吡咯替尼是中国原创的HER1、HER2、HER4酪氨酸激酶不可逆抑制剂，联合卡培他滨治疗HER2阳性晚期乳腺癌已被证实可以显著改善患者生存，且耐受性良好。 2022年12月27日，英国生物医学中心《医学》正式发表复旦大学附属肿瘤医院吴炅✉️杨犇龙、解放军总医院第五医学中心江泽飞、河南省肿瘤医院刘真真、浙江省肿瘤医院杨红健、江苏省人民医院唐金海、广东省人民医院王坤、河北省肿瘤医院刘运江、青岛大学附属医院王海波、浙江大学医学院附属第一医院傅佩芬、西安交通大学附属第二医院张淑群、中山大学孙逸仙纪念医院刘强、中山大学附属肿瘤医院王树森、浙江大学医学院附属第二医院黄建、福建医科大学附属协和医院王川、北京大学人民医院王殊、山东省肿瘤医院王永胜、南京医科大学附属淮安第一医院甄林林、恒瑞医药朱晓宇、吴非、林翔、邹建军等学者的PHEDRA研究报告全文，进一步证实HER2阳性早期或局部晚期乳腺癌术前吡咯替尼＋曲妥珠单抗＋多西他赛新辅助治疗的有效性和安全性。 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) 该多中心双盲安慰剂随机对照三期临床研究于2018年7月23日～2021年1月8日从中国17家医院入组HER2阳性早期或局部晚期乳腺癌术前女性355例，按1∶1随机分为两组，每天口服400mg吡咯替尼或安慰剂＋每3周静脉注射曲妥珠单抗首次8mg/kg随后6mg/kg＋多西他赛100mg/m²共计4轮术前新辅助治疗。主要终点为独立中心评定的总体（乳房＋淋巴结）病理完全缓解率（ypT0/is和ypN0）。
BMC Med. 2022 Dec 27;20(1):498. IF: 11.150 Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial. Wu J, Jiang Z, Liu Z, Yang B, Yang H, Tang J, Wang K, Liu Y, Wang H, Fu P, Zhang S, Liu Q, Wang S, Huang J, Wang C, Wang S, Wang Y, Zhen L, Zhu X, Wu F, Lin X, Zou J. Fudan University Shanghai Cancer Center, Shanghai, China; The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China; Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; Zhejiang Cancer Hospital, Hangzhou, China; Jiangsu Province Hospital, Nanjing, China; Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; The Affiliated Hospital of Qingdao University, Qingdao, China; The First Affiliated Hospital Zhejiang University, Hangzhou, China; The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Sun Yat-Sen University Cancer Center, Guangzhou, China; The Second Affiliated Hospital, Zhejiang University, Hangzhou, China; Fujian Medical University Union Hospital, Fuzhou, China; Peking University People's Hospital, Beijing, China; Shandong Cancer Hospital, Jinan, China; The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, China; Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China. BACKGROUND: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. METHODS: In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. RESULTS: Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. CONCLUSIONS: The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03588091. KEYWORDS: Breast cancer; HER2; Neoadjuvant treatment; Phase 3; Pyrotinib PMID: 36575513 DOI: 10.1186/s12916-022-02708-3
