The epidermal growth factor receptor (EGFR)-K745_E746insIPVAIK and others with rare PVAI amino-acid insertions are exon 19 insertion mutations (<1% of all EGFR mutations), which, at the structural modeling level, resemble EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants. An important unmet clinical need is the characterization of therapeutic windows of rare exon 19 PVAI amino-acid insertions to available EGFR TKIs. A limited number of preclinical and clinical reports have studied the response of these mutants to all classes of approved EGFR TKIs. We used models of EGFR-K745_E746insIPVAIK and more typical EGFR mutations (exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA, other exon 20 insertion mutations) to probe representative 1st (erlotinib), 2nd (afatinib), 3rd generation (osimertinib), and EGFR exon 20 active (mobocertinib) TKIs. We used human lung-cancer derived cell lines and transduced Ba/F3 cells to measure the treatment efficacy. We also compiled outcomes of EGFR exon 19 insertion mutated lung cancers−from our institution plus the literature−treated with EGFR TKIs. Cells driven by EGFR-K745_E746insIPVAIK had sensitivity to all classes of EGFR TKIs when compared to cells driven by EGFR-wild type in proliferation assays and at the protein level. However, the therapeutic window (calculated in preclinical models as the logarithm of the 50% inhibitory concentration of EGFR mutation compared to wild-type EGFR) of EGFR-K745_E746insIPVAIK driven cells was most akin to those of cells driven by EGFR-L861Q, EGFR-G719S and EGFR- A763_Y764insFQEA than the more sensitive patterns seen with cells driven by an EGFR exon 19 deletion or EGFR-L858R. The majority of patients with lung cancers harboring EGFR- K745_E746insIPVAIK and other mutations with rare PVAI amino-acid insertions responded to clinically available EGFR TKIs (including icotinib, gefitinib, erlotinib, afatinib and osimertinib), with heterogeneous periods of progression-free survival. This is the largest preclinical/clinical report to highlight that EGFR- K745_E746insIPVAIK and other mutations with rare exon 19 PVAI amino-acid insertions are sensitive to clinically available TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q, EGFR-G719S and EGFR-A763_Y764insFQEA mutations. These findings are consistent with the proposed mechanism of activation of mutant EGFR by alteration of the proposed hydrophobic core. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these rare EGFR mutated lung cancers. / 2026-03-08T00:00:00Z