Discussion
HER2-positive advanced, breast cancer
To our knowledge, this phase 2 trial was the first positive multicenter study for patients with HER2-positive advanced breast cancer and primary trastuzumab resistance, in contrast to previous failed trials in this clinical setting. The median PFS of 11.8 months met the primary endpoint, significantly longer than the pre-trial hypothesis of 8.0 months in the trial protocol. The combination of pyrotinib and capecitabine was also demonstrated well-tolerated and had no new safety signals in this study.Patients with primary trastuzumab resistance are under-represented in two pivotal phase 3 trials (EMILIA and DESTINY-Breast 03). Even for those who received real second-line treatment in these two trials, they were either primary- or secondary-resistant to trastuzumab. The EMILIA study confirmed the role of T-DM1 in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane when compared with lapatinib plus capecitabine (PFS: 9.6 vs. 6.4 months; hazard ratio, 0.65; Among previous clinical trials focusing on trastuzumab-resistant patients, the definition of primary trastuzumab resistance is not unified, leading to hard indirect comparisons across studies (Additional file Patients who had progression within 12 months of completing adjuvant trastuzumab (subgroup B in our study) are generally included in the trastuzumab-resistant population [The safety profile of pyrotinib plus capecitabine was consistent with results from previous clinical trials [This study has some limitations. First, there might be potential bias due to the single-arm design without control group. In fact, it is very hard to conduct randomized controlled trials since such patients were rare due to advance in early diagnosis and HER2-targeted therapy, and it took us 27 months to enroll 100 patients at 16 sites. In the future, direct comparison between our study treatment and modern treatment option, especially T-DXd, is urgently needed. Second, only Chinese patients were enrolled and the effect of pyrotinib plus capecitabine in other populations needs to be established. Third, the efficacy was assessed by investigators rather than independent review committee. Fourth, due to the small sample size, multivariable analyses were not performed to analyze the independent factors influencing the treatment response and survival. Finally, OS data are not mature yet, which will be reported in the future.