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Sai-Hong Ignatius Ou
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FP07 - Pathology (ID 109)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP07.12 - Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets (ID 3399)
00:00 - 00:00 | Author(s): Sai-Hong Ignatius Ou
- Abstract
- Presentation
Introduction
Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them.
Methods
Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use.
Results
The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure).
Conclusion
PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.
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MA04 - Health Policy and the Real World (ID 217)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA04.07 - Comparative Clinical Outcomes for Patients with NSCLC Harboring EGFR Exon 20 Insertion Mutations and Common EGFR Mutations (ID 3390)
16:45 - 17:45 | Author(s): Sai-Hong Ignatius Ou
- Abstract
- Presentation
Introduction
Approximately 85–90% of the mutations seen in EGFR-mutant non-small cell lung cancers (NSCLCs) are common mutations (cEGFR), Exon 19 deletions and Exon 21 L858R. Up to 10% of EGFR-mutant NSCLC harbors Exon 20 insertion mutations (Exon20ins). We conducted a retrospective cohort study using real-world data to compare clinical outcomes between patients harboring Exon20ins and cEGFR.
Methods
This retrospective cohort study included patients from the Flatiron Health database (1 January 2011 through 31 May 2020) who had advanced NSCLC. The objectives of the study were to assess the prognostic value of Exon20ins compared with cEGFR (start date of first-line therapy as the index date) and the effect of tyrosine kinase inhibitor (TKI) treatment between the groups (start date of first TKI line as the index date). Analysis was stratified by line of TKI use. Endpoints included real-world overall survival (rwOS), progression-free survival (rwPFS), and time to next therapy (rwTTNT) and were analyzed using multivariable Cox proportional hazards model and summarized by Kaplan-Meier method.
Results
Among 62,464 patients with advanced NSCLC, 181 with Exon20ins and 2833 with cEGFR met eligibility criteria. Population demographics between the groups were comparable with minor exceptions. With median 34-month follow-up, Exon20ins was associated with a 75% increased risk of death (adjusted hazard ratio [adjHR] of 1.75 [95%CI, 1.45–2.13]; p˂0.0001); median rwOS was 16.23 (95%CI, 11.04–19.38) for Exon20ins and 25.49 months (95%CI, 24.48–27.04) for cEGFR (Table). The estimated 5-year survival rate for Exon20ins is 8% compared with 19% for cEGFR.
The predictive value of TKI treatment, stratified by line, was assessed in 76 Exon20ins and 2749 cEGFR patients who were treated with TKIs. With median 20.6-month follow-up, there was a 170% increase in risk of progression or death associated with Exon20ins (adjHR of 2.7 [95% CI, 2.06–3.55]; p˂0.0001); median rwPFS was 2.86 months (95%CI, 2.14–3.91) compared with 10.45 months (95%CI: 10.05–10.94) for cEGFR. Furthermore, there was a 170% increased risk of death (adjHR of 2.70 [95% CI, 2.04–3.57]; p˂0.0001) associated with Exon20ins; median rwOS was 7.46 months (95%CI, 5.45–13.34) for Exon20ins and 25.49 months (95%CI, 24.28–26.81) for cEGFR (Table).
Conclusion
Patients with Exon20ins have a worse prognosis compared with patients with cEGFR. Furthermore, EGFR TKI treatment was substantially less effective for patients with Exon20ins, as the risk of disease progression and mortality was higher compared with patients with cEGFR. These findings highlight the need for new treatment options for Exon20ins.
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.
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P37 - Pathology - Biomarker Testing (ID 107)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P37.31 - Trends in the Detection of EGFR Exon 20 Insertions in Patients with NSCLC in the US (ID 3334)
00:00 - 00:00 | Author(s): Sai-Hong Ignatius Ou
- Abstract
Introduction
Epidermal growth factor receptor exon 20 insertions (EGFRex20ins) are an uncommon subset of EGFR-activating mutations that are associated with a lack of responsiveness to tyrosine kinase inhibitor (TKI) therapy. With the clinical development of TKIs and monoclonal antibodies targeting EGFRex20ins, broad molecular profiling is needed to direct patients to these therapies. We describe real-world EGFRex20ins detection patterns in patients with advanced non-small cell lung cancer (NSCLC) in the United States.
Methods
Data were extracted from the Flatiron Health electronic health record-derived deidentified database. Patients ≥ 18 years, diagnosed with advanced NSCLC, and ≥ 2 clinic visits between 01/01/2011 and 12/31/2019 were included.
Results
A total of 60,025 patients with advanced NSCLC were identified 38,990 patients (65%) were tested for EGFR mutations, of which 326 (0.8%) harbored an EGFRex20ins; clinicopathologic characteristics of patients with an EGFRex20ins were similar to the canonical EGFR mutations. The frequency of EGFRex20ins among all NSCLC cases tested (by year of advanced diagnosis) increased from 0.6% in 2011 to 1.2% in 2019. In patients with an EGFRex20ins-positive result, the proportion of testing conducted by polymerase chain reaction (PCR) declined from 67% in 2011 to 16% in 2019, and use of next-generation sequencing (NGS) increased from 0% in 2011 to 64% in 2019. In EGFRex20ins-positive patients, tissue samples were most commonly used for testing (83%), while blood samples were also used (16%). Treatment was initiated in 26% of patients prior to confirmation of the first EGFRex20ins-positive result and in 2019, the most common treatment was immunotherapy-based (55.6%). The median time from advanced diagnosis to first EGFRex20ins result was 25 days, including a laboratory turnaround time of 10 days.
Conclusion
The detection rate of EGFRex20ins in NSCLC patients has increased, coinciding with a shift in testing methods from PCR to NGS. However, a notable proportion of patients initiated therapy before receipt of test results. With the development of EGFRex20ins targeted therapy, there is a need for early and broad biomarker testing.
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.08 - Phase 2 Study of Zenocutuzumab (MCLA-128), a Bispecific HER2/HER3 Antibody in NRG1 Fusion-Positive Advanced Solid Tumors (ID 3619)
00:00 - 00:00 | Author(s): Sai-Hong Ignatius Ou
- Abstract
Introduction
Neuregulin 1 (NRG1) gene fusions are oncogenic drivers in multiple cancer types. NRG1 fusion proteins bind to HER3 and signal through HER2/HER3 heterodimers, leading to increased downstream signaling and tumor growth. Clinical responses to agents that target this pathway have been reported. Zenocutuzumab (Zeno, MCLA-128) is a HER2/HER3 bispecific antibody that binds to or ‘docks’ onto the more abundant cell surface HER2 protein, potently blocking NRG1 fusion protein binding and preventing HER2/HER3 dimerization. As an initial proof-of-concept, three patients with chemotherapy-resistant NRG1-positive KRAS-wild-type pancreatic adenocarcinoma or non-small cell lung cancer (NSCLC) who received Zeno through FDA-approved single-patient protocols showed significant tumor shrinkage. These data supported the further evaluation of Zeno in NRG1 fusion-positive cancers. A version of this Clinical Trials in Progress abstract was presented previously at ESMO Congress 2019 (685TiP, Schram et al. Reused with permission) and ASCO Virtual Congress 2020 (#302671; © 2020 American Society of Clinical Oncology, Inc. Reused with permission. All rights reserved).
Methods
The eNRGy trial is a global, open-label, multicenter phase 2 trial of Zeno in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria include previously treated, locally advanced unresectable or metastatic NRG1 fusion-positive cancer. Genomic screening of tumor tissue is performed by local (with post-hoc central confirmation) or central (RNA sequencing) laboratories. Three cohorts of patients with NRG1 fusion-positive cancers are being enrolled: NSCLC, pancreatic cancer, and other solid tumors. The primary endpoint in all cohorts is investigator-assessed objective response rate (RECIST v1.1), and the key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a dosing regimen of 750 mg of Zeno (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in more than 30 sites across North America, Europe, and Asia.
