中国医学科学院北京协和医学院徐兵河团队比较了吡咯替尼与安慰剂对未经治疗的HER2阳性转移性乳腺癌症的疗效和安全性。2023年10月31日出版的《英国医学杂志》发表了这项成果。

为了评估吡咯替尼（一种不可逆的泛-HER（人表皮生长因子受体）抑制剂）、曲妥珠单抗和多西他赛与安慰剂、曲妥珠单抗和多西他赛相比，对未经治疗的HER2阳性转移性乳腺癌症的疗效和安全性，2019年5月6日至2022年1月17日，研究组在中国的40个中心进行了一项随机、双盲、安慰剂对照、多中心、3期临床试验。

共招募590名女性患者（中位年龄52岁），患有未经治疗的HER2阳性转移性癌症。符合条件的患者被1:1随机分组，在每个21天周期的第1天接受口服吡咯替尼（400 mg，每日一次）或安慰剂治疗，两者均联合静脉注射曲妥珠单抗（第1周期为8 mg/kg，随后周期为6 mg/kg）和多西他赛（75 mg/m²）。随机分组根据曲妥珠单抗在（新）佐剂环境下的治疗史和激素受体状态进行分层。患者、研究人员和申办方的研究团队双盲接受治疗任务。主要终点是研究者评估的无进展生存率。

在590名随机患者中，297名接受了吡咯替尼、曲妥珠单抗和多西他赛治疗（吡咯替尼组），293名接受了安慰剂、曲妥珠单抗和多西他赛治疗（安慰剂组）。截至2022年5月25日数据截止时，中位随访时间为15.5个月。根据研究者报道，吡咯替尼组的中位无进展生存期明显长于安慰剂组（分别为24.3个月与10.4个月；危险比为0.41；单侧P＜0.001）。吡咯替尼组297名患者中有267名（90%）和安慰剂组293名患者中有224名（76%）报道了3级或更高级别的治疗相关不良事件。吡咯替尼组未发生与治疗相关的死亡，安慰剂组发生1例（<1%；糖尿病高渗昏迷）。存活率和毒性仍在评估中，随访时间更长。

研究结果表明，在未经治疗的HER2阳性转移性癌症患者中，与安慰剂、曲妥珠单抗和多西他赛相比，吡咯替尼、曲妥珠单抗和多西他赛显著提高了无进展生存率，显示出优越性。毒性是可控的。研究结果支持这种双重抗HER2方案作为该患者群体的替代一线治疗方案。

附：英文原文

Title: Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial

Author: Fei Ma, Min Yan, Wei Li, Quchang Ouyang, Zhongsheng Tong, Yuee Teng, Yongsheng Wang, Shusen Wang, Cuizhi Geng, Ting Luo, Jincai Zhong, Qingyuan Zhang, Qiang Liu, Xiaohua Zeng, Tao Sun, Qinguo Mo, Hu Liu, Ying Cheng, Jing Cheng, Xiaojia Wang, Jianyun Nie, Jin Yang, Xinhong Wu, Xinshuai Wang, Huiping Li, Changsheng Ye, Fangli Dong, Shuchao Wu, Xiaoyu Zhu, Binghe Xu

Issue&Volume: 2023/10/31

Abstract:

Objective To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer.

Design Randomised, double blind, placebo controlled, multicentre, phase 3 trial.

Setting 40 centres in China between 6 May 2019 and 17 January 2022.

Participants 590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer.

Interventions Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor’s study team were masked to treatment assignment.

Main outcome measures The primary endpoint was progression-free survival as assessed by the investigator.

Results Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up.

Conclusions Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population.

DOI: 10.1136/bmj-2023-076065

Source: https://www.bmj.com/content/383/bmj-2023-076065