Unveiling the Landscape of uncommon EGFR Mutations in Non-Small Cell Lung Cancer - A Systematic Review.

INTRODUCTION: Uncommon EGFR mutations represent a rare subgroup of non-small cell lung cancer. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations is scattered and limited to mostly retrospective small cohorts, as these patients were usually excluded from clinical trials.

METHODS: This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than ex20ins or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes (PACC). This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

RESULTS: 1,836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first or second-generation TKIs. G719X, S768I, E709X, L747X and E709-T710delinsD demonstrated RRs ranging from 47.8%-72.3% to second-generation TKIs, generally higher than for 1st or 3rd generation TKIs. L861Q mutation exhibited 75% (95% CI: 56.6-88.5%) RRs to 3rd generation TKIs. Compound mutations with G719X, E709X or S768I consistently showed RRs above 50% to 2nd and 3rd generation TKIs, though fewer data were available for 3rd generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2-44.2%), 51.9% (95% CI: 44.4-59.3%) and 67.9% (95% CI: 47.6-84.1%) to first, second and third generation TKIs, while for PACC mutations, RRs were 37.2% (95% CI: 32.4-42.1%), 59.6% (95% CI: 54.8-64.3%) and 46.3% (95% CI: 32.6-60.4%) respectively.

CONCLUSIONS: This systematic review supports the use of 2nd generation TKI afatinib for G719X, S768I, E709X and L747X mutations, as well as for compound uncommon mutations. For other uncommon mutations such as L861Q, 3rd generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.