National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
Lancet Oncol. 2021 Mar;22(3):351-360. doi: 10.1016/S1470-2045(20)30702-6. Epub 2021 Feb 11.
Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab.
This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805.
Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related.
Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy.
Jiangsu Hengrui Medicine and National Key R&D Program of China.
For the Chinese translation of the abstract see Supplementary Materials section.
尽管在曲妥珠单抗治疗 HER2 阳性转移性乳腺癌方面取得了治疗进展，但不可避免地会产生对曲妥珠单抗的耐药性。在 PHOEBE 研究中，我们旨在评估吡咯替尼（一种不可逆的泛 HER 抑制剂）联合卡培他滨在先前接受曲妥珠单抗治疗后的疗效和安全性。
这是一项在中国 29 家医院进行的开放性、随机、对照、III 期试验。入组的患者为经病理证实的 HER2 阳性转移性乳腺癌，年龄 18-70 岁，东部肿瘤协作组体能状态 0 或 1 分，且先前接受过曲妥珠单抗和紫杉类药物治疗。患者以 1:1 的比例随机分配（1:1）接受口服吡咯替尼 400 mg 或拉帕替尼 1250 mg 每日一次联合卡培他滨 1000 mg/m 每日两次，每 21 天周期的第 1-14 天。通过中央交互网络响应系统进行随机分组，区组大小为 4 或 6，并按激素受体状态和转移性疾病的先前化疗线分层。主要终点为根据盲法独立中心评估的无进展生存期。所有至少接受一剂研究药物的患者均进行了疗效和安全性评估。本研究结果来自于预先指定的中期分析。本研究在 ClinicalTrials.gov 注册，NCT03080805。
2017 年 7 月 31 日至 2018 年 10 月 30 日，共纳入 267 例患者并随机分组。134 例患者接受吡咯替尼联合卡培他滨治疗，132 例患者接受拉帕替尼联合卡培他滨治疗。截至 2019 年 3 月 31 日的中期分析数据截止日期，吡咯替尼联合卡培他滨治疗的中位无进展生存期显著长于拉帕替尼联合卡培他滨治疗（吡咯替尼组未达到[95%CI9.7-]，12.5 个月；拉帕替尼组 6.8 个月[5.4-8.1]；风险比 0.39[95%CI0.27-0.56]；单侧 p<0.0001）。最常见的 3 级或更高级别的不良事件为腹泻（吡咯替尼组 41 例[31%]，拉帕替尼组 11 例[8%]）和手足综合征（吡咯替尼组 22 例[16%]，拉帕替尼组 20 例[15%]）。吡咯替尼组有 14 例（10%）患者和拉帕替尼组有 11 例（8%）患者报告了严重不良事件。吡咯替尼组无治疗相关死亡，拉帕替尼组有 1 例猝死被认为与治疗相关。
吡咯替尼联合卡培他滨与拉帕替尼联合卡培他滨相比，显著改善了无进展生存期，且毒性可管理，可作为曲妥珠单抗和化疗后 HER2 阳性转移性乳腺癌患者的另一种治疗选择。
江苏恒瑞医药和国家重点研发计划。
