转氨酶和/或丙氨酸转氨酶水平升高，但胆红素不升高；(D) 胆红素增加。根据肝转移的存在对患者进行亚分类。分析了药物暴露、剂量强度和治疗中出现的不良事件 (TEAE)。甲磺酸艾日布林平均剂量为 0.82（A 组）–0.65 mg/m2/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，导致剂量调整的 TEAE 增多，并且客观反应率和临床受益率在数值上较低。在没有肝转移的情况下，导致剂量调整的 TEAE 率在 D 组（45.5%）和 A-C 组（范围，43.5-54.9%）之间相似，但与 A-C 组相比，D 组（91.3%）更高（范围，41.7-54.3%）如果存在肝转移。胆红素水平轻度升高与毒性增加和对剂量调整的更大要求有关。基于这些研究数据和现有的建议，我们提出了一种新的方案来指导转移性乳腺癌和肝功能损害患者的初始剂量选择，该方案基于 LFT 而不是 Child-Pugh 评分。胆红素水平轻度升高与毒性增加和对剂量调整的更大要求有关。基于这些研究数据和现有的建议，我们提出了一种新的方案来指导转移性乳腺癌和肝功能损害患者的初始剂量选择，该方案基于 LFT 而不是 Child-Pugh 评分。胆红素水平轻度升高与毒性增加和对剂量调整的更大要求有关。基于这些研究数据和现有的建议，我们提出了一种新的方案来指导转移性乳腺癌和肝功能损害患者的初始剂量选择，该方案基于 LFT 而不是 Child-Pugh 评分。