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Aaron C Tan
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-19 - High-Throughput Next Generation Sequencing of Treatment-Naïve Non-Squamous NSCLC: The Singapore National Lung Profiling Study (ID 68)
09:45 - 18:00 | Presenting Author(s): Aaron C Tan
- Abstract
Background
Scaling traditional single biomarker assays are hampered by the need to evaluate an expanding list of therapeutically relevant biomarkers in small biopsies. We sought to compare the performance of targeted NGS panels with traditional assays, and correlate the mutational landscape with PD-L1 status in Singaporean lung cancer patients (pts).
Method
We identified consecutive pts diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing (for EGFR, ALK, ROS1, MET, RET alterations). Tissue samples were tested using a targeted NGS panel (29 selected genes including BRAF, ERBB2, KRAS/NRAS, TP53) and an RNA fusion panel (ALK, ROS1, RET). PD-L1 immunohistochemistry (E1L3) was also performed (TPS: <1%, 1-49%, >50%).
Result
A total of 174 samples were evaluated: PD-L1 (n=170), NGS DNA panel (n=161) and RNA fusion panel (n=118). Median age was 68 years, 53% were male, 58% were non-smokers, 85% were Chinese, 66% had metastatic disease and 95% had adenocarcinoma histology. In NGS DNA profiled pts, EGFR (55%), KRAS (16%), ERBB2 (4%) and BRAF (2%) alterations were found. RNA fusion testing revealed ALK (6%), RET (3%) and ROS1 (1%) fusions. The sensitivity and specificity for NGS versus standard molecular testing was >90% for all subtypes of EGFR mutation. Only 11% of the cohort had both no detectable actionable alteration on NGS (with targeted agents that are approved or in ongoing clinical trials) and PD-L1 <1%. Median turnaround time for NGS was 10 days (range 6-30). Cost-effectiveness analysis demonstrated that current standard testing was less effective and more costly than the other three testing strategies. Compared to sequential testing of NGS in EGFR negative pts only, upfront NGS testing resulted in an additional 1% of pts receiving targeted therapy for an additional SGD$110 and compared to upfront NGS testing, hotspot testing (NGS in EGFR, ALK/RET/ROS1 FISH negative pts only) resulted in an additional 4% of pts receiving targeted therapy for an additional SGD$1044. In the subset of pts with metastatic EGFR mutant NSCLC after first-line therapy with EGFR TKI (n=64), PFS was worse in patients with EGFR and TP53 co-mutation (n=32) compared to EGFR mutation alone (n=32; HR 0.54, 95%CI 0.30-0.98, p=0.042).
Conclusion
We demonstrated that even in an EGFR mutant predominant population, upfront NGS and PD-L1 testing represents a feasible, cost-effective method of diagnostic molecular profiling. The additional information from NGS in characterizing the wider genomic profile may also have prognostic significance in EGFR mutant pts. More broadly, our results support the implementation of NGS in non-squamous NSCLC to allow pts access to the most appropriate personalized therapy.
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P1.17 - Treatment of Early Stage/Localized Disease (ID 188)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.17-07 - Neoadjuvant Gefitinib in Resectable Early Stage EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): A Window-of-Opportunity Study (ID 754)
09:45 - 18:00 | Presenting Author(s): Aaron C Tan
- Abstract
Background
EGFR TKI therapy is standard of care in metastatic EGFR mutant NSCLC, however its role in resectable NSCLC remains unclear. Furthermore, although EGFR TKIs elicit tumor shrinkage in 60% of patients, determinants of response are poorly understood. This was a window-of-opportunity study of neoadjuvant gefitinib prior to surgery for resectable NSCLC with serial plasma and tissue sequencing.
Method
From Feb 2015 to Nov 2018, stage IA-IIIA EGFRmt NSCLC pts received minimum 4 weeks oral gefitinib 250mg daily before surgery. Biomarkers for TKI sensitivity were correlated with RECIST response, pharmacodynamic changes with serial PET-CT scans and pathologic response. Safety and feasibility were determined. Translational studies included multiregion whole exome sequencing (WES, n=44 sectors total) and RNAseq (n=39 sectors).
Result
14 pts were treated, 1 pt withdrew consent prior to surgery without toxicity or progression. Gefitinib (median exposure 1.4 mths) was well tolerated, 1 (8%) pt had ≥G3 AE, with G3 AST/ALT elevation leading to gefitinib cessation. ORR was 62% and DCR was 100%. 13/13 pts underwent resection, 6 (46%) pts had pathological downstaging, 4 (31%) pts had nodal pathCR and 1 (8%) pt had a major pathological response (<10% residual viable tumor cells). There was no correlation between CT response or residual FDG uptake post TKI with % residual viable tumor. WES (up to 370x) showed low tumor purities (median 0.17, range 0.1-0.37) across sectors. Purity correlated with number of coding mutations (r2=0.29, p<0.01) but not ploidy (r2=0.04, p=0.2). Compared to a matched treatment naïve cohort (n=18), phylogenetic analysis showed higher proportions of private driver mutations (p=0.04) and sub-clonal copy number variations. The presence of co-occurring truncal drivers did not account for the 5 pts with SD. On RNAseq, all pts had upregulation of immune regulatory and inflammatory response related genes, with significantly higher GEP score (median score; -0.17 vs -1.06, p=0.01) compared to the treatment naive cohort, although with heterogeneity across sectors. EPIC and xCell de-convolution showed high residual FDG uptake may be due to CAFs or infiltrating T-cells. After median 23 mths follow-up, 7/13 pts recurred, median RFS was 20.2 mths. Of 4 evaluable pts re-treated with palliative EGFR TKI, 3 had PR, 1 had PD (leptomeningeal only recurrence).
Conclusion
Neoadjuvant gefitinib is safe, feasible and effective. Post EGFR TKI treatment samples had low tumor purities influencing genomic and transcriptomic analyses. Percentage residual disease did not correlate with residual FDG uptake or tumor response. There was pervasive upregulation of immune regulatory and inflammatory response genes, indicating infiltration of fibroblasts and T cells, providing unique insight into adaptive response and for the development of rational combination approaches in EGFR mutant NSCLC.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-20 - ATORG-003: Dacomitinib With or Without Dose Titration as First-Line Therapy for Metastatic EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 67)
10:15 - 18:15 | Presenting Author(s): Aaron C Tan
- Abstract
Background
Dacomitinib is a second generation EGFR tyrosine kinase inhibitor (TKI) with irreversible pan-HER inhibitory activity. In the phase III ARCHER 1050 trial, median PFS was improved from 9.2 months to 14.7 months in the gefitinib and dacomitinib groups respectively. Significantly, median overall survival (OS) was also improved from 26.8 months to 34.1 months. However, dacomitinib commenced at 45 mg orally daily was associated with increased toxicity, higher rates of dose reductions and treatment discontinuation. Despite this, post-hoc analysis revealed the efficacy of dacomitinib (PFS and OS) was similar in dose-reduced patients and the overall study population. This investigator-initiated trial aims to evaluate an alternative dose titration strategy to improve the safety and tolerability of dacomitinib while maintaining treatment efficacy. The trial is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – a co-operative lung cancer trials group in Asia.
Method
ATORG-003 is a multi-national, multi-centre, single-arm, open-label, phase 2 clinical trial of dacomitinib in newly diagnosed stage IIIB/IV or recurrent EGFR mutant (exon 19 deletion or L858R mutation) NSCLC patients. Importantly, subjects with asymptomatic central nervous system (CNS) metastases will be eligible. Patients will be administered dacomitinib 30 mg orally daily for one cycle (4 weeks), after which subjects with <G1 toxicity attributable to dacomitinib may escalate to 45 mg with shared investigator and patient decision. Dose reductions to 30 or 15 mg daily will be permitted. The primary objective is to evaluate PFS rate at 12 months. Key secondary objectives include OS, objective response rate (ORR), time to treatment failure (TTF) and intracranial objective response rate (iORR). Exploratory objectives include evaluation of dacomitinib resistance mechanism(s) using next-generation sequencing (NGS) on tissue and plasma circulating tumour DNA (ctDNA). Across 15 sites in six Asian countries (Hong Kong, Korea, Malaysia, Singapore, Taiwan, Thailand), a planned 118 subjects will be enrolled. Primary analysis will be conducted on subjects without CNS metastases only, with 94 subjects required to achieve a one-sided significance level of 5% and 90% power to detect a 15% improvement in 12 month PFS rate for dacomitinib versus historical control for gefitinib (i.e. 55% versus 40%) using the intent-to-treat (ITT) analysis population. Enrollment is due to begin in July 2019.
Result
Section not applicable.
Conclusion
Section not applicable.
