Preliminary results of the Lung Cancer Mutation Consortium LCMC4 evaluation of actionable drivers in early stage lung cancer (LEADER) screening trial.
Authors: Chaft Jamie E. , Swanson Scott , Lee Jay M. , Lin Jules , Tsukada Hisashi , Li Tianhong , Ripley R. Taylor , Kaifi Jussuf T. , Baik Christina S , Bunn Paul A. , Tambaoan Candice Francheska , Huang Richard S.P. , Jones David R , Kris Mark G. 
Published: June 2024

8068

Background: Neoadjuvant chemotherapy and immunotherapy have become standard for patients with resectable non-small cell lung cancer with no targetable oncogenic driver. For patients with tumors driven by most actionable oncogenes, little benefit has been seen. The LEADER Screening Trial designed by the LCMC and supported by the Thoracic Surgical Oncology Group aims to determine the proportion of clinical Stage IA2-III lung adenocarcinomas and adenosquamous carcinomas with one of 12 actionable oncogenes, detected through tumor and blood genomics. This abstract presents data from the first 110 tumors, all tested at Foundation Medicine. Methods: This analysis includes eligible patients on the LEADER trial with recectable NSCLC (not purely squamous) tested centrally with FoundationOneCDx (F1CDx, tissue) and/or FoundationOneLiquidCDx (F1LCDx, liquid biopsy) prior to 15Dec2023. An actionable oncogene is defined as: EGFR sensitizing or exon 20; KRAS G12C; BRAFV600E; HER2 mutation or amplification, MET ex14 skipping mutation or amplification; or RET, ROS1, ALK,or NTRK1/2/3 fusion. Detectable ct DNA was defined as tumor fraction > 0. Results: Of the 110 patients, 95% (105/110) had a successful tissue and/or liquid profiling. Of samples received, 91% (64/70) yielded successful tissue profiling, and 86% (91/ 106) successful blood profiling. All unsuccessful tests were due to inadequate DNA extraction. Some ctDNA was present in 37% (34/91) of blood samples; 62% (56/91) had no detectable. We found an actionable oncogenic driver in 35% (38/110, 95% confidence interval 26-44%) of patients tested. If any ctDNA was detected in blood, there was a 100% agreement with tumor tissue whether a driver was present or absent. In blood samples without paired tumor, an actionable alteration was found in 19% of cases (8/42). Identified driver alterations included: 12 EGFR sensitizing, 12 KRAS G12C, 4 EGFRexon 20 insertions, 2 BRAFV600E, 2 RET fusions, 2 HER2 mutations, 1 ALK fusion, 1 HER2 amplification, 1 MET ex14 skipping, and 1 ROS1 fusion. Alterations detected on liquid biopsy included EGFRexon 20 insertion, EGFR sensitizing mutations, KRAS G12C, RETfusion, and HER2 mutation. Conclusions: In this national study using both tissue and blood NGS testing, actionable oncogenic drivers were found in 35% of patients with clinical stages IA2-III lung adenocarcinoma at diagnosis. Blood testing identified an actionable driver 19% of the time when tumor testing was not done. Comprehensive genomics testing on patients with early-stage lung cancer should be standard. It identifies relevant oncogenic drivers and provides important ‘negative selection’ to identify the patients appropriate for neoadjuvant chemoimmunotherapy. Accrual to the LEADER trial continues. Clinical trial information: NCT04712877 .