Discussion
tumor, HER2-positive ABC.Prior, toxicity, DAP-HER-01, HR-negative, HR-negative disease, HR-positive, HER2-positive
TUMOR
DAP-HER-01 is a prospective study to report the activity and safety of a CDK4/6 inhibitor plus a HER2 TKI in patients with HER2-positive ABC regardless of HR status, and obtained positive results. Our results suggest that this chemo-free regimen has anti-tumor activity in HER2-positive ABC, including HR-negative, HER2-positive patients, and exhibits efficacy in patients with BM, providing an alternative fully oral regimen for patients with HER2-positive ABC.Prior to our study, Goel et al.Pyrotinib has shown preliminary efficacy in trastuzumab-sensitive patientsIt has been reported that HR status could affect the outcome of HER2-positive BC, and HR-negative subset usually benefits more from standard HER2-targeted therapy compared with HR-positive onesBM occurred in 37.3% of patients with HER2-positive ABC, which suggests worse outcomesThe safety profile of dalpiciclib and pyrotinib combination was consistent with the previous toxicity profile of either drug in previous clinical trialsThere are some limitations in this study. Firstly, the current study adopted single-arm design with limited sample size, and only Chinese patients were enrolled. Secondly, biomarker analysis might provide more information to identify who can derive more benefits from this combination, but such analysis was absent due to insufficient amount of collected tumor tissues and limited financial resources. Thirdly, though dose schedules used in the study were based on the approved doses and safety profiles derived from studies of these two agents, a dose exploration of this combination might be more convincing. Fourthly, though the activity of dalpiciclib and pyrotinib in patients with HR-negative disease and in those with BM was promising, the findings should be interpreted with cautions since the subgroup analyses were not pre-specified or powered, and further investigation is needed.Overall, the combination of dalpiciclib plus pyrotinib shows promising activity and manageable toxicity in the front-line treatment of HER2-positive ABC patients regardless of HR status, and patients with asymptomatic active BM may also benefit from it. The inaccessibility of study drugs in some countries and regions, coupled with the plethora of anti-HER2 therapies available, may constrain the generalizability of our findings in clinical settings. Nevertheless, this fully oral regimen provides a convenient alternative option for patients with HER2-positive ABC. Furthermore, this study may represent a direction for further exploration into the role of CDK4/6 inhibitors in BC patients.