Abstract LB078: Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study
Authors: Hartmaier Ryan J. , Markovets Aleksandra , Cho Byoung Chul , de Langen Adrianus J. , Goldberg Sarah B. , Goldman Jonathan , Le Xiuning , Okamoto Isamu , Riess Jonathan W. , Cosaert Jan , Yu Helena , Piotrowska Zofia 
Published: June 2022

Abstract
Background/Purpose: Osimertinib, a third-generation, irreversible, EGFR tyrosine kinase inhibitor (TKI), is the preferred 1L treatment for pts with EGFRm NSCLC. Unfortunately, most of these pts will eventually develop treatment resistance. ORCHARD is an ongoing Phase II platform study (NCT03944772) enrolling pts with EGFRm NSCLC, whose tumors progressed on 1L osimertinib, to a treatment group based on their tumor molecular profile. This exploratory analysis aimed to further understand the genomic landscape of resistance detected in tumor samples from pts with EGFRm NSCLC post-1L osimertinib, and to evaluate the concordance of resistance mechanisms identified in plasma and tissue.
Methods: Pts enrolled on ORCHARD (with advanced EGFRm NSCLC) provided tissue/plasma samples after progression on 1L osimertinib. Samples were analyzed for resistance mechanisms and testing concordance using next generation sequencing (NGS) either centrally (tissue [Foundation Medicine]; plasma [Guardant Health]) or locally. Alterations were determined based on reported results from respective assay.
Results: In total, 195 tissue samples (21 local and 174 central NGS) and 69 plasma samples (central NGS) were collected. The 174 central tissue samples were used for the genomic profiling: MET amplification occurred in 24% (42/174) of tumors; EGFR amplifications in 36% (62/174). Secondary EGFR mutations (C797X, L718X) and BRAF fusions were less common, 7% (13/174) and 5% (9/174), respectively, while other potentially actionable genomic alterations were rare: ERBB2 amplified/mutated (2%), ALK fusion (2%), RET fusions (1%), KRAS mutation (1%), BRAF V600E (1%).In the concordance analysis, 69 samples of matched tumor and plasma were used. Concordance was high between tissue and plasma for point mutations, particularly for sensitizing (64 samples; 89% concordance) and uncommon (G719X, L861X, S768I; 5 samples; 100% concordance) EGFR resistance mutations. The majority of EGFR (21/38 samples) and MET (16/30) amplifications were detected via tissue only. For BRAF, concordance was low: 4/5 BRAF fusions were found in tissue only, 1/5 in plasma only; 5/5 BRAF V600E mutations could be identified in plasma but only one of these was also identified in tissue.
Conclusions: Genomic profiling of pts with disease progression after 1L osimertinib showed that the most common identifiable resistance mutations were consistent with previous studies, however MET, EGFR amplifications and BRAF fusions were identified at higher rates than expected. Tissue and plasma provided different but potentially complementary results for detecting mechanisms of resistance, with differing levels of concordance across the mutations; further study is required in this area. Further exploration of 1L osimertinib resistance is continuing in the ongoing ORCHARD study.
Citation Format: Ryan J. Hartmaier, Aleksandra Markovets, Byoung Chul Cho, Adrianus J. de Langen, Sarah B. Goldberg, Jonathan Goldman, Xiuning Le, Isamu Okamoto, Jonathan W. Riess, Jan Cosaert, Helena Yu, Zofia Piotrowska. Tumor genomics in patients (pts) with advanced epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib therapy in the Phase II ORCHARD study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB078.