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
Authors: Ma Fei , Yan Min , Li Wei , Ouyang Quchang , Tong Zhongsheng , Teng Yuee , Wang Yongsheng , Wang Shusen , Geng Cuizhi , Luo Ting , Zhong Jincai , Zhang Qingyuan , Liu Qiang , Zeng Xiaohua , Sun Tao , Mo Qinguo , Liu Hu , Cheng Ying , Cheng Jing , Wang Xiaojia , Nie Jianyun , Yang Jin , Wu Xinhong , Wang Xinshuai , Li Huiping , Ye Changsheng , Dong Fangli , Wu Shuchao , Zhu Xiaoyu , Xu Binghe 
Published: October 2023

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/m
2
) 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.

Trial registration

ClinicalTrials.gov
NCT03863223
.