Abstract PS5-01-02: Pyrotinib or placebo in combination with trastuzumab and docetaxel for untreated HER2-positive metastatic breast cancer: long-term survival results from the phase 3 PHILA study

Abstract Background: PHILA, a randomized, double-blind, placebo-controlled phase 3 trial (NCT03863223), assessed the efficacy and safety of pyrotinib plus trastuzumab and docetaxel (PyroHT) as first-line therapy in HER2-positive metastatic breast cancer. PyroHT significantly prolonged progression-free survival (PFS) and improved overall survival (OS) compared with placebo plus trastuzumab and docetaxel (HT), with manageable safety (Xu et al., BMJ 2023; Xu et al., SABCS 2024). Here, we report updated survival results after a median follow-up of 45.5 months. Methods: Patients (pts) with untreated HER2-positive metastatic breast cancer were enrolled across 40 centers in China and randomized (1:1) to receive either oral pyrotinib (400 mg once daily) or placebo plus intravenous trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and docetaxel (75 mg/m2) on day 1 of each 21-day cycle. The primary endpoint was investigator-assessed PFS. Results: From May 2019 to January 2022, 590 pts were randomized and received treatment (PyroHT n=297; HT n=293). As of May 30, 2025, the median follow-up was 46.5 months (IQR 36-55) for PyroHT and 44.6 months (IQR 31-53) for HT. In the PyroHT group, 75 pts (25.3%) were still receiving study treatment, compared with 19 (6.5%) in the HT group. Following treatment discontinuation, 174 pts (58.6%) in the PyroHT group and 229 pts (78.2%) in the HT group received post-discontinuation therapies. Although cross-over was not allowed, the proportions of pts receiving pyrotinib, trastuzumab, pertuzumab, or anti-HER2 antibody-drug conjugate (incl. T-DM1, T-DXd, SHR-A1811) after study treatment discontinuation in each group were 18.5% vs. 51.9%, 26.3% vs. 25.6%, 15.5% vs. 14.0%, and 22.6% vs. 28.0%, respectively. At data cutoff, 85 deaths (28.6%) occurred in the PyroHT group and 108 (36.9%) in the HT group. OS was superior in the PyroHT group compared to the HT group (HR 0.74, 95% CI 0.56-0.98; nominal 1-sided P=0.0188). The median OS was not reached in either group. OS rates were 79.6% in the PyroHT group and 72.1% in the HT group at 3 years, 72.9% and 63.5% at 4 years, 65.7% and 58.5% at 5 years, respectively. As reported previously, consistent and prolonged benefit of investigator-assessed PFS in the PyroHT group was observed (HR 0.44, 95% CI 0.36-0.54; nominal 1-sided P<0.0001). The PFS rates were 40.4% in the PyroHT group and 9.7% in the HT group at 3 years, 31.9% and 7.6% at 4 years, 29.2% and 4.3% at 5 years, respectively. Additionally, the benefits in PFS with PyroHT were consistent across nearly all analyzed subgroups. For pts with prior (neo)adjuvant trastuzumab, median PFS was 62.8 months (95% CI 19.2-not evaluable) in the PyroHT group (n=46) vs 10.4 months (95% CI 6.4-13.2) in the HT group (n=42). Among pts who developed brain metastases, the median time to onset was 16.6 months (IQR 13-28) with PyroHT (n=34) compared to 9.1 months (IQR 8-14) with HT (n=30). Safety data cutoff was April 30, 2024. The incidence of all adverse events decreased considerably after docetaxel discontinuation. In the PyroHT group, the incidence of any grade diarrhea decreased from 98.4% (245/249) to 79.9% (199/249), and grade 3 diarrhea incidence declined from 46.2% (115/249) to 16.1% (40/249). No grade 4 or 5 diarrhea was reported. Conclusions: The long-term analysis confirms that the previously observed improvements in OS and PFS with PyroHT compared to HT in the first-line treatment of HER2-positive metastatic breast cancer were maintained after 45.5 months of median follow-up. Notably, with PyroHT, 5-year OS rate remained at 66% and nearly 30% of pts remained progression-free at 5 years. PyroHT treatment delayed time to onset of brain metastasis. It reinforces dual anti-HER2 regimen (pyrotinib plus trastuzumab) as an established therapeutic strategy for this patient population. Citation Format: B. Xu, F. Ma, M. Yan, W. Li, Q. Ouyang, Z. Tong, Y. Teng, Y. Wang, S. Wang, C. Geng, T. Luo, J. Zhong, Q. Zhang, Q. Liu, X. Zeng, T. Sun, Q. Mo, S. Zhou, Y. Cheng, J. Cheng, X. Wang, J. Nie, J. Yang, X. Wu, X. Wang, H. Li, G. Yao, Y. Fan, J. Lin, X. Zhu. Pyrotinib or placebo in combination with trastuzumab and docetaxel for untreated HER2-positive metastatic breast cancer: long-term survival results from the phase 3 PHILA study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-02.