DISCUSSION
toxicity, diarrhea
DISEASE
Pyrotinib is an irreversible pan‐ErbB small‐molecular TKI, which has been approved in HER2‐positive BC. While the safety and efficacy data were limited in HER2‐positive GC, only several small‐sample retrospective studies and case reports involved it.In the monotherapy part, diarrhea was the most common TRAE. And two patients (13%) experienced Grade 3 diarrhea in the 400 mg dose cohort, one of which was defined as DLT. In the phase I study in HER2‐positive BC, pyrotinib monotherapy was generally well tolerated at doses up to 480 mg.Pyrotinib exposure was dose‐dependent with a nonlinear relationship versus dose, which was different from the PK profile data reported in the metastatic BC population. Besides, limited data suggested coadministration with docetaxel had no apparent effect on the PK of pyrotinib.The ORR of pyrotinib alone and pyrotinib combined with docetaxel was 21% and 20%, which was relatively unsatisfied in patients with pretreated HER2‐positive GC. Unlike BC, pyrotinib alone could not show encouraged efficacy in HER2‐positive GC. But there were indeed some patients who achieved long‐lasting disease control time for more than 12 months. So, pyrotinib might be effective in some selected patients. This similar result was also shown in studies of other anti‐HER2 TKIs, including lapatinib, afatinib, and neranib.The main limitations of this study are typical of early‐phase clinical studies. Most clinical cohorts had a small size and required further investigations. The lack of a control arm makes it difficult to accurately confirm the effect of combination with docetaxel. But based on the early signs demonstrated in this study, the combination with docetaxel increased the toxicity, rather than the efficacy, which might suggest us to try other combination strategy. Furthermore, the resistance mechanism of pyrotinib had been explored in cell lines and patient‐derived xenograft models. Dysregulation of the CCND1‐CDK4/6‐Rb pathway was found to be to the main cause of pyrotinib resistance in preclinical AVATAR mouse.