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Adam Pluzanski
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P37 - Pathology - Biomarker Testing (ID 107)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P37.02 - Identification of Gene Fusions and Mutations in Patients with NSCLC using two Diagnostic Approaches: Rapid qPCR and NGS (ID 3731)
00:00 - 00:00 | Author(s): Adam Pluzanski
- Abstract
Introduction
Background
The mutation detection, and especially fusion gene identification in patients with non-small cell lung cancers (NSCLCs), is currently a key step in the diagnosis and treatment decision. Therefore, methods are constantly being developed to be more specific, rapid and provide extensive biomarker analysis. NGS seems to be the most suitable diagnostic approach. However, this method is time-consuming, costly, and requires highly specialized devices and analytical background. Consequently, novel rapid and sensitive tests basing on qPCR emerge.
Aim
The aim of this study was to compare the diagnostic yield of NGS (RNA based sequencing) and qPCR- based Lung Cancer PCR Panel, which identifies 231 variants (gene fusions and point mutations) in 11 genes (ROS, ALK, NTRK1/2/3, RET, MET, KRAS, HER2, BRAF, EGFR) in patients treated in a single cancer center.
Methods
194 solid tumors formalin-fixed paraffin-embedded (FFPE) specimens from NSCLC patients were selected for the study. The samples were primarily analyzed using NGS (Archer, RNA-based anchored multiplex-PCR) where gene fusions or point mutations (single nucleotide substitutions and small insertions/deletions) were detected or negative results were obtained. In a second step samples were analyzed again by using a qPCR panel (AmoyDx, Lung Cancer PCR Panel).
Results
194 samples (66 with gene fusions, 72 with point mutations and 56 negative samples) were analyzed with both methods. The qPCR enabled detection of 45/66 gene fusions (68%). In 21/66 cases fusions were not detected (32%), of which 12 were beyond the scope of the qPCR test. In 9 cases the fusions were not detected due to unknown reason. The qPCR test enabled detection of 74 point mutations. 72 of them were also detected using NGS, while 2 were found in cases previously classified as negative by NGS testing. Finally, 54cases were negative in both tests.
Conclusion
This comparative study showed high concordance (89%) between qPCR and NGS panels. The multigene PCR panels seem to be good alternative to NGS panels and can be seriously considered as screening methods due to their universality, methodological simplicity, cost, and short time of analysis
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P37.09 - Comparison of 3 Different Methods for Determination of EGFR p.Thr790Met mutation in patients with NSCLC (ID 3761)
00:00 - 00:00 | Author(s): Adam Pluzanski
- Abstract
Introduction
Due to the frequent lack of tissue, liquid biopsy testing is a widely accepted method in the diagnosis and monitoring of patients with NSCLC. This is also more convenient for patients than (re-) biopsy of tumor tissue. In 2016 we started analysis of p.Thr790Met resistance mutation in circulating tumor DNA (ctDNA) of NSCLC patients using classical quantitative Polymerase Chain Reaction (qPCR). However, among 22 cases, we only detected 5 positive, which gave us relatively low detection rate of 23%. Hence, we introduced high sensitivity qPCR, which enabled detection of 19 p.Thr790Met -positive cases among 31 tested (61%).
Considering those large outcome differences and the fact that molecular methods become more sensitive, the aim of the study was to compare the diagnostic yield of 3 different methods that are commonly used.
Methods
Patients with NSCLC were primarily treated with an EGFR tyrosine kinase inhibitor (TKI). When progressing, blood was taken to determine p.Thr790Met mutation as a marker of resistance and decision point for further treatment. CtDNA determination was performed using three different approaches: Classic qPCR (AmoyDx, EGFR29 test), highly sensitive qPCR (AmoyDx, SuperARMS EGFR) and digital droplet PCR (ddPCR). 41 samples from patients after diagnosis of progression by radiological imaging were analyzed using classic qPCR and highly sensitive qPCR and 90 samples from patients before and after diagnosis of progression by radiological imaging using highly sensitive qPCR and ddPCR.
Results
The classic qPCR found 14/41 mutations (34%), while highly sensitive qPCR detected mutations in 30/41 samples (73%). Further analysis revealed that among 90 samples, both highly sensitive qPCR and ddPCR were concordant in 85 cases, including 23 positive and 52 negative cases (94% concordance rate). In 13 cases ddPCR detected mutation in the sample that was negative in highly sensitive qPCR, and 2 cases were only detected by highly sensitive qPCR and remained negative in ddPCR.
Conclusion
Classical qPCR tests (sensitivity level 1%-5%) can be used for the identification of activating mutations in the EGFR gene in tissue, but are not suitable for the detection of p.Thr790Met resistance mutation in plasma even in patients with progression demonstrated by radiological imaging.
Although the gold standard for detection of mutations in ctDNA is ddPCR, high-sensitivity qPCR tests (sensitivity level <1%) seem to be equally effective.
The practical experience in p.Thr790Met mutation detection may be regarded as a model procedure for detection of other resistance mutations e.g. p. Cys797Ser in EGFR or mutations in the ALK, ROS1, or NTRK genes.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- 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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P76.67 - Safety and Efficacy of First-Line Dacomitinib in Advanced Non-Small Cell Lung Cancer by EGFR Mutation SUBtype in ARCHER 1050 (ID 3335)
00:00 - 00:00 | Presenting Author(s): Adam Pluzanski
- Abstract
Introduction
ARCHER 1050 (NCT01774721) compared dacomitinib versus gefitinib in newly diagnosed patients with advanced EGFR-mutation positive non-small cell lung cancer (NSCLC). Updated overall survival (OS) analysis showed significant improvement in OS with dacomitinib versus gefitinib in the overall population and exon 21 L858R substitution mutation (L858R) subgroup. We report analysis of efficacy and safety by EGFR mutation subtype.
Methods
In this ongoing, open-label, phase III trial, eligible patients were randomized 1:1 to dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225), stratified by race and EGFR mutation subtype (exon 19 deletion [Del19] or L858R). The primary endpoint was PFS (blinded independent radiologic central review). Post-hoc exploratory efficacy analyses for patients with dacomitinib dose reductions were also conducted.
Results
Improvements in PFS and updated OS with dacomitinib over gefitinib were observed in patients with dacomitinib dose reduction in both EGFR mutation subgroups (Table 1). In responding patients, duration of response was longer with dacomitinib versus gefitinib in both EGFR mutation subgroups. Dacomitinib dose reduction was reported in 66% (Del19) and 67% (L858R) of patients for PFS (data cutoff date July 29, 2016) and 68% (Del19 and L858R) of patients for updated OS (data cutoff date May 13, 2019; extended median follow-up 47.9 months). Median duration of treatment with dacomitinib was 16.5 months (range 0.2-35.0) and 13.2 months (range 0.1-37.4) in the Del19 and L858R subgroups, respectively. Safety data are in Table 2.
Conclusion
Dacomitinib is the first second-generation TKI to improve PFS and OS over gefitinib in patients with dose reduction in both Del19 and L858R subgroups. The difference in treatment durations of the dacomitinib subgroups may affect frequency of Grade ≥3 TEAEs. Potential differences in safety between EGFR mutation subgroups will warrant further exploration.
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P78 - Immunotherapy (Phase II/III Trials) - Immune Checkpoint Inhibitor Single Agent (ID 255)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P78.08 - Prediction of Pembrolizumab Efficacy in Non-Small-Cell Lung Cancer (NSCLC) Based on Experience From Expanded Access Program in Poland (ID 2972)
00:00 - 00:00 | Author(s): Adam Pluzanski
- Abstract
Introduction
Efficacy of pembrolizumab in advanced pretreated NSCLC was documented in prospective trials. We aimed to confirm the benefits of pembrolizumab in daily practice.
Methods
This study was a retrospective analysis of patients (pts) treated in the Expanded Access Program in Poland. Median of progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Analyses were performed with R 3.6.0 software.
Results
A total of 34 pts were qualified to pembrolizumab in second or third line of NSCLC treatment. Poor performance status (ECOG 2) was found in 14.7% of pts, brain and liver metastases were diagnosed in 8.8% and 17.6%, respectively. 38% of pts ended the treatment before radiological assessment mainly due to clinical deterioration. In the landmark of 12 and 24 months 35% and 17.6% pts remained alive.
Median PFS and OS were 4.4 months (95% confidence interval [CI]: 3.4–9.0) and 8.2 months (95% CI: 4.1–16.1). Immune related adverse events (irAE) were reported in 23% of pts. No treatment-related deaths were reported. In an univariate analysis an ECOG PS 2 (p < 0.001), tumor diameter of >100 mm (p = 0.019), PD during previous chemotherapy (p = 0.037), platelet count (PLT) >409 109/L (p = 0.011), a neutrophil-to-lymphocyte ratio (NLR) ≥3.1 (p = 0.0001) and platelet-to-lymphocyte ratio (PLR) of >183 (p = 0.018) had a negative impact on PFS. The age, sex, histology, location of metastases, PD-L1 expression, level of tumor-infiltrating lymphocytes and comorbidities had no impact. In terms of OS, an ECOG 2 (p < 0.001), PD during chemotherapy (p = 0.037), lack of irAE (p = 0.026), NLR of ≥3.1 (p < 0.001), PLT of ≥409 109 /L (p = 0.011), and PLR of ≥183 (p = 0.018) were negative prognostic factors.
ECOG 2 (hazard ratio [HR] 72.63, 95% CI 6.64–794.4; p <0.001), PD during chemotherapy (HR 8.18, 95% CI 1.32–50.4; p = 0.024), and a PLT >409 109 /L (HR 6.18, 95% CI 1.35–28.32; p = 0.019) were independent prognostic factors for OS in multivariate analysis.
Conclusion
Pembrolizumab produces durable benefit in 20% of pts with pretreated NSCLC. Clinical and laboratory factors may help to indicate subgroups likely to benefit. Poor PS and lack of response to previous chemotherapy are major determinants of worse prognosis.
