Abstract 3886: Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study
Authors: Kim In Ae , Kim Seung Joon , Lee Sung Yong , Choi Chang Min , Lee Jae Cheol , Jang Tae Won , Jang Seung Hun , Park Chan Kwon , Kim Wan Seop , Hur Jae Young , Kim Hee Joung , Kim Young Whan , Lee Key Young 
Published: April 2023

Background:The response of 1st-line EGFR-TKI treatment in advanced EGFR-mutated lung adenocarcinoma patients are highly effective, but its sustainability and clinical course are quite variable from patient to patient. In this study, we investigated the clinical impact of concomitant genetic mutations analyzed by targeted NGS on PFS and acquired resistance in advanced EGFR-mutated lung adenocarcinoma patients.

Methods: Eighty-five advanced NSCLC patients harboring EGFR mutations were enrolled prospectively in multi-centers from 2019 to 2022 (NCT04122833). We performed the targeted next generation sequencing on 324 cancer-related genes by Foundation One CDx with pre-treated tumor samples. First- or second-generation EGFR-TKIs(gefitinib, afatinib, or erlotinib) were administered in 1st-line setting. After the progression, tissue re-biopsy or plasma liquid biopsy (FoundationOne Liquid CDx) for NGS if tissue biopsy is difficult or risk was performed.

Results: Of the 85 patients (70.6% of female, 65.8% of nonsmoker, 56.4% of E19del and 38.8% of E21 L858R mutation), 50 patients experienced a disease progression in November, 2022. The median PFS was 20 months (95 %CI: 15.2-24.8). The most frequent co-mutations were TP53 (47.1%), CDKN2A/B loss (34.1%), MTAP loss (20%), NKX2-1amp(15.3%), MDM2amp (14.1%), RMB10, CCNE/CCND1 amp, NFKB1 amp (11.8%) and CDK4/6 amp (10.6%). Patients with TP53, CDK4/6 amp and MYC amp were independently associated with shorter PFS. In a multivariate analysis, tumors with copy number alterations such as CDK4/6 amp or Myc amp were also independently associated with shorter PFS. However, the CDKN2A/2B loss, MTAP loss, and MDM amp were not related with the PFS. In the number of co-mutations, patients harboring ≥5 co-mutations identified by NGS had shorter median PFS than patients with 0-1 or 2-4 co-mutations. (mPFS 0-1: 2-4: ≥5 co-mutations=35: 18: 9.3 months, p&lt;0.001). At progression, 22 patients harbored an acquired T790M mutation (25.8%). Before TKI treatment, patients with CDKN2A/B loss, MTP loss or CCND/CCNE1 amp in pretreatment tumor have more acquired T790M mutation after progression significantly (p&lt;0.05)

Conclusion: We have demonstrated that concomitant mutations detected by targeted NGS analysis provide significant impact on the drug response and clinical course of advanced EGFR-mutated adenocarcinoma patients treated by 1st-line EGFR-TKIs. It is suggested that targeted NGS along with PCR-based detection will be necessary for precision medicine-based individualized practice of 1st-line EGFR-TKI-based combination treatment.

Citation Format: In Ae Kim, Seung Joon Kim, Sung Yong Lee, Chang Min Choi, Jae Cheol Lee, Tae Won Jang, Seung Hun Jang, Chan Kwon Park, Wan Seop Kim, Jae Young Hur, Hee Joung Kim, Young Whan Kim, Key Young Lee. Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3886.