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Key Points
• The authors of this narrative review explored the most important predictive biomarkers in advanced non-small cell lung cancer (NSCLC). Here are their results with respect to EGFR.
• In advanced lung adenocarcinoma, EGFR is the main actionable target with a mutation frequency of 15% in Whites and 40% Asians.
• Nearly all patients treated with EGFR tyrosine kinase inhibitors (EGFR TKIs) become resistant to the drugs within 1 year, with the most important mechanism of resistance with respect to first and second generation TKIs being the secondary EGFR mutation T790M, which increases affinity for ATP.
• The most varied resistance mechanisms occur secondary to osimertinib and differ between first- and second-line settings.
• Tumor heterogeneity is an issue because according to the literature, several resistance mechanisms can present in the same tumor, thus a multi-gene analysis of both tissue re-biopsy and ctDNA should be considered. The authors wrote, “Apart from the most frequent targetable alterations, about 10–14% of EGFR-mutated lung cancers harbor uncommon mutations alone or co-occurring with the most common activating mutations (i.e., exon 19 deletions and L858R) (35). The main sensitive rare mutations are E709x (1.5%) and G719x (1.5–3%) in exon 18, S768I (0.6–1%) in exon 20 and L861Q (3%) in exon 21 (20); patients harboring these mutations can be treated with afatinib.”

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