Pyrotinib plus capecitabine for human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab and taxanes (PHENIX): a randomized, double-blind, placebo-controlled phase 3 study

Background: Pyrotinib is an irreversible pan-ErbB inhibitor targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and HER4. This randomized, double-blinded phase 3 study evaluated the efficacy and safety of pyrotinib plus capecitabine for HER2-positive local relapsed or metastatic breast cancer. Methods: Patients who had been treated with trastuzumab and taxanes were randomized (2:1) to receive either oral pyrotinib or placebo (400 mg, qd) plus capecitabine (1,000 mg/m2, bid on days 1-14) for 21-day cycles, using stratified block randomization. The primary endpoint was progression-free survival (PFS) per independent review committee. Patients who progressed on placebo plus capecitabine received subsequent pyrotinib monotherapy. This study is registered with ClinicalTrials.gov (NCT02973737), enrollment is closed. Results: Between Jul 25, 2016 and Nov 27, 2017, 279 patients were randomly assigned to pyrotinib (n=185) and placebo (n=94) groups. As of May 27, 2018, median PFS was 11.1 months [95% confidence interval (CI), 9.7-16.5] vs. 4.1 months (95% CI, 2.8-4.2) in the pyrotinib vs. placebo groups, respectively [hazard ratio, 0.18 (95% CI, 0.13-0.26); P<0.001]. Seventy-one patients in the placebo group subsequently received pyrotinib, showing a response rate of 38.0% (95% CI, 26.7-49.3%) and median PFS of 5.5 months (95% CI, 4.1-6.9). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea (30.8% vs. 12.8%) and hand-foot syndrome (15.7% vs. 5.3%). No treatment-related deaths were reported. Conclusions: For HER2-positive local relapsed or metastatic breast cancer after prior trastuzumab and taxanes, pyrotinib plus capecitabine yielded a statistically significant increase in PFS over placebo plus capecitabine. Pyrotinib monotherapy also showed potent anti-tumor activity.