Dacomitinib exhibits promising activity against the rare exon 20 insertion M774delinsWLV in lung cancer: A case report and literature review.

A775_G776insYVMA, the typical and predominant exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent -targeted tyrosine kinase inhibitors. However, other less common insertions have shown better responses to -targeted inhibitors. M774delinsWLV is a rare exon 20 insertion subtype and its clinical sensitivity to -targeted inhibitors remains unclear. Furthermore, there is a lack of current studies to elucidate its structure and predict its sensitivity to -targeted tyrosine kinase inhibitors. Herein, we presented a case of non-small cell lung cancer harboring M774delinsWLV who derived favorable response and significant survival benefit from -targeted tyrosine kinase inhibitors. A 60-year-old male with metastatic lung adenocarcinoma carrying M774delinsWLV received pyrotinib monotherapy as first-line treatment. After rapid disease progression at three months, sequential combination therapy with pyrotinib and bevacizumab yielded promising antitumor activity and sustained progression-free survival benefits for nearly a year. Subsequent dacomitinib monotherapy displayed significant activity against this uncommon insertion, resulting in a rapid decrease in tumor markers and partial response, along with progression-free survival of one year. The molecular simulation revealed no significant differences in the overall protein structure and binding pocket region between M774delinsWLV and the wild type. Drug binding dynamics simulation indicated that dacomitinib exhibited the most potent binding activity compared to afatinib, pyrotinib and poziotinib. Conclusively, dacomitinib exhibited promising efficacy against the rare exon 20 insertion M774delinsWLV. Extensive investigation is needed to elucidate the effects of -targeted tyrosine kinase inhibitors on non-small cell lung cancer with different insertion subtypes.