Background Most patients with EGFR-driven NSCLC harbor exon 19 deletions or exon 20 L858R point mutations, which have established sensitivity to tyrosine kinase inhibitors (TKI) with a median overall survival (OS) of several years. However, the outcome of patients with other EGFR alterations is variable and not well-defined.
Patients and Methods We retrospectively analyzed the clinical course of TKI-treated NSCLC patients at our institution (n = 303).
Results In total, “rare” EGFR point mutations were detected in 33 cases (11%), nine of which harboured compound mutations (3%). Most atypical EGFR mutations affected exons 18 (n = 12 or 36%, mostly G719X) and 21 (n = 14 or 42%, mostly L891Q), while mutations of exons 19 (n = 3) and 20 (n = 4) were less frequent. Overall survival (OS) did not differ by the affected exon (p = 0.58) and was 13 months in median, significantly shorter than the survival of patients with exon 19 deletions (59% of cases with 31 months median OS) and L858R point mutations (23% of cases with 18 months median OS, p < 0.0001). Progression-free survival under TKI treatment was generally longer for exon 18 and 21 (9 and 7 months in median) than for exon 19 and 20 mutations in our cohort (3 months in median, p < 0.05). No differences in the number of metastatic sites at diagnosis of stage IV disease were noted among mutations of different exons. Within the entire cohort of EGFR+ NSCLC patients, presence of “rare” EGFR mutations correlated negatively with never-/light-smoker history (< 10 pack-years, p < 0.001) and emergence of T790M mutations at the time of TKI failure (p < 0.011), and positively with the presence of non-adenocarcinoma histologies, i.e. squamous and NOS-NSCLC (15%, p = 0.002).
Conclusions Presence of atypical EGFR mutations is associated with heavier smoking history, non-adenocarcinoma histologies, complex, non-T790 M-mediated resistance mechanisms at the time of TKI failure and shorter overall survival in EGFR+ NSCLC.
