Extended analysis of the phase III PHILA trial confirms superiority of pyrotinib in combination with trastuzumab and docetaxel (TD) vs placebo in combination with TD in sustaining longer progression-free survival (PFS) and improving overall survival (OS) in treatment-naïve patients with HER2-positive (HER2+) metastatic breast cancer (mBC).
Pyrotinib is a small-molecule, irreversible, pan-HER receptor tyrosine kinase inhibitor that has shown promising antitumour activity in mBC, both as a single agent and in combination with other treatments. [Clin Cancer Res 2019;25:5212-5220; Lancet Oncol 2019;20:e562; Lancet Oncol 2021;22:351-360] The interim analysis of the PHILA trial demonstrated that the combination of pyrotinib and TD was superior to placebo plus TD in terms of PFS (median, 24.3 vs 10.4 months; hazard ratio [HR], 0.41; 95 percent confidence interval [CI], 0.32–0.53) and had an acceptable toxicity profile. [BMJ 2023;383:e076065]
The present extended analysis was conducted 2 years after the previous interim analysis and reports the final PFS results, OS, duration of response, and updated safety findings. [BMJ 2026;392:e087259]
The trial was conducted across 40 centres in China between May 2019 and January 2022, and included 590 treatment-naïve patients (median age, 52 years) with HER2+ mBC who were randomized 1:1 to receive pyrotinib (400 mg orally once daily) or placebo, both in combination with intravenous trastuzumab (8 mg/kg for the first cycle, then 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m2) on day 1 of each 21-day treatment cycle.
The median follow-up was 35.7 months in the pyrotinib group and 34.3 months in the placebo group. Pyrotinib achieved a sustained benefit in investigator-assessed PFS vs placebo, with a median of 22.1 vs 10.5 months (HR, 0.44; 95 percent CI, 0.36–0.53; nominal one-sided p<0.001). The respective 3-year PFS rates were 40 vs 10 percent.
“Pyrotinib combination treatment showed a consistent PFS benefit across all protocol prespecified subgroups,” highlighted the investigators.
The median follow-up duration for long-term survival analysis was 46.5 months in the pyrotinib group and 44.6 months in the placebo group. OS was longer in the pyrotinib vs placebo group (HR, 0.74; 95 percent CI, 0.56–0.98; nominal one-sided p=0.02). The respective 3-year OS rates were 80 vs 72 percent in. Neither group reached median OS. Subgroup analyses of OS were generally consistent for all patients.
The estimated median duration of response per investigator assessment was 22.3 months in the pyrotinib group and 10.4 months in the placebo group.
Grade ≥3 treatment-related adverse events (TRAEs) occurred in 91 vs 77 percent of the patients in the pyrotinib vs placebo group, with decreased neutrophil count (63 vs 65 percent), decreased white blood cell count (53 vs 51 percent), and diarrhoea (48 vs 4 percent) as the most prevalent events. “The high rate [of diarrhoea] observed in this study could be attributed to the unique pharmacodynamics of pyrotinib, which targets multiple HER receptors. However, prophylactic loperamide hydrochloride and dose adjustments effectively managed these events, resulting in no discontinuations due to grade 3 diarrhoea,” noted the investigators.
TRAEs that led to dose reduction of any treatment component were reported in 28 vs 3 percent of patients in the pyrotinib vs placebo group. Treatment interruptions of any component due to TRAEs occurred in 61 vs 26 percent of patients, while discontinuation of any treatment component due to TRAEs was reported in 15 vs 8 percent of patients.
“The safety profile remained consistent with interim findings, with no new safety signals identified during extended follow-up. The final analysis reinforces the efficacy and safety of pyrotinib in combination with TD for initial treatment of HER2+ mBC,” concluded the investigators.