The high degree of structural homology between EGFR and HER2 makes it challenging to design HER2-selective inhibitors. Most approved and investigational agents are dual EGFR/HER2 inhibitors that are dose-limited by EGFR-driven toxicity. Tucatinib is the only approved HER2-selective tyrosine kinase inhibitor (TKI), but lacks potency against key mutants, including HER2 YVMA, the most common exon 20 insertion mutation (E20IM) in non–small cell lung cancer (NSCLC), and L755S/P, the most common HER2 mutation in breast cancer (22%)…