Outcomes of atypical EGFR mutations in early-stage EGFR -mutated non-small cell lung cancer (NSCLC).

8034 Background: Adjuvant osimertinib (osi) improves survival outcomes in patients (pts) with early-stage EGFR -mutated NSCLC harboring the classical EGFR exon 19 deletions (ex19del) or L858R mutation after surgery or chemoradiotherapy. Pts with early-stage NSCLC harboring atypical EGFR mutations were excluded from the respective clinical trials. Outcomes in this pt population remain unknown. Methods: We conducted a multi-institutional retrospective analysis of pts with stage IA-IIIC EGFR -mutated NSCLC (2010-2024) who were classified into two groups: those with tumors harboring classical EGFR mutations (c- EGFR : ex19del or L858R) or atypical EGFR mutations (a- EGFR : non-ex19del or L858R). Kaplan-Meier analyses compared disease-free survival (DFS), central nervous system (CNS) DFS, and overall survival (OS). Multivariable Cox regression adjusted for disease stage, definitive therapy, and adjuvant therapy. Results: Among 417 pts, 293 had tumors harboring c- EGFR and 124 had a- EGFR mutations. Baseline characteristics were similar between groups (Table). Median follow-up was 4 years. Among pts not treated with adjuvant osi (n = 346), a- EGFR was associated with a significantly lower 3-year DFS compared to c- EGFR (52.5% vs 71.2%; HR 1.71, 95% CI 1.21-2.42; P = 0.003). Compared to c- EGFR , a- EGFR had higher rates of recurrence to the ipsilateral lung (24% vs 14%) and bone (12% vs 6%). A- EGFR was associated with a significantly lower 3-year CNS DFS (81.3% vs 87.1%; P = 0.002) and 5-year OS (77.7% vs 85.6%; P = 0.007) compared to c- EGFR . Among pts with a- EGFR mutations, EGFR exon 20 insertions (ex20ins) were associated with a significantly reduced 3-year DFS compared to other alterations (35.9% vs 68.2%; HR 2.04, 95% CI 1.10-3.77; P = 0.013), and with a lower 3-year CNS DFS (70.9% vs 92.2%; P = 0.028) and trend towards lower 5-year OS (71.3% vs 84.4%; P = 0.141). Among pts who underwent surgery for stage IB-IIIA NSCLC (n = 209), adjuvant osi improved 3-year DFS among c- EGFR (84.2% with osi vs 63.4% without osi) whereas a- EGFR had a lower 3-year DFS (36.4%; P < 0.001), which was driven by EGFR ex20ins compared to other alterations (19.9% vs 59.2%; P = 0.003). Conclusions: Atypical EGFR mutations are associated with inferior survival outcomes compared to classical EGFR mutations in early-stage NSCLC. EGFR ex20ins appear to drive poor outcomes among the atypical EGFR mutations. Novel adjuvant therapy strategies are warranted to improve definitive treatment of early-stage atypical EGFR -mutated NSCLC. Classical EGFR , N=293 (%) Atypical EGFR , N=124 (%) Ex19del / L858R 46 / 54 - Ex20ins / G719X / L861Q / Other - 49 / 26 / 17 / 8 Stage IA / IB / II / III 35 / 23 / 17 / 25 38 / 14 / 23 / 25 Surgery / XRT / CRT 81 / 8 / 8 82 / 8 / 7 Neoadjuvant Chemo / EGFR TKI 4 / 3 7 / 2 Adjuvant Chemo / EGFR TKI / Osi 26 / 25 / 23 26 / 8 / 4 3-year DFS* 71.2 52.5 3-year CNS DFS* 87.1 81.3 5-year OS* 85.6 77.7 *In non-adjuvant osi cohort (n=346). Statistically significant difference.