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R.B. Lanman
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.02 - Characteristics of Lung Cancer Cell-Free Tumor DNA (CfDNA) Shedding and Correlation with Tumor Burden as Measured by RECIST (ID 9663)
15:55 - 16:05 | Author(s): R.B. Lanman
- Abstract
- Presentation
Background:
cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.
Method:
We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.
Result:
There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1
Conclusion:
In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.
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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.B. Lanman
- 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.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.05 - Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer (ID 9984)
11:40 - 11:50 | Author(s): R.B. Lanman
- Abstract
- Presentation
Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.
Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.
Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.
Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-046 - Longitudinal Analysis of Plasma CtDNA in EGFR-Mutant NSCLC: SWOG S1403 Trial of Afatinib with or Without Cetuximab (ID 9535)
09:30 - 09:30 | Author(s): R.B. Lanman
- Abstract
Background:
Detection of actionable mutations using circulating tumor DNA (ctDNA) isolated from patient plasma is now accepted as clinical practice in NSCLC. Nevertheless, the full extent to which longitudinal plasma analysis can be utilized to guide clinical decision-making has yet to be realized. We prospectively incorporated serial next-generation sequencing (NGS) of ctDNA into the ongoing SWOG S1403 clinical trial (NCT02438722) of afatinib+cetuximab vs afatinib in treatment-naïve NSCLC patients with EGFR-mutant tumors.
Method:
Time points for specimen collection were pre-treatment, after two months of therapy on Cycle 3 Day1 (C3D1) and at progression. Objectives were to: 1) determine the prognostic and predictive significance the EGFR mutant allele frequency (MAF) at each time point; 2) correlate changes in MAF over time with regard to patient outcome, and 3) identify putative emergent resistance mechanisms and companion mutations. Specimen analysis was conducted using the Guardant360 73-gene digital NGS panel.
Result:
To date, 53 patients with advanced EGFR-mutant NSCLC have contributed baseline samples. Of these, 46 had ctDNA detectable at baseline (87%). 39 of these 46 (85%) had detectable, tissue-identical EGFR mutations, for an overall EGFR detection rate of 74% (39/53). A positive finding for EGFR amplification (Amp) in plasma correlated with high ctDNA MAF: median for Amp 16.9 vs nonAmp 0.9 (range/n: 11.6-43.7/10 vs 0.11-7.7/17; p<0.0001). Of patients with detectable EGFR mutation at baseline, 27 had analyzable ctDNA collected at C3D1. Of these, 26/27 showed decreasing MAFs on-treatment (mean for baseline: 9.8 vs C3D1: 0.14; p<0.0001), with 20 cases having no detectable EGFR mutation at C3D1 (mean of 7 positives at C3D1: 0.55). At progression, samples were collected from 14 patients and 10 had EGFR mutations detectable, with T790M present in 3. Another patient had an FGFR3 fusion at PD, but no previous draws were available to determine if it was emergent.
Conclusion:
Longitudinal analysis of plasma ctDNA in S1403 patients demonstrated significant treatment-induced changes in mutation burden and identified resistance mechanisms at progression. EGFR gene amplification, as assessed in plasma, was significantly associated with increased ctDNA MAFs. Patients showed a significant, one-to-two orders of magnitude decline in EGFR MAF after two months of therapy, with 74% dropping below detectable levels. At progression, EGFR mutation detection rates increased, often concomitantly with a putative emergent resistance factor. Accrual to S1403 is ongoing and patient treatment and outcomes remain blinded. The prognostic and predictive utility of baseline and therapy-induced changes in ctDNA MAF kinetics will be determined at study unblinding.
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P3.01-060 - The Clinical Utility of ctDNA Gene Analysis in Lung Cancer (ID 9948)
09:30 - 09:30 | Author(s): R.B. Lanman
- Abstract
Background:
Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. In this study, we evaluated the impact of ctDNA sequencing on outcomes and treatment strategy.
Method:
In this retrospective study, data was collected from files of advanced non-small cell lung cancer (NSCLC) patients at the Thoracic Cancer Unit, Rabin Medical Center, Israel, between 2014-2017. Plasma samples were analyzed by a commercial test (Guardant360[TM]), using massively parallel paired-end synthesis to sequence a targeted 68-73 gene panel.
Result:
116 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63 years, 74% had adenocarcinoma. 41% performed ctDNA analysis before 1st line therapy (Group A) and 59% on progression (Group B), among them 41% after progression on EGFR TKIs (Group B1) and 59% on other treatments (Group B2). ctDNA analysis yielded actionable mutations (EGFR, ALK, RET, BRAF, MET, ERBB2 (HER2)) in 40.5%: 31% in group A, 47% in group B, 71% in group B1 and 30% in group B2. Treatment decision was taken toward targeted therapy subsequent to NGS in 26%.Genetic alterations frequencies among groups A, B, B1 and B2
Response assessment (RECIST) to targeted therapy showed complete response in 4%, partial response in 44%, stable disease in 37% and progressive disease in 15%. Response rate was 44% for group A, 50% for group B, 60% for group B1, 37.5% for group B2. Total objective response rate was 48% and disease control rate was 85%. Overall survival was evaluated for 40%, median was 14.4 months for patients who received targeted therapy vs 13.6 months for patients who received standard treatment.Group A 19 individual mutations Group B 52 individual mutations Group B1 34 individual mutations Group B2 18 individual mutations EGFR Sensitizing 52.5% (10/19) EGFR Sensitizing 42% (22/52) EGFR Sensitizing 59% (20/34) MET 55.6% (10/18) MET 16% (3/19) MET 27% (14/52) EGFR T790M 23% (8/34) ERBB2 16.7% (3/18) ERBB2 10.5% (2/19) EGFR T790M 15% (8/52) MET 12% (4/34) RET 16.7% (3/18) BRAF V600E 10.5% (2/19) ERBB2 8% (4/52) ERBB2 3% (1/34) EGFR Sensitizing 11.1% (2/18) RET 10.5% (2/19) RET 6% (3/52) ALK 3% (1/34) ALK 2% (1/52)
Conclusion:
Comprehensive ctDNA testing revealed treatment options for 40.5% of patients analyzed. The highest impact was seen in progressors on EGFR therapy. These positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the most efficacious therapy for each patient.
