Case Report: A patient with the rare third-generation TKI-resistant mutation L718Q who responded to afatinib plus cetuximab combination therapy.

Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, almonertinib and furmonertinib, overcome the mechanisms of resistance to first-generation inhibitors (such as gefitinib, erlotinib and icotinib) by incorporating an acrylamide group that alkylates the Cys797 of T790M. However, drug resistance is inevitable, even for third-generation TKIs. Screening for drug-resistant mutations by repeat biopsy and repeat gene sequencing is necessary after TKI treatment. Among various third-generation TKI-resistant mutations, secondary mutation of the L718 residue of exon 18 was found in approximately 8% of patients and is responsible for drug resistance and . Furthermore, there is limited clinical experience of targeted therapy for this mutation. Herein, we report for the first time that afatinib and cetuximab combination therapy can overcome such drug resistance.