Immunotherapy for uncommon <i>EGFR</i> mutations in lung adenocarcinoma.

e20613 Background: While common EGFR mutations (ex19del/L858R) are associated with poor response to immune checkpoint inhibitors (IO) in lung adenocarcinoma (LUAD), data on IO efficacy in uncommon EGFR mutations remains limited . We evaluated the clinicogenomic features and outcomes of individuals with uncommon EGFR- mutant LUAD treated with IO-based therapy. Methods: Using next-gen sequencing data, we identified patients with uncommon (non-ex19del/L858R) EGFR- mutant LUAD seen at Indiana University Health from Jan 1 st 2018 to Dec 31 st 2025. Uncommon mutations excluding ex20ins were categorized as atypical. Endpoints were collected retrospectively through chart review for individuals with advanced disease. Kaplan-Meier was used to assess progression-free survival (PFS) and overall survival (OS). Results: Among 1497 patients with LUAD identified, 56 (3.7%) had uncommon EGFR mutations, including 49 (89%) with Stage IV disease. Median age was 69, 39% were male, 86% were White (86%), 65% had tobacco use history (median pack-years: 20), 25% had brain metastases, and 10% had ≥3 metastatic sites. Median tumor mutation burden (TMB) was 4.5 mut/Mb (range, 0-14). PD-L1 TPS were &lt; 1%,1-49%, and &gt; 50% in 39%, 44%, and 17% of cases. EGFR atypical mutations (most commonly G719X, S768I, and L961Q) comprised of 34 (69%) uncommon cases. Among 40 patients undergoing systemic therapy for metastatic disease, 14 received IO-based therapy. First-line (1L) treatments included IO-based +/- chemotherapy (33%), targeted based with tyrosine kinase inhibitor +/- chemotherapy or amivantamab/chemotherapy (62%), or chemotherapy alone (5%). Detailed outcomes of 1L IO-based and targeted based therapies were illustrated in Table 1, with trend towards favoring targeted-based therapies. Median OS for IO-treated and IO-naïve patients was 31.5 mo vs 61 mo (IO-treated (n = 14) vs IO-naïve (n = 26)) in uncommon and 40.9 vs 61 mo (IO-treated (n = 7) vs IO-naïve (n = 21)) in atypical mutant group. Among IO-treated patients with available PD-L1 data, mOS seemed to improve with higher PD-L1 levels (26 mo, &lt; 1%, n = 3; 24 mo, 1-49%, n = 5; 35 mo, ≥50%, n = 4). Response was independent of TMB status and smoking history. Notably, one patient with EGFR G719A and PD-L1 TPS 100% demonstrated a complete response to pembrolizumab after three cycles. Conclusions: While 1L targeted therapy trended toward longer survival, the small sample size limits interpretation. Immunotherapy could be a beneficial option for select patients with atypical EGFR mutations (especially if high PD-L1). Given its rare incidence, prospective evaluation of IO in this patient population warrants further evaluation through multi-institutional consortium studies. 1L therapy Median PFS (mo) 3-year OS (%) Uncommon (n=40)IO-based (n=13)Targeted based (n=25) 9.931.4 4068.9 Atypical (n=27)IO-based (n=7)Targeted based (n=20) 630.1 62.574.7