Abstract CT096: Mechanisms of acquired resistance and ctDNA clearance in <i>EGFR</i>-mutated advanced NSCLC following lazertinib treatment: Results from the phase 3 LASER301 study

Abstract Background: Patients (pts) with treatment-naïve, EGFR-mutated (EGFRm), advanced non-small cell lung cancer (NSCLC) who received lazertinib (CNS-penetrant, third-generation EGFR tyrosine kinase inhibitor) in the LASER301 study had significantly longer median progression-free survival versus gefitinib. Here we report results on mechanisms of acquired resistance and circulating tumor DNA (ctDNA) clearance in pts who received lazertinib in LASER301. Methods: Next-generation sequencing (NGS; Guardant360; Guardant Health) of circulating cell-free DNA (cfDNA) was performed on paired blood samples collected at baseline and at disease progression from pts who received lazertinib to evaluate the emergence of potential resistance mechanisms. To evaluate ctDNA clearance, exon 19 deletion (Ex19Del) and L858R ctDNA in blood was analyzed at baseline and Week 6 (Cycle 3, Day 1) with droplet digital PCR and EGFRm testing (Droplex EGFR Mutation Test v2; Gencurix). ctDNA clearance was defined as undetectable EGFRm determined at Week 6 in pts with detectable EGFRm ctDNA at baseline. Results: NGS analysis included 168 pts, of which 82 pts had detectable plasma EGFRm at baseline and were eligible for acquired resistance analysis. The most frequently occurring alterations acquired at disease progression were EGFR C797S alteration (9%) as well as MET and ERBB2 amplifications (7% each; Table). For the ctDNA clearance analysis, 149 pts were included. At baseline, ctDNA was detected in 52% of pts (77/149), with Ex19Del detected in 64% (49/77) and L858R detected in 36% (28/77). At Week 6, ctDNA was cleared in 94% of pts (72/77). Conclusions: In eligible pts with advanced EGFRm NSCLC treated with lazertinib from LASER301, EGFR C797S was the most commonly detected alteration at the time of disease progression, representing a potential mechanism of acquired resistance. ctDNA clearance was achieved in the majority of these pts by Week 6. Citation Format: Byoung Chul Cho, Ki Hyeong Lee, Chin Heng Fong, Anastasia Zimina, Yong Kek Pang, Sergey Orlov, Joo-Hang Kim, Jason K. Sa, YuKyung Kim, Mi-Jung Kwon, SeokYoung Choi, Dongmin Kim, Min Kim, Myung-Ju Ahn. Mechanisms of acquired resistance and ctDNA clearance in EGFR-mutated advanced NSCLC following lazertinib treatment: Results from the phase 3 LASER301 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT096.