Abstract
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.
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.
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.
The unfavorable risk‐benefit ratio did not warrant further investigation of bosutinib plus letrozole.
Abstract
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
Discussion
This phase II study was designed to evaluate bosutinib plus letrozole versus letrozole as first‐line endocrine therapy in postmenopausal women with locally advanced or metastatic HR+/HER2− BC (Table 1). The DLT‐evaluable population included all part 1 patients who received ≥21 of 28 planned cycle 1 bosutinib and letrozole doses or who experienced a DLT in cycle 1, regardless of the number of doses received. Hepatotoxicity was common in part 1. Two patients experienced serious AEs of ALT/AST elevations that led to treatment discontinuation and met DLT criteria, including one case that met Hy's law criteria, an indicator of drug‐induced hepatic injury [1]; liver function test abnormalities resolved after bosutinib discontinuation. Specific class II human leukocyte antigen alleles may play a role in tyrosine kinase inhibitor‐induced hepatotoxicity [2]. One patient achieved a confirmed partial disease response. Although the safety profile for bosutinib plus letrozole was not fully determined because the upper bound of the 80% confidence interval (CI) for the 12% DLT rate (80% CI: 12%–46%) was not ≤34%, per protocol, it was decided that the observed risks exceeded potential benefits, and the study was terminated prematurely by the sponsor before part 2.
Treatment summary (safety population)
Treatment summary (safety population)
In another phase II trial with a similar design evaluating bosutinib at 400 mg/day plus exemestane at 25 mg/day as second‐line therapy in postmenopausal women with HR+/HER2− BC (ClinicalTrials.gov identifier NCT00793546), 5 of 13 evaluable patients had a DLT, and these were all hepatic or gastrointestinal events [3]. The recommended phase II dose (RP2D) of bosutinib 300 mg/day plus exemestane 25 mg/day had a generally acceptable safety profile: 3 of 26 evaluable patients (12% [80% CI: 4%–24%]) had a DLT, and again, all were hepatic or gastrointestinal events. No hepatic toxicity met Hy's law criteria; however, the treatment‐related hepatotoxicity rate of 26% did not support further evaluation of this combination. One patient achieved a confirmed partial disease response on the RP2D; however, the 80% CI upper boundary for median progression‐free survival (PFS) was below the benchmark of 16 weeks for exemestane [3].
Preclinical studies had demonstrated that bosutinib inhibits BC cell proliferation, invasion, and migration, as well as tumor growth and metastasis in vivo [4–6]. A phase II trial of bosutinib monotherapy utilizing a dose of 400 mg/day in heavily pretreated advanced BC patients unselected for HR status demonstrated a clinical benefit rate of 27% and a 16‐week PFS rate of 40%; all four patients whose tumors responded had HR+ BC [7]. Common toxicities included gastrointestinal events (diarrhea [66%], nausea [55%], vomiting [47%]), and grade 3/4 ALT/AST laboratory elevations (19%) [7]. A similar safety profile was observed in a phase I study of bosutinib in advanced solid tumors [8].
Bosutinib plus letrozole has a worse safety profile than single‐agent bosutinib, which is characterized by manageable events and the absence of life‐threatening events [7, 8]. Given the efficacy of bosutinib monotherapy in metastatic BC, Src/Abl inhibition remains a novel treatment strategy. Alternative combination regimens with bosutinib warrant consideration in metastatic BC.
Author disclosures and references available online.
Access the full results at: Moy‐14‐21.theoncologist.com
ClinicalTrials.gov Identifier: NCT00880009 Sponsor(s): Wyeth Research (acquired by Pfizer in October 2009)
Principal Investigator: Beverly Moy IRB Approved: Yes
