Abstract 1944: Longitudinal circulating tumor DNA (ctDNA) analysis and acquired mechanisms of resistance to osimertinib (osi) in the China cohort of the FLAURA study

Abstract Background: In the China cohort of the FLAURA study (NCT02296125), first-line (1L) osi demonstrated clinically meaningful progression-free survival (PFS) and overall survival benefits vs comparator EGFR-TKI in Chinese patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC. This exploratory longitudinal ctDNA analysis from the FLAURA China cohort assessed if EGFRm alone vs 168-gene panel (including EGFRm) ctDNA testing identified PD before RECIST PD, the correlation of baseline (BL) plasma EGFRm detection and its clearance with PFS and investigated acquired resistance mechanisms to osi. Methods: Pts ≥18 yrs with untreated, EGFRm (Ex19del or L858R) locally advanced or metastatic NSCLC were randomized 1:1 to osi 80 mg once daily (QD; n=71) or comparator EGFR-TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg QD, n=65). ctDNA samples were collected at BL, throughout the osi treatment period, and after investigator-assessed RECIST PD and were sequenced by a capture-based 168-gene panel (Burning Rock OncoCompassTM). ctDNA profiling was assessed for acquired resistance and vs PFS for molecular response and ctDNA PD. Results: Overall, 2426 ctDNA samples from 127 pts in China were analyzed. At BL, pts with undetected plasma EGFRm (n=17, 13%) had longer median PFS (mPFS) vs pts with detected EGFRm (n=110); 20.6 mo vs 13.8 mo, respectively (HR 0.68; 95% CI 0.33, 1.25). At Week 3, 64% (38/59) and 72% (36/50) of pts in the osi and comparator arms, respectively, had EGFRm clearance. In both arms, pts with EGFRm clearance had longer mPFS than pts with non-clearance (osi: HR 0.38; 95% CI 0.19, 0.77; comparator: HR 0.23; 95% CI 0.12, 0.48); a positive association with mPFS was also seen at Week 6. When analyzing all mutations (mut) in the 168-gene panel at Week 3, the results were consistent; those pts with EGFRm clearance also had clearance of other BL detected mut. For pts with samples at Week 3 and RECIST PD, 52/81 (64%) had EGFRm ctDNA PD (by predefined criteria) that was equivalent (within 1 week) or earlier than RECIST PD, with median lead times of 2.4 and 2.1 mo for the osi and comparator arms, respectively. Similarly, using the entire 168-gene panel, 56/81 pts (69%) had total ctDNA PD equivalent/earlier than RECIST PD, with median lead times of 2.7 and 2.8 mo for the osi and comparator arms, respectively. In 35 pts in the osi arm with detected EGFRm at BL and PFS events, the most common acquired mut in the last 3 samples up to RECIST PD were MET amplification (6%), EGFR L718Q (6%), PIK3CA mut (6%) and CDKN1B/CDKN2A (6%). Conclusions: BL undetected or early clearance of EGFRm ctDNA were associated with longer mPFS. Longitudinal ctDNA analysis could detect molecular PD before RECIST PD. Analysis of EGFRm was as informative as a 168-gene panel in its association with PFS and detection of molecular PD lead time. Acquired resistance mut profiles to 1L osi were consistent with prior reports. Citation Format: Ying Cheng, Dan Wang, Jacqulyne Robichaux, Yong He, Wei Li, He-long Zhang, Qing Zhou, Buhai Wang, Chunling Liu, Yao Wang, Xiangning Huang, Zhanjian Dong, Rui Mao, Tianyuan Zhou, Ryan Hartmaier. Longitudinal circulating tumor DNA (ctDNA) analysis and acquired mechanisms of resistance to osimertinib (osi) in the China cohort of the FLAURA study. [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 1944.