Primary resistance to afatinib in a patient with NSCLC harboring EGFR p.E709_T710delinsD and brain metastases: a case report and literature review

EGFR p.E709_T710delinsD is a rare in-frame deletion-insertion P-loop and alpha-C-helix compressing (PACC) mutation of EGFR exon 18. Current evidence suggests that patients with non-small cell lung cancer (NSCLC) harboring this variant generally respond to afatinib. However, primary resistance to afatinib in this molecular subset is rarely reported. We report a 68-year-old man diagnosed with stage IV lung adenocarcinoma harboring an EGFR p.E709_T710delinsD mutation (variant allele frequency, 45.9%) with co-occurring EGFR amplification (fold change 1.5). Brain metastases were present at baseline. The patient was treated with oral afatinib at an initial dose of 30 mg once daily but the disease progressed rapidly, suggesting possible primary targeted resistance. The patient died 5 weeks later. This case represents a rare example of primary resistance to afatinib in non-small cell lung cancer (NSCLC) harboring the EGFR p.E709_T710delinsD mutation. Given the lack of tissue and molecular evidence to confirm the resistance mechanism in this case, this report combines previous literature to explore the potential factors associated with treatment failure and their clinical implications. This case does not refute the overall sensitivity of this variant to afatinib, but suggests that in patients with high baseline disease burden and aggressive tumor biology, this variant may present as a phenotype with no initial benefit and rapid progression. For such rapidly progressive cases, early radiographic reassessment should be performed, and repeat biopsy or circulating tumor DNA (ctDNA) testing should be pursued as soon as safely feasible to clarify the resistance mechanism and guide subsequent treatment.