<i>EGFR</i> -mutated lung cancer: A comparative analysis of common and uncommon variants.

Abstract

8635 Background: Uncommon EGFR mutations represent a heterogeneous subset of EGFR-positive NSCLC with limited characterization. This study compares clinical, molecular, and survival outcomes between common and uncommon EGFR variants in a large real-world cohort. Methods: A retrospective analysis of 1,501 EGFR-positive NSCLC cases from MSK-CHORD was performed. Patients were classified as having common (Ex19del, L858R) or uncommon mutations (G719X, L861Q, S768I). Clinical and genomic variables were analysed using Wilcoxon and chi-square tests (significance p &lt; 0.05). Results: The study included 1,501 EGFR-mutated NSCLC patients, with 195 (13.0%) harboring uncommon and 1,306 (87.0%) harboring common EGFR mutations. Patients with uncommon mutations were older at diagnosis (median 73 vs 69 years; p = 0.003), while sex distribution remained similar (p = 0.868). Race distribution differed (p = 0.005), with more White patients in the uncommon EGFR group (80.3% vs. 69.5%) and fewer Asian patients (11.8% vs. 25.5%), while Black patient proportions were similar (7.9% vs. 5.0%). Smoking history also varied (p &lt; 0.005), with substantially fewer never-smokers among patients with uncommon mutations (25.6% vs 59.6%). Uncommon mutations were associated with higher genomic burden, including elevated TMB (median 4.92 vs 3.46 mut/Mb; p &lt; 0.001) and mutation count (median 6 vs 4; p &lt; 0.001). Stage at diagnosis did not differ (p = 0.3), nor did metastatic site distributions (p = 0.477). Median OS was significantly shorter for patients with uncommon EGFR mutations (36.69 vs 56.52 months), with HR 1.425 (p &lt; 0.005). In Stage IV patients receiving osimertinib, OS was numerically shorter for uncommon mutations but not statistically significant (29.98 vs 34.32 months; HR 1.351; p = 0.08). Among Stage IV patients with uncommon mutations, OS was comparable between afatinib and osimertinib (25.48 vs 26.70 months; p = 0.88). KRAS co-mutations were significantly more frequent in the uncommon group (4.62% vs 1.15%; p = 1.985×10⁻³). Conclusions: Uncommon EGFR mutations exhibit distinct clinical and genomic features and poorer survival compared with common variants, highlighting their heterogeneity and the need for tailored therapeutic strategies.