In a prespecified interim analysis of the Chinese phase III PHOEBE trial reported in The Lancet Oncology, Xu et al found that the combination of the irreversible pan-HER inhibitor pyrotinib plus capecitabine significantly prolonged progression-free survival vs lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes.

Study Details

In the open-label trial, 267 patients from 29 sites in China were randomly assigned between July 2017 and October 2018 to receive oral pyrotinib at 400 mg (n = 134) or lapatinib at 1,250 mg (n = 133) once daily plus oral capecitabine at 1,000 mg/m² twice daily on days 1 to 14 of 21-day cycles. Treatment continued until disease progression or unacceptable toxicity.

The primary endpoint was progression-free survival on masked independent central review. Follow-up continues for overall survival.

Progression-Free Survival

At interim analysis data cutoff (March 2019), median follow-up was 10.5 months in the pyrotinib group and 9.7 months in the lapatinib group. Median progression-free survival was 12.5 months (95% confidence interval [CI] = 9.7 months to not reached) in the pyrotinib group vs 6.8 months (95% CI = 5.4–8.1 months) in the lapatinib group (hazard ratio [HR] = 0.39, 95% CI = 0.27–0.56, P < .0001).  Findings in subgroup analyses were consistent with the overall result.

At the time of interim analysis, objective response rates were 67% vs 52%, with complete responses in 5% vs 1%. Rates of clinical benefit (including stable disease for ≥ 24 weeks) were 73% vs 59%. Estimated median durations of response were 11.1 months (95% CI = 9.7 months to not reached) vs 7.0 months (95% CI = 5.6–9.8 months).

Overall survival was assessed at a cutoff date in March 2020, with a median follow-up of 21.8 months in the pyrotinib group and 21.5 months in the lapatinib group. Median overall survival was 26.8 months (95% CI = 26.2 months to not reached) in the pyrotinib group vs not reached (95% CI = 21.8 months to not reached) in the lapatinib group, with 12-month rates of 90.9% vs 80.1%.

Adverse Events

Grade ≥ 3 adverse events occurred in 64% of patients in the pyrotinib group vs 43% of the lapatinib group, with the most common in the pyrotinib group being diarrhea (31% vs 8% in the lapatinib group; all grade 3), hand-foot syndrome (16% vs 15%; all grade 3), and decreased white blood cell count (8% vs 2%). Serious adverse events occurred in 10% vs 8% of patients.

Adverse events led to treatment discontinuation in 3% vs 2% of patients, with all discontinuations considered related to treatment. No treatment-related deaths were reported in the pyrotinib group; one sudden death in the lapatinib group was considered treatment-related.

The investigators concluded: “Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy.”

Binghe Xu, MD, of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Jiangsu Hengrui Medicine and National Key R&D Program of China. For full disclosures of the study authors, visit thelancet.com.