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