This systematic review examines the efficacy of tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations in non-small cell lung cancer (NSCLC). The study included 1836 patients from 38 studies, focusing on mutations other than exon 20 insertions or T790M. Response rates (RRs) for different generations of TKIs were analyzed for individual uncommon mutations, compound mutations, and classical-like and P-loop alpha helix compressing (PACC) mutations. The results show that second-generation TKIs, particularly afatinib, exhibited moderate activity in uncommon EGFR mutations, with RRs ranging from 47.8% to 72.3% for G719X, S768I, L747X, E709X, and E709-T710delinsD. For the L861Q mutation, RRs were 52% to 75% for second- and third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% for second- and third-generation TKIs. Classical-like mutations had RRs of 35.4%, 51.9%, and 67.9% for first-, second-, and third-generation TKIs, respectively. PACC mutations had RRs of 37.2%, 59.6%, and 46.3% for first-, second-, and third-generation TKIs, respectively. The review supports the use of afatinib for G719X, S768I, E709X, and L747X mutations and compound uncommon mutations, while third-generation TKIs like osimertinib can also be considered for other uncommon mutations. The findings highlight the evolving clinical evidence for treatment choices in uncommon EGFR mutations, particularly regarding the efficacy of third-generation TKIs.This systematic review examines the efficacy of tyrosine kinase inhibitors (TKIs) in patients with uncommon EGFR mutations in non-small cell lung cancer (NSCLC). The study included 1836 patients from 38 studies, focusing on mutations other than exon 20 insertions or T790M. Response rates (RRs) for different generations of TKIs were analyzed for individual uncommon mutations, compound mutations, and classical-like and P-loop alpha helix compressing (PACC) mutations. The results show that second-generation TKIs, particularly afatinib, exhibited moderate activity in uncommon EGFR mutations, with RRs ranging from 47.8% to 72.3% for G719X, S768I, L747X, E709X, and E709-T710delinsD. For the L861Q mutation, RRs were 52% to 75% for second- and third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% for second- and third-generation TKIs. Classical-like mutations had RRs of 35.4%, 51.9%, and 67.9% for first-, second-, and third-generation TKIs, respectively. PACC mutations had RRs of 37.2%, 59.6%, and 46.3% for first-, second-, and third-generation TKIs, respectively. The review supports the use of afatinib for G719X, S768I, E709X, and L747X mutations and compound uncommon mutations, while third-generation TKIs like osimertinib can also be considered for other uncommon mutations. The findings highlight the evolving clinical evidence for treatment choices in uncommon EGFR mutations, particularly regarding the efficacy of third-generation TKIs.