PHOEBE, a phase 3 trial comparing pyrotinib and lapatinib in HER2-positive metastatic breast cancer

The open-label, multicentre, randomised, phase 3 PHOEBE study compared pyrotinib plus capecitabine versus lapatinib plus capecitabine in metastatic HER2-positive breast cancer patients. Results showed an improvement in progression-free survival (PFS) and multiple secondary endpoints. The pyrotinib combination therapy is now approved in China as second-line standard-of-care for this patient group.

Pyrotinib is a small-molecular, irreversible, pan-ErbB receptor kinase inhibitor targeting EGFR, HER2, and HER4 [1]. In previous phase 2 and phase 3 studies, pyrotinib in combination with capecitabine has shown clinically meaningful benefits and tolerability on patients with metastatic HER2-positive breast cancer after prior treatment with taxanes, anthracyclines, and/or trastuzumab. Pyrotinib plus capecitabine showed better overall response rates (ORR) and PFS compared with lapatinib plus capecitabine, which was standard second line of care for these patients in China [2].

In the phase 3 PHOEBE trial, 267 patients with metastatic HER2-positive breast cancer who had prior treatment with trastuzumab and taxanes, and/or anthracyclines were randomised 1:1 to treatment with pyrotinib (400 mg once daily) plus capecitabine (1,000 mg/m² twice daily on days 1-14 of each 21 day cycle) or lapatinib (1,250 mg once daily) plus capecitabine [3]. Primary endpoint of the study was PFS, secondary endpoints were overall survival (OS), ORR, duration of response (DoR), clinical benefit rate, and safety.

Median PFS was 12.5 months for the pyrotinib combination versus 6.8 months for the lapatinib combination (HR 0.39; 95% CI 0.27-0.56; P<0.0001). Among trastuzumab-resistant patients (n=69), prolonged PFS with the pyrotinib combination was also observed (12.5 months vs 6.9 months; HR 0.60; 95% CI 0.29 -1.21). ORR was 67.2% in the pyrotinib arm versus 51.5% in the lapatinib arm. Clinical benefit rates were 73.1% and 59.1%, respectively and median DoR was 11.1 months versus 7.0 months. OS rates after 12 months were 91.3% and 77.4%, respectively; however, these data are not yet mature.

Treatment-related adverse events grade ≥3 were observed in 77 (57.5%) of the patients in the pyrotinib arm and in 45 (34.1%) of the patients in the lapatinib arm. Serious treatment-related adverse events were observed in 8 (6%) and 2 (1.5%), respectively. The most common grade ≥3 treatment-related adverse event was diarrhoea: 30.6% versus 8.3%; the median cumulative duration of grade 3 diarrhoea was 7.0 days versus 6.0 days.

1. Li X, et al. Eur J Pharm Sci. 2017; 110: 51-61.
2. Ma F, et al. J Clin Oncol. 2019; 37: 2610-2619.
3. Xu B, et al. ASCO Virtual Meeting, 29-31 May 2020, Abstract 1003.

Posted on 8 September 202029 February 2024