雖然越來(lái)越多的證據(jù)表明，雙重阻斷人類表皮生長(zhǎng)因子受體HER2可治療局部晚期HER2陽(yáng)性乳腺癌，但是仍然缺乏影響因子10分以上期刊發(fā)表強(qiáng)有力的前瞻研究證據(jù)支持將吡咯替尼加入曲妥珠單抗新輔助治療。2020年9月，美國(guó)轉(zhuǎn)化腫瘤學(xué)會(huì)《腫瘤學(xué)家》發(fā)表重慶西南醫(yī)院的二期臨床研究報(bào)告，首次探討了19例HER2陽(yáng)性I～I(xiàn)II期（II期占75%）乳腺癌術(shù)前24周吡咯替尼＋12周表柔比星和環(huán)磷酰胺→12周多西他賽和曲妥珠單抗新輔助治療，病理完全緩解率為73.7%。2022年1月，AME旗下《腺體外科》發(fā)表四川大學(xué)華西醫(yī)院的二期臨床研究報(bào)告，探討了21例HER2陽(yáng)性IIA～I(xiàn)IIC期（III期占81.0%）乳腺癌術(shù)前12周吡咯替尼＋曲妥珠單抗＋白蛋白紫杉醇新輔助治療，病理完全緩解率為57.1%。2022年2月，歐洲癌癥治療研究組織《歐洲癌癥雜志》發(fā)表河南省腫瘤醫(yī)院、新鄉(xiāng)市中心醫(yī)院、安陽(yáng)市腫瘤醫(yī)院的二期臨床研究報(bào)告，探討了21例HER2陽(yáng)性II～I(xiàn)II期（II期占78.3%）乳腺癌術(shù)前18周吡咯替尼＋多西他賽＋卡鉑＋曲妥珠單抗新輔助治療，病理完全緩解率為55.1%。不過(guò)，這些期刊影響因子均未超過(guò)10分。 2022年6月17日，美國(guó)癌癥研究協(xié)會(huì)《臨床癌癥研究》在線發(fā)表上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院的二期臨床研究NeoATP初步分析報(bào)告，探討了HER2陽(yáng)性局部晚期乳腺癌術(shù)前16周曲妥珠單抗＋吡咯替尼＋紫杉醇+順鉑新輔助治療的有效性和安全性。NeoATP (NCT04126525): Neoadjuvant Study of Pyrotinib in HER-2 Positive Breast Cancer (NeoAdjuvant Trastuzumab/ Pyrotinib Plus Weekly Paclitaxel/Cisplatin in HER2-positive Locally Advanced Breast Cancer Patients)
該單中心單組二期臨床研究于2019年7月2日～2021年7月27日從上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院入組組織學(xué)證實(shí)為IIA～I(xiàn)IIC期（III期占73.58%）HER2陽(yáng)性原發(fā)乳腺浸潤(rùn)癌女性患者53例（中位年齡47歲）接受16周吡咯替尼＋曲妥珠單抗＋每周紫杉醇＋順鉑新輔助化療。主要終點(diǎn)為病理完全緩解（ypT0 ypN0）。關(guān)鍵次要終點(diǎn)包括局部區(qū)域病理完全緩解（ypT0/is ypN0）、生物標(biāo)志物分析和安全性。 結(jié)果，52例完成研究治療和手術(shù)，其中37例（69.81%）實(shí)現(xiàn)病理完全緩解、39例（73.58%）實(shí)現(xiàn)局部區(qū)域病理完全緩解。 激素受體陰性和陽(yáng)性腫瘤患者的病理完全緩解率分別為85.71%和59.38%（P=0.041），而PIK3CA突變和未突變患者的病理完全緩解率分別為69.23%和70.00%（P=0.958）。 發(fā)生率最高的3～4級(jí)不良事件為腹瀉（45.28%）、白細(xì)胞減少（39.62%）和中性粒細(xì)胞減少（32.08%）。未發(fā)生死亡，未報(bào)告基線至手術(shù)前未報(bào)告左心室射血分?jǐn)?shù)<50%或下降>10個(gè)百分點(diǎn)。 因此，該研究結(jié)果表明，曲妥珠單抗＋化療＋吡咯替尼對(duì)于HER2陽(yáng)性局部晚期乳腺癌患者是安全有效的方案之一，故有必要進(jìn)一步開(kāi)展隨機(jī)對(duì)照三期臨床研究PHEDRA進(jìn)行驗(yàn)證。PHEDRA (NCT03588091): Neoadjuvant Study of Pyrotinib in Combination With Trastuzumab in Patients With HER2 Positive Breast Cancer (A Randomized, Muticenter Double-blind Phase III Study of Neoadjuvant Pyrotinib Plus Trastuzumab and Docetaxel Compared With Placebo Plus Trastuzumab and Docetaxel in Women With HER2 Positive Early Stage or Locally Advanced Breast Cancer)
據(jù)悉，根據(jù)PHEDRA研究結(jié)果，國(guó)家藥品監(jiān)督管理局已于2022年6月6日正式批準(zhǔn)吡咯替尼與曲妥珠單抗和多西他賽聯(lián)合用于HER2陽(yáng)性早期或局部晚期乳腺癌患者的新輔助治療。讓我們期待PHEDRA研究早日全文發(fā)表。Clin Cancer Res. 2022 Jun 17. Online ahead of print.Neoadjuvant Trastuzumab and Pyrotinib for Locally Advanced HER2-Positive Breast Cancer (NeoATP): Primary Analysis of a Phase II Study.Yin W, Wang Y, Wu Z, Ye Y, Zhou L, Xu S, Lin Y, Du Y, Yan T, Yang F, Zhang J, Liu Q, Lu J.Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.PURPOSE: Despite accumulating evidence on dual blockade of human epidermal growth factor receptor 2 (HER2) for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy.METHODS: The phase II NeoATP trial included female patients with histologically confirmed stage IIA-IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel-cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathological complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis and safety.RESULTS: Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor negative and positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00% respectively for those with and without PIK3CA mutation (P = 0.958). The most frequently reported grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%) and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction <50% or >10 points drop from baseline to before surgery was reported.CONCLUSIONS: The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.DOI: 10.1158/1078-0432.CCR-22-0446
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