LAUSR

Background: The interim analysis of the PHILA trial (NCT03863223) revealed that pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2, and HER4) in combination with trastuzumab and docetaxel (PyroHT) significantly improved PFS compared to placebo in combination with trastuzumab and docetaxel (HT) in untreated HER2-positive mBC patients (Ma et al., BMJ, 2023). However, the overall survival (OS) data was immature at that time. Here, we present the prespecified final analysis of PFS, as well as long-term efficacy and safety outcomes from the PHILA trial following an additional 2-year of follow-up. Methods: The PHILA study was a randomized, double-blind, multicenter, phase 3 trial conducted at 40 centers in China. Eligible patients were randomly assigned in a 1:1 ratio to receive either oral pyrotinib (400 mg once daily) or placebo, both in combination with intravenous trastuzumab (8 mg/kg in the first cycle and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21-day cycle. The primary endpoint was investigator-assessed PFS. The data cutoff date for this final analysis of PFS was April 30, 2024. Results: Between May 2019 and January 2022, 590 eligible patients were randomized and received their allocated treatment (297 patients in the PyroHT group and 293 patients in the HT group). The median follow-up duration was 35.7 months for the PyroHT group and 34.3 months for the HT group. The benefit of investigator-assessed PFS associated with the PyroHT group, compared to the HT group, was sustained in this final analysis (22.1 months [95% CI 19.3–27.8] vs 10.5 months [95% CI 9.5–12.4], HR 0.44 [95% CI 0.36–0.53]; 1-sided P<0.0001), meeting the protocol-prespecified criteria for statistical significance. The PFS rates were 92.8% in the PyroHT group and 84.1% in the HT group at 6 months, 74.3% and 46.8% at 1 years, 47.6% and 20.2% at 2 years, and 39.7% and 9.9% at 3 years, respectively. Additionally, the benefits in PFS with PyroHT were observed across nearly all analyzed subgroups. As of the data cutoff, 59 patients (19.9%) in the PyroHT group and 87 patients (29.7%) in the HT group had died. The OS exhibited superiority in the PyroHT group compared to the HT group, with a HR of 0.64 (95% CI 0.46–0.89; 1-sided P=0.0038). The estimated Kaplan–Meier OS rates were 96.6% in the PyroHT group and 94.5% in the HT group at 1 year, 88.7% and 84.1% at 2 years, 80.9% and 72.4% at 3 years, and 74.5% and 64.3% at 4 years, respectively. The safety profiles in the updated analysis remained consistent with those reported in the previous interim analysis in terms of frequency, severity, and specificity. No new safety signals were identified. Grade ≥3 treatment-related adverse events were reported in 270 patients (90.9%) in the PyroHT group and 227 patients (77.5%) in the HT group, with decreased neutrophil count (63.0% vs 64.8%) and decreased white blood cell count (53.2% vs 50.9%) being the most frequent. Grade 3 diarrhea was predominantly observed during the first cycle and notably decreased in subsequent cycles, with no grade 4 or 5 diarrhea events reported. Treatment-related serious adverse events were experienced by 27.3% vs 7.5% of patients, and treatment-related deaths occurred in 0% vs 0.3% of patients in the PyroHT and HT groups, respectively. Conclusion: After an extended follow-up period, the updated analysis demonstrates that PyroHT provides sustained longer PFS compared to HT, which translates into longer OS for PyroHT than HT in the first-line treatment of HER2-positive mBC. The safety profile of PyroHT remained manageable throughout the extended treatment duration. This updated analysis further reinforces PyroHT as a well-established and efficacious therapeutic strategy for this patient population. Citation Format: Binghe Xu, 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, Yang Fan, Jiaman Lin, Xiaoyu Zhu. Pyrotinib or placebo in combination with trastuzumab and docetaxel for untreated HER2-positive metastatic breast cancer (mBC): prespecified final analysis of progression-free survival (PFS) of the phase 3 PHILA trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS1-03.