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R.J. Nagy
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.02 - Plasma CfDNA next Generation Sequencing in Non-Small Cell Lung Cancer: Clinical Outcomes and Comparison to Tissue (ID 9502)
15:50 - 15:55 | Author(s): R.J. Nagy
- Abstract
- Presentation
Background:
Next-generation sequencing (NGS) of cell-free DNA (cfDNA) in plasma can be an alternative or complement to tissue biopsy for genomic analysis of non-small cell lung cancer (NSCLC), particularly for identifying driver and resistance alterations. We presented preliminary data in 67 patients comparing NGS in plasma vs. tissue (Santos et al. JTO; 11:10, S199-200) and found EGFR mutation agreement of 68% between plasma and tissue. We now present an expanded patient cohort with more extensive concordance analysis, longer follow-up, and clinical outcomes.
Method:
We analyzed data from advanced (stage III/IV) NSCLC patients seen at three cancer centers in Florida (US; Memorial Cancer Institute, Florida Hospital Cancer Center, Mount Sinai Cancer Center) that had alterations detected on Guardant360 (G360) testing through January 2017. G360 is a plasma cfDNA NGS assay that detects single nucleotide variations, amplifications, fusions, and indels in targeted genes using massively parallel digital sequencing; panel composition expanded from 54 to 73 genes over the course of the cohort. NGS performed on solid tumor biopsies from each subject were reviewed for comparison where available but may not have been collected contemporaneously to the plasma samples. Treatment information and clinical outcomes were collected for those patients with actionable mutations per NCCN guidelines (v3.2017).
Result:
A total of 190 G360 test results on 171 unique patients were identified (some patients underwent serial testing at multiple clinical timepoints, e.g. progression). Forty percent of patients were male; the median age was 65 (32-94). Excluding variants of uncertain significance, patients were most likely to have cfDNA alterations in TP53 (44%), EGFR (21%), KRAS (19%), BRAF (8%), and MET (8%). Forty-seven patients (28%) had at least one actionable mutation identified on G360, including SNVs, indels, fusions, and amplifications. Preliminary clinical outcomes data include durable (³10 months) partial responses on targeted therapy based on multiple plasma-detected alterations in EGFR and BRAF V600E; complete analysis will be presented at the meeting.
Conclusion:
Liquid biopsy plays an important role in genomic analysis of NSCLC, offering reliable information to guide therapeutic decision-making. Results in our cohort include a noteworthy proportion of patients with highly actionable mutations, like EGFR drivers and targetable resistance mutations, and G360 offers an alternative to tissue biopsy in these patients.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.01 - Characterizing the Genomic Landscape of EGFR C797S in Lung Cancer Using ctDNA Next-Generation Sequencing (ID 10213)
11:00 - 11:10 | Author(s): R.J. Nagy
- Abstract
- Presentation
Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.
Method:
We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.
Result:
We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).
Conclusion:
Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.
Only 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.
