BIBW2992, an irreversible dual EGFR/HER2 inhibitor, demonstrates potent activity against wild-type and mutant forms of EGFR and HER2 kinases. In vitro, BIBW2992 inhibits the kinase activity of EGFR and HER2, including erlotinib-resistant mutants, with an IC50 of 10 nM for the L858R-T790M double mutant. In cell-based assays, BIBW2992 suppresses transformation and inhibits the survival of cancer cell lines, showing superior efficacy compared to first-generation EGFR inhibitors like erlotinib. In vivo, BIBW2992 induces tumor regression in xenograft models of lung adenocarcinoma and HER2-driven gastric cancer, with a cumulative treated/control tumor volume ratio of 2%. The combination of BIBW2992 with rapamycin further enhances tumor regression in a murine model of *EGFR L858R/T790M*-driven lung cancer. These findings suggest that BIBW2992 is a promising candidate for the treatment of lung cancers with EGFR or HER2 oncogenes, particularly those with acquired resistance to first-generation EGFR inhibitors.BIBW2992, an irreversible dual EGFR/HER2 inhibitor, demonstrates potent activity against wild-type and mutant forms of EGFR and HER2 kinases. In vitro, BIBW2992 inhibits the kinase activity of EGFR and HER2, including erlotinib-resistant mutants, with an IC50 of 10 nM for the L858R-T790M double mutant. In cell-based assays, BIBW2992 suppresses transformation and inhibits the survival of cancer cell lines, showing superior efficacy compared to first-generation EGFR inhibitors like erlotinib. In vivo, BIBW2992 induces tumor regression in xenograft models of lung adenocarcinoma and HER2-driven gastric cancer, with a cumulative treated/control tumor volume ratio of 2%. The combination of BIBW2992 with rapamycin further enhances tumor regression in a murine model of *EGFR L858R/T790M*-driven lung cancer. These findings suggest that BIBW2992 is a promising candidate for the treatment of lung cancers with EGFR or HER2 oncogenes, particularly those with acquired resistance to first-generation EGFR inhibitors.