Virtual Library
Start Your Search
Rebecca J Nagy
Author of
-
+
MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
-
+
MA16.01 - Frequency and Genomic Context of Emerging Markers for Molecular Testing in Lung Adenocarcinoma in Cell-Free DNA NGS Analysis (ID 13465)
13:30 - 13:35 | Author(s): Rebecca J Nagy
- Abstract
- Presentation
Background
The recently updated CAP/IASLC/AMP lung cancer molecular testing guideline (Lindeman et al 2018) recommends several genes be analyzed by next-generation sequencing (NGS) in lung adenocarcinoma (LUAD), including EGFR, ALK, BRAF, KRAS, and others. It also includes a list of 20 emerging markers (EMs) for molecular testing and suggests practitioners remain aware of these and other genes between guideline updates. We investigated the frequency of genomic alterations (GAs) in several of these EMs in a cohort of patients with advanced lung adenocarcinoma who underwent clinical cell-free DNA (cfDNA) NGS analysis and assessed co-occurrence with canonical driver GAs.
a9ded1e5ce5d75814730bb4caaf49419 Method
Genomic data was reviewed from 6530 patients with at least one GA detected on clinical Guardant360 cfDNA NGS testing (Guardant Health, Inc) with an indicated diagnosis of lung adenocarcinoma from 11/25/16-3/1/18. Synonymous alterations were excluded from further analyses.
4c3880bb027f159e801041b1021e88e8 Result
2600 patients (40%) had at least one nonsynonymous alteration in the EM genes assessed; excluding GAs classified as variants of unknown significance (VUS), 1350 patients (21%) had at least one characterized alteration. Table 1 shows number and frequency of GAs observed per patient by gene and alteration type. Of EMs assessed, GAs were observed most commonly in NF1, PIK3CA, PDGFRA, KIT, and FGFR1-2. GAs in multiple EMs, including RIT1, NRAS, FGFR2-3, NTRK1, KIT, and AKT1, were observed co-occurring with established driver alterations, often in a genomic context consistent with resistance to targeted therapy at allelic fractions suggestive of subclonality.
8eea62084ca7e541d918e823422bd82e Conclusion
Effective therapies are continually emerging for a growing number of molecular biomarkers in lung cancer. Comprehensive genomic profiling with cfDNA NGS can identify GAs in both recommended and EM genes to guide therapeutic decision-making and catalyze clinical trial enrollment. Further investigation of mutual exclusivity and co-occurrence of established drivers and EMs may reveal novel resistance mechanisms and facilitate identification of rational combination therapeutic strategies.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MA16.08 - Clinical Utility of Detecting ROS1 Genetic Alterations in Plasma (ID 13522)
14:25 - 14:30 | Author(s): Rebecca J Nagy
- Abstract
- Presentation
Background
ROS1-rearranged lung cancer harbors an oncogenic fusion protein created by the juxtaposition of the ROS1 gene to various fusion partners. Due to the lack of a conserved breakpoint and inclusion of intronic segments, ROS1 rearrangements can be challenging to identify with DNA-based sequencing approaches. The feasibility and clinical utility of detecting ROS1 fusions in circulating tumor DNA is not well established.
a9ded1e5ce5d75814730bb4caaf49419 Method
The Guardant360 de-identified database was queried to identify lung cancer cases with plasma ROS1 fusions and describe the molecular features of the ROS1-rearranged cohort. In addition, we performed longitudinal analysis of plasma specimens from four patients at our institution who were treated with next-generation ROS1 inhibitors after progressing on crizotinib.
4c3880bb027f159e801041b1021e88e8 Result
From review of 24,009 plasma specimens from lung cancer patients, we identified 56 patients with ROS1 fusions. CD74 was the most common of 7 identified fusion partners [n=35 (62%) CD74, n=7 (12.5%) SDC4, n=7 (12.5%) EZR, n=3 (5%) TPM3, n=2 (4%) TFG, and n=1 (2%) each of CCDC6 and SLC34A2]. ROS1 fusions commonly co-occurred with TP53 mutations (n=36, 64%) and genes involved in cell-cycle regulation (n=11, 20%) or the WNT/ß-catenin pathway (n=16, 29%). In 4 (80%) of 5 cases where plasma genotyping occurred at crizotinib progression, we identified a putative resistance mechanism, including a ROS1 resistance mutation in 3 patients (n=2 G2032R & n=1 L2026M) and a BRAF V600E mutation in 1 patient. We analyzed longitudinal plasma specimens from 4 patients with crizotinib-resistant lung cancer who were subsequently treated with a next-generation ROS1 inhibitor (n=3 lorlatinib, n=1 entrectinib). One patient treated with lorlatinib had a pretreatment ROS1 G2032R mutation (in plasma and tissue); plasma analysis revealed stability of the G2032R allelic fraction in the setting of primary progression of pleural disease. Of the 2 patients without pretreatment ROS1 mutations who received lorlatinib, one developed a ROS1 G2032R mutation after initial response to treatment. The second patient experienced primary progression and plasma genotyping revealed low level FGFR1 copy number gain (3.3 copies); pre-crizotinib plasma was not available for comparison. One patient had a plasma PIK3CA E545K mutation at the time of crizotinib progression, and did not respond to next-line entrectinib.
8eea62084ca7e541d918e823422bd82e Conclusion
Next-generation sequencing can be used to detect ROS1 fusions and resistance mutations in plasma. Longitudinal plasma analysis may provide insight into the activity of investigational drugs against ROS1 mutations that mediate resistance to crizotinib.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
-
+
MA26.03 - Activity of Osimertinib and the Selective RET Inhibitor BLU-667 in an EGFR-Mutant Patient with Acquired RET Rearrangement (ID 14731)
13:40 - 13:45 | Author(s): Rebecca J Nagy
- Abstract
- Presentation
Background
The spectrum of acquired resistance (AR) to osimertinib is not yet fully characterized. We present a single-center cohort of osimertinib AR biopsies and results of a patient with RET-mediated AR treated with the investigational RET-specific TKI BLU-667 and osimertinib.
a9ded1e5ce5d75814730bb4caaf49419 Method
We assayed tissue via SNaPshot or Foundation One next-generation sequencing (NGS) and plasma via Guardant360 NGS under an IRB-approved protocol. In vitro studies assessed implications of RET fusions in EGFR-mutant cancers. We treated one patient with osimertinib/BLU-667 using an IRB and FDA-approved compassionate use protocol.
4c3880bb027f159e801041b1021e88e8 Result
41 EGFR-mutant patients with AR to osimertinib were assessed histologically and queried by tissue NGS (n=22), plasma NGS (n=9) or both (n=10). Key AR findings: SCLC transformation (2/32 tissue); EGFR C797S (5/32 tissue, 5/19 plasma, all cis with T790M); MET amplification (7/32 tissue, 3/19 plasma); BRAF rearrangement (2/32 tissue) and CCDC6-RET rearrangement (1/32 tissue, 1/19 plasma [distinct case]).
CCDC6-RET was expressed in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells, which maintained MAPK signaling and conferred resistance to osimertinib and afatinib. Inhibition of RET by BLU-667 or cabozantinib resensitized cells expressing CCDC6-RET to EGFR inhibition.
A 60-year-old woman with EGFR del19 progressed on afatinib (T790M+), then osimertinib. Tissue biopsy at osimertinib AR showed acquired CCDC6-RET (T790-wt). She began osimertinib 80mg/BLU-667 200mg daily x2 weeks, then BLU-667 was increased to 300mg daily. Her dyspnea improved within days of initiation. Scans after 8 weeks revealed a marked response with RECIST tumor shrinkage of 78% (Figure). She experienced only grade 1 toxicities of fatigue, leukopenia, hypertension, dry mouth, and elevated transaminases.
8eea62084ca7e541d918e823422bd82e Conclusion
RET rearrangements are rare but recurrent in EGFR-mutant patients with AR to osimertinib. In vivo models suggest they mediate AR and this patient provides proof-of-concept that combination EGFR+RET inhibition with osimertinib/BLU-667 is a well-tolerated and effective regimen for RET-mediated AR. Further study is ongoing.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
