SABCS 2021

At this year's San Antonio Breast Cancer Symposium (SABCS), Dr Binghe Xu from the Chinese Academy of Medical Sciences presented updated overall survival (OS) results from the phase III, open-label, randomised, controlled PHOEBE trial in HER2+ metastatic breast cancer (mBC).

"In [the] second-line setting, T-DM1 [trastuzumab emtansine] after trastuzumab-based therapy is the preferred regimen recommended by international treatment guidelines" commented Dr Xu, "however, in some countries, T-DM1 has not been approved for use in [the] metastatic setting in all countries and regions worldwide; country-specific issues should be considered."

Pyrotinib is a tyrosine kinase inhibitor that targets EGFR, HER2 and HER4. Pyrotinib in combination with capecitabine has previously demonstrated clinically meaningful benefits and acceptable tolerability in patients with HER2+ mBC who had been treated with taxanes, anthracycline and/or trastuzumab (phase II).¹

The PHOEBE trial included patients with pathologically confirmed HER2+ mBC who had been treated with trastuzumab, taxanes and/or anthracyclines. Patients were eligible if they had received up to two prior lines of chemotherapy for mBC, had at least one measurable lesion and had an ECOG performance status of 0 or 1. The study population was randomised 1:1 to receive pyrotinib + capecitabine (n=134) or lapatinib + capecitabine (n=133).

Stratification factors in the study were hormone receptor status (ER- and/or PR+ versus ER- and PR-) and the number of prior lines of chemotherapy for mBC (≤1 versus 2).

At the interim analysis data cut-off (March 2019), progression-free survival per BICR (primary endpoint) was longer in the pyrotinib group versus the lapatinib group (12.5 versus 6.8 months, HR: 0.39; 95% CI: 0.27-0.56, p<0.0001). OS data were not mature at this stage.² Dr Xu noted that, in July 2020, these results led to the approval of pyrotinib in combination with capecitabine as second-line standard of care treatment in HER2+ mBC in China.

He then moved on to describe the updated OS analysis findings, with a median follow-up of 33.2 months for the pyrotinib group and 31.8 months in the lapatinib group. In the pyrotinib group, median OS was not reached and in the lapatinib group it was 26.9 months. Pyrotinib demonstrated an OS benefit versus lapatinib with a hazard ratio of 0.69 (95% CI: 0.48-0.98, p=0.02). At 2 years, the OS rates were 66.6% and 58.8% in the pyrotinib and lapatinib groups, respectively. This benefit was consistent across all subgroups:

• No trastuzumab resistance: HR: 0.60 (95% CI: 0.39-0.91)
• Trastuzumab resistance: HR: 0.94 (95% CI: 0.48-1.85)
• No prior chemotherapy: HR: 0.72 (95% CI: 0.38-1.35)
• One line of prior chemotherapy: HR: 0.73 (95% CI: 0.44-1.22)
• Two lines of prior chemotherapy: HR: 0.56 (95% CI: 0.24-1.32)

Investigator-assessed median PFS also consistently improved with pyrotinib (12.5 months) versus lapatinib (5.6 months) with a hazard ratio of 0.48 (95% CI: 0.37-0.63), p<0.0001. The PFS benefit was, once again, consistent across all subgroups:

• No trastuzumab resistance: HR: 0.44 (95% CI: 0.32-0.61)
• Trastuzumab resistance: HR: 0.58 (95% CI: 0.35-0.98)
• No prior chemotherapy: HR: 0.47 (95% CI: 0.30-0.74)
• One line of prior chemotherapy: HR: 0.49 (95% CI: 0.32-0.73)
• Two lines of prior chemotherapy: HR: 0.56 (95% CI: 0.28-1.08)

"In conclusion, with extended follow-up, pyrotinib plus capecitabine demonstrated statistically significant OS improvement compared with lapatinib plus capecitabine in patients with HER2+ mBC after trastuzumab and chemotherapy" stated Dr Xu, "the benefits of pyrotinib plus capecitabine were observed in most clinically relevant subgroups for both OS and PFS. This updated analysis of OS in the PHOEBE trial reaffirmed pyrotinib plus capecitabine as an established treatment option in this patient population."

BICR: Blinded Independent Central Review; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; EGFR: epidermal growth factor receptor; ER: oestrogen receptor; HER: human epidermal growth factor receptor; PR: progesterone receptor