Mobocertinib and T-DM1 combination is the most effective among all three combinations. A, Dot plot of tumor volume change on MRI at the time point of weeks 2, 4, and 6 from HER2 exon 20YVMA insertion–mutant GEMMs treated with monotherapy (mobocertinib, T-DM1, alisertib, and sapanisertib) and combinations (mobocertinib combined with T-DM1, alisertib, and sapanisertib). B, Representative MRI image of HER2 exon 20YVMA insertion–mutant GEMMs treated with mobocertinib and T-DM1 combination. C, Survival curve of HER2 exon 20YVMA insertion–mutant GEMMs treated with vehicle, mobocertinib, T-DM1, and combination. D, Tumor volume change of acquired resistant HER2 exon 20YVMA insertion–mutant tumors treated with monotherapies (mobocertinib and T-DM1) and combinations (mobocertinib plus alisertib or T-DM1). E, Representative MRI image of acquired resistant HER2 exon 20YVMA insertion–mutant tumors treated with mobocertinib and T-DM1 combination therapy. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; NS, nonsignificant.