Marcelo Vailati Negrao

Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to Osimertinib in NSCLC

Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Sequential liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation. Erlotinib was discontinued and osimertinib was initiated. Blood samples were collected at erlotinib progression and during osimertinib treatment for the detection of the activating (EGFR-exon19del) and resistance mutations (EGFR-T790M, EGFR-C797S, BRAF-V600E, METamp and ERBB2amp) in the plasma DNA using digital droplet PCR. Plasma levels of the activating EGFR-exon19del accurately paralleled the clinical and radiological progression of disease and allowed early detection of AR to osimertinib. Resistance to osimertinib coincided with the emergence of a small tumor cell subpopulation carrying the known EGFR-C797S resistance mutation and an additional subpopulation carrying amplified copies of EGFR-exon19del. Given the existence of multiple AR mechanisms, quantification of the original EGFR activation mutation, instead of the resistance mutations, can be efficiently used to monitor response to osimertinib, allowing early detection of AR. Absolute quantification of both activation and resistance mutations can provide important information on tumor clonal evolution upon progression to osimertinib. Selective amplification of the EGFR-exon19del allele may represent a novel resistance mechanism to osimertinib.

TRACERx: Tracking tumor evolution to impact the course of lung cancer

From the Division of Cancer Medicine, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, Department of Genomic Medicine, and Division of Surgery, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Tex. Funded by the MDAnderson Lung Cancer Moon Shots Program, MDAnderson Physician Scientist Program, and The Cancer Prevention & Research Institute of Texas Multi-Investigator Research Award grant (RP160668). Drs Negrao and Quek contributed equally to this article. Received for publication Sept 5, 2017; revisions received Sept 27, 2017; accepted for publication Oct 11, 2017. Address for reprints: Boris Sepesi, MD, T. Boone Pickens Academic Towe (FCT19.5084), 1515 Holcombe Blvd, Unit 1489, Houston, TX 77030 (E-mail: BSepesi@mdanderson.org). J Thorac Cardiovasc Surg 2017;-:1-4 0022-5223/

Local Consolidation Therapy (LCT) After First Line Tyrosine Kinase Inhibitor (TKI) for Patients With EGFR Mutant Metastatic Non–small-cell Lung Cancer (NSCLC)

36.00 Copyright 2017 by The American Association for Thoracic Surgery https://doi.org/10.1016/j.jtcvs.2017.10.134 Adapted from Jamal-Hanjani et al.

Abstract B03: Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC

Introduction: Although most NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) mutations have an impressive initial response, the vast majority has residual disease and develops acquired resistance after 9 to 14 months of EGFR tyrosine kinase (TKI) therapy. We recently reported a phase II trial showing that, for patients with molecularly unselected oligometastatic NSCLC who did not progress after first‐line systemic therapy, local consolidation therapy (LCT) with surgery or radiation improved progression‐free survival (PFS), compared with maintenance therapy alone. Herein, we report a retrospective analysis of LCT after TKI in patients with metastatic EGFR mutant NSCLC. Patients and Methods: We identified patients with metastatic EGFR mutant NSCLC treated with TKI plus LCT or with TKI alone in the MD Anderson GEMINI (Genomic Marker‐Guided Therapy Initiative) database and in our recently published LCT trial. PFS was compared between LCT plus TKI and TKI only treated patients using the log‐rank test. Results: We identified 129 patients with EGFR mutant NSCLC who were treated with first‐line TKI and 12 that were treated with TKI followed by LCT. Among the 12 patients treated with TKI plus LCT, 8 patients had oligometastatic disease (defined as ≤ 3 metastases), and 4 patients had > 3 metastases. LCT regimens were hypofractionated radiotherapy or stereotactic ablative body radiotherapy for 11 patients and surgery for 1 patient. TKI followed by LCT resulted in a significantly longer PFS (36 months) compared with TKI alone (PFS, 14 months; log‐rank P = .0024). Conclusions: Our data suggests that first‐line TKI plus LCT is a promising therapeutic strategy for patients with EGFR mutant NSCLC that merits further investigation.

Abstract B168: Monitoring acquired resistance to EGFR-TKIs and clonal evolution in metastatic NSCLC patients using liquid biopsies

Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Serial liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation. Erlotinib was discontinued and she received osimertinib. Blood samples were collected at erlotinib progression and during osimertinib treatment for the detection of the activating (EGFR-exon19del) and resistance mutations (EGFR-T790M, EGFR-C797S, BRAF-V600E, METamp and ERBB2amp) in the plasma DNA using digital droplet PCR. Plasma levels of the activating EGFR-exon19del accurately paralleled the clinical and radiologic progression of the disease and allowed early detection of AR to osimertinib. Resistance to osimertinib coincided with the emergence of a small tumor cell subpopulation carrying the known EGFR-C797S resistance mutation and an additional subpopulation carrying amplified copies of EGFR-exon19del. Given the existence of multiple AR mechanism, quantification of the original EGFR activation mutation, instead of the resistance mutations, can be efficiently used to monitor response to osimertinib, allowing early detection of AR. Absolute quantification of both activation and resistance mutations can provide important information on tumor clonal evolution upon progression to osimertinib. Selective amplification of the EGFR-exon19del allele may represent a novel resistance mechanism to osimertinib. Citation Format: Franciele Knebel, Fabiana Bettoni, Andrea Shimada, Manoel Cruz, Joao Victor Alessi, Marcelo Negrao, Luiz Fernando Reis, Artur Katz, Anamaria Camargo. Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B03.