Clinical and molecular profile of de novo vs. secondary EGFR mutated metastatic non-small-cell lung cancer

Purpose: Epidermal growth factor receptor mutated (EGFR)⁺ non-small-cell lung cancer (NSCLC) is a model disease for the effectiveness of tyrosine kinase inhibitors (TKI) in thoracic oncology. The majority of patients present directly with metastatic tumors, however some show relapse of previous nonmetastatic disease after varying treatments including surgery, chemotherapy and/or radiotherapy. Potential clinical and biologic differences between these two patient subsets are unclear at present.

Methods: We retrospectively analyzed the baseline characteristics and clinical course of EGFR⁺ NSCLC patients treated with TKI at our institutions.

Results: Overall, 406 cases were identified, with de novo stage IV disease in 322 (79%) and initially nonmetastatic disease in 86 (21%). No differences were noted between the two groups regarding median age at initial diagnosis (66 vs. 67 years), sex (35% males in both), smoking history (68% vs. 62% never/light-smokers, i.e. with tobacco exposure < 10 pack-years) and histology (> 95% adenocarcinoma), but presentation with nonmetastatic disease was linked to a better ECOG performance status (68% and 31% vs. 45% and 52% with 0 and 1, p = 0.002). At development of stage IV disease, initially nonmetastatic cases featured more limited metastatic spread (mean 1.4 vs. 2.0 sites, p < 0.001, and 37% vs. 45% of cases with brain metastases, p < 0.001), but only slight, non-significant differences were noted regarding benefit from TKI (median progression-free survival [PFS] 17 vs. 12 months, p = 0.26), chemotherapy (median PFS3 vs. 5 months, p = 0.84) and overall survival (OS) from the start of palliative systemic treatment (25 vs. 21 months, p = 0.31). In a bivariable Cox regression, only presence of brain metastases at the time of stage IV diagnosis (hazard ratio = 1.6, p = 0.002), but not initial stage (M0 vs. IV, p = 0.52) was a significant predictor for inferior OS. The profile of EGFR alterations (e.g. 54% vs. 60% exon 19 deletions), frequency of TP53 mutations at the time of stage IV diagnosis (44% vs. 39%, n = 297 tested cases) and rate of T790M positivity at the time of TKI failure were also similar (53% vs. 57%, n = 181 tested cases).

Conclusions: Clinical and molecular features of EGFR⁺ metastatic NSCLC appear to be largely independent of preceding nonmetastatic disease in about one-fifth of cases.