Not all EGFR mutations are the same when it comes to therapy for NSCLC

Certain rare epidermal growth factor receptor (EGFR) mutations are associated with tobacco smoking, worse prognosis, and poor response to EGFR tyrosine kinase inhibitor (TKI) therapy compared to the more common “classical” EGFR mutations. However, as not all rare mutations are the same, testing and therapy may need to be evaluated for each individual mutation.

Mutations within the EGFR gene lead to an oncogenic EGFR protein which can be turned off with EGFR TKIs. These alterations with EGFR are the most frequently therapeutically-targeted genomic alterations in non-small cell lung cancer (NSCLC). Deletions within Exon 19 or a point mutation in Exon 21 are the common mutations predictive of response to EGFR TKI therapy and the ones most often and sometimes exclusively tested for. However, less common EGFR mutations exist and some, e.g., G719x and L861Q, appear sensitive to TKI therapy.

Researchers in Austria and Hungary examined the EGFR mutation status of 814 Hungarian patients with pathologically confirmed adenocarcinoma, a histological subtype of NSCLC, and compared the epidemiology and clinical consequence of rare and classic EGFR mutations. Clinical and pathological data were available for 645 of those examined and disease outcome data were available for 419.

The results, published in the Journal of Thoracic Oncology, show that the 5% had classic (Exon 19 or 21) mutations, 6% rare mutations, and 3% synonymous (non-protein altering) mutations. Of note, 10% of patients with rare mutations carried alterations known to be sensitive to EGFR TKIs. As expected, the classic mutations were associated with never smokers (p<0.0001); however, the rare mutations were associated with tobacco smokers (p=0.0062). Classic EGFR mutations but not rare ones were independent predictors of increased overall survival (HR,0.45; 95% CI, 0.25-0.82; p=0.009). The response rate to TKI therapy was significantly higher (71% vs 37%; p=0.039) in classic vs. rare mutations. Patients with classic or sensitizing rare (G719x and L861Q) EGFR mutations had significantly longer progression-free survival when compared to the remaining rare mutation cases (12 vs 6.2 months; p=0.048).