Abstract 4617: Blood-based biomarkers for predicting treatment response to immune checkpoint inhibitors after EGFR-TKI resistance
Authors: Jun Hyeok Lim, Min Seok Park, Nuri Park, Yejin Cho, Sehan Kwak, Beom Seok Han, Minseo Lee, Donghyun Seo, Woo Kyung Ryu, Jeong-Seon Ryu, Soon-sun Hong, Kyung Hee Jung
Journal: Cancer Research (2025)

Abstract Background: Immune checkpoint inhibitors (ICIs) improve survival in advanced non-small cell lung cancer (NSCLC), but their benefits are limited in EGFR-mutant NSCLC. ICIs are often used after resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since EGFR-TKI treatment alters the tumor microenvironment, predictive biomarkers for ICI response should ideally be identified post-EGFR-TKI resistance. However, obtaining re-biopsy samples is challenging. This study explores predictive biomarkers for ICI response using plasma samples collected before and after EGFR-TKI therapy. Methods: We retrospectively analyzed 28 EGFR-mutant NSCLC patients treated with ICIs at Inha University Hospital (2016-2023). All patients received first-line EGFR-TKI therapy and transitioned to ICIs after resistance. Plasma samples were collected before EGFR-TKI initiation and post-resistance. Ninety-six plasma proteins were quantified using the Olink Immuno-Oncology panel. PD-L1 expression in tumor tissues was assessed at diagnosis with SP263 or 22C3 assays. Progression-free survival (PFS) was defined as time from ICI initiation to progression. Responders were defined as PFS ≥6 months, and non-responders as PFS &amp;lt;6 months. Results: Among 28 patients, 25 had adenocarcinoma, 1 squamous cell carcinoma, 1 adenosquamous carcinoma, and 1 poorly differentiated NSCLC. EGFR mutations included exon 19 deletion (n=14), L858R (n=10), and uncommon mutations (n=4). First-line EGFR-TKIs included erlotinib (n=15), afatinib (n=9), and gefitinib (n=4). T790M mutations were identified in 11 patients, of whom 10 received osimertinib and 1 received lazertinib. ICIs included atezolizumab (n=15), pembrolizumab (n=5), and nivolumab (n=8). PD-L1 expression was evaluated in 23 patients using SP263 (5 negative, 15 with 1-49%, 3 with ≥50%) and in 22 patients using 22C3 (7 negative, 11 with 1-49%, 4 with ≥50%). Median PFS for ICIs was 2.7 months (95% CI: 1.7-3.7), with 6 responders and 22 non-responders. Plasma levels of IL-4, IL-6, GZMH, and Gal-9 differed significantly between responders and non-responders post-EGFR-TKI resistance. These findings were validated using tissue samples obtained post-resistance. Progression-free survival (PFS) showed significant differences according to plasma biomarker expression. Conclusions: Plasma samples collected after EGFR-TKI resistance can predict ICI responses in EGFR-mutant NSCLC. Post-resistance plasma biomarker levels may serve as a minimally invasive approach to guide therapeutic decisions in this challenging patient population. Citation Format: Jun Hyeok Lim, Min Seok Park, Nuri Park, Yejin Cho, Sehan Kwak, Beom Seok Han, Minseo Lee, Donghyun Seo, Woo Kyung Ryu, Jeong-Seon Ryu, Soon-sun Hong, Kyung Hee Jung. Blood-based biomarkers for predicting treatment response to immune checkpoint inhibitors after EGFR-TKI resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4617.