Bosutinib in Combination With the Aromatase Inhibitor Letrozole: A Phase II Trial in Postmenopausal Women Evaluating First‐Line Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor‐Positive/HER2‐Negative Breast Cancer

Background. Endocrine therapy resistance in hormone receptor‐positive (HR+) breast cancer (BC) may involve crosstalk between HRs and growth factor signaling pathways. We evaluated bosutinib, a dual Src/Abl tyrosine kinase inhibitor that has previously demonstrated some antitumor activity in BC, plus letrozole as first‐line endocrine therapy in locally advanced or metastatic HR+/HER2− BC. Methods. Sixteen postmenopausal women were enrolled in a phase II study evaluating the safety/efficacy of bosutinib plus letrozole. In the single‐arm safety/dose‐confirming lead‐in (part 1), patients received oral bosutinib at 400 mg/day plus letrozole at 2.5 mg/day; adverse events (AEs) and dose‐limiting toxicities (DLTs) were monitored, and initial efficacy was assessed. A randomized efficacy/safety phase (part 2) was planned to evaluate the combination versus letrozole monotherapy. Results. Fifteen of 16 subjects experienced treatment‐related AEs, most commonly diarrhea (69%). Treatment‐related hepatotoxicity AEs (primarily alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations) occurred in 6 of 16 patients (38%). Four of 15 evaluable patients (27%) experienced a DLT (grade 3/4 ALT/AST elevations, n = 2; grade 3 rash, n = 1; grade 3 diarrhea or vomiting, n = 1), including 1 Hy's law hepatotoxicity case. All DLTs resolved following treatment discontinuation. One patient achieved confirmed partial response; one had stable disease for >24 weeks. Study termination occurred before part 2. Conclusion. The unfavorable risk‐benefit ratio did not warrant further investigation of bosutinib plus letrozole. 摘要 背景. 激素受体阳性（HR+）乳腺癌（BC）对内分泌治疗耐药的原因可能归于HR和生长因子信号通路之间的信号串扰。作为双重Src/Abl酪氨酸激酶抑制剂，博舒替尼已在既往研究中显示出对BC的抗肿瘤效应，本文则评估了博舒替尼联合来曲唑作为一线内分泌治疗用于局部晚期或转移性HR+/HER2‐ BC的疗效。 方法. 16例绝经后女性入组本次评估博舒替尼联合来曲唑的安全性/疗效II期研究。在单臂安全性/剂量确认的前期阶段（第1阶段），接受口服博舒替尼400 mg/d联合来曲唑2.5 mg/d；同时监测不良事件（AE）和剂量限制性毒性反应（DLT），评估最初的疗效。随后则计划进入随机化疗效/安全性阶段（第2阶段），以对比评估联合方案与来曲唑单药。 结果. 16例受试者中有15例出现治疗相关的AE，最常见为腹泻（69%）。治疗相关的肝毒性AE[主要为丙氨酸转氨酶（ALT）或天冬氨酸转氨酶（AST）升高]发生于16例患者中的6例（38%）。15例可评估患者中有4例（27%）出现DLT（3/4级 ALT/AST升高，n = 2；3级皮疹，n = 1；3级腹泻或呕吐，n = 1），包括1例海氏法则肝毒性。全部DLT均在治疗停止后缓解。1例患者证实达到部分缓解；1例疾病稳定> 24周。研究在第2阶段开始前结束。 结论. 博舒替尼联合来曲唑方案的风险‐获益比结果欠佳，因此研究不再深入进行。The Oncologist 2014;19:348‐349