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V. Georgoulias
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.01 - Tumor Genomic Analysis from LUX-Lung 8: A Phase III Trial of Afatinib versus Erlotinib in Squamous Cell Carcinoma of the Lung (ID 1401)
16:45 - 18:15 | Author(s): V. Georgoulias
- Abstract
- Presentation
Background:
Overexpression of EGFR and other ErbB receptors, and/or dysregulation of their downstream pathways are implicated in the pathogenesis of squamous cell carcinoma (SCC) of the lung, generating interest in exploring EGFR/ErbB-targeted agents in this setting. Recent analyses from the global LUX-Lung 8 trial (n=795) in patients with SCC of the lung demonstrated that second-line afatinib (an irreversible ErbB family blocker) conferred overall survival (OS; median 7.9 vs 6.8 months; HR [95% CI] 0.81 [0.69‒0.95]; p=0.008) and progression-free survival (PFS; median 2.6 vs 1.9 months; HR [95% CI] 0.81 [0.69‒0.96]; p=0.010) benefit over erlotinib (a reversible EGFR inhibitor). To assess biomarkers for efficacy for these agents in SCC we conducted an exploratory analysis using archival tumor tissue collected at time of study entry.
Methods:
Among all randomized patients, samples were retrospectively enriched for those from patients with PFS >2 months and appropriate controls (PFS ≤2 months; Figure 1) and were selected for analysis using the Foundation Medicine (FM) FoundationOne™ next-generation sequencing (NGS) platform (n=433); 300 cancer-related genes were analyzed for copy number alterations (CNAs), rearrangements and single nucleotide variants (SVs). Preliminary results from the 238 samples analyzable so far (~30% of the randomized patients), focusing on genomic alterations of EGFR and their potential association to survival endpoints PFS and OS, are presented.
Results:
Fourteen EGFR SVs (5.8%) were detected of which 10 were novel with unknown clinical significance (Figure 1). Figure 1 Four had been previously reported; 2 (E114K [afatinib arm], Q1021* [erlotinib arm]) occurred in the non-kinase domains and 2 (L861Q [afatinib arm], L858R [erlotinib arm]) in the kinase domain. The frequency of EGFR CNAs (n=15 [6.3%]; afatinib: 9; erlotinib: 6) was also low. At the time of these ongoing analyses, these low frequencies of EGFR mutations/amplifications were deemed not to be associated with the observed improvements in PFS and OS. Genomic alterations aggregated across two key gene groups (ErbB and FGF families) and their association with survival outcomes will be presented.
Conclusion:
The frequency of EGFR genomic aberrations in the samples tested was low. Based on this analysis of a subgroup of patients, PFS and OS improvements conferred by afatinib in LUX-Lung 8 were not driven by the presence of activating EGFR mutations or amplifications and may be related to afatinib’s ability to inactivate multiple aberrant signaling cascades associated with, and downstream of, ErbB receptors.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-083 - Prognostic Significance of CK19mRNA Positive Cells in the Peripheral Blood of Patients with Advanced Non Small Cell Lung Cancer (NSCLC) (ID 760)
09:30 - 17:00 | Author(s): V. Georgoulias
- Abstract
Background:
Circulating Tumor Cells (CTCs) have been shown to be a useful prognostic tool in several cancers. Non-small-cell-lung cancer (NSCLC) lacks validated prognostic biomarkers and, thus, this study aimed to explore the sensitivity and clinical significance of the detection of CK19mRNA (+) CTCs in NSCLC patients.
Methods:
Peripheral blood was obtained from 642 patients with previously untreated stage IIIB/IV NSCLC and from 455 patients after the completion of 1[st] line chemotherapy. RNA extracted from the Calu-3 and ARH-77 cell lines was used as positive and negative controls, respectively. The detection of CK19mRNA-positive cells was performed using an RT-qPCR assay.
Results:
The analytical detection limit of the method was found to correspond to 0.42 Calu-3 cell equivalents/5μg RNA. One hundred and sixty seven (26.0%) patients had detectable CK19mRNA (+) CTCs at baseline; the detection of CK19mRNA (+) CTCs post chemotherapy was associated with significantly decreased PFS and OS (PFS: 2.6 vs 3.8 months, p=0.008; OS: 5.7 vs 10.0 months, p=0.006). Multivariate analysis revealed that gender, performance status and the detection of CK19mRNA (+) CTCs post chemotherapy emerged as independent factors associated with reduced PFS (HR=1.350, p=0.010) and OS (HR=1.608; p=0.001).
Conclusion:
Detection of peripheral blood CK19mRNA (+) CTCs post chemotherapy is an adverse prognostic factor correlated with poor clinical outcome in patients with stage IIIB/IV NSCLC.
