We characterized the landscape and drug sensitivity of ERBB2 ( HER2 ) mutations in cancers. In eleven datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro , and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant NSCLC resulted in a confirmed objective response rate of 42% in the first twelve evaluable patients. In preclinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regressions with combination treatment. Robichaux et al. show that ERBB2 mutation hotspots vary across human tumor types, which affect the volume of the HER2 TKI binding pocket and dictate drug sensitivity. Poziotinib is the most potent HER2 TKI among those tested. Moreover, poziotinib enhances T-DM1 efficacy by increasing the cell surface HER2 level.