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Thanyanan Reungwetwattana
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-09 - Characterization of Actionable BRAF<sup>V600E</sup> and Co-Mutations in Non-Small Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 1056)
08:00 - 18:00 | Author(s): Thanyanan Reungwetwattana
- Abstract
Background
Targeting activated-mutations in NSCLC offers unique benefit that outperforms other cancers. Multiplex Next Generation Sequencing (NGS) platform provides opportunity for detection of low-frequency actionable-mutations such as BRAF V600E, which was previously reported in 1-2% of NSCLC and correlated with poorer response to chemotherapy. In this study, we used the NGS platform to determine the prevalence and characteristics of BRAF V600E-mutated NSCLC.
Method
Tissue archive of stage I-IV NSCLC from Ramathibodi and Phramongkutklao Hospitals during 2012-2015 was retrieved for DNA extraction. Samples were analyzed by NGS with Lung Cancer Panel 45 Genes on Ion Torrent system. Variants from NGS with coverage of higher than 1000X and ≥3% alternate variant frequency were considered as positive. The cutoff-point was validated by Real- time PCR. Clinical data correlation was analyzed.
Result
Of the 159 FFPE-samples, 16 samples (10.1%) with BRAFV600E mutation were identified. The median age was 66.6 years old. Majority of the patients were female (81.3%) and never-smoker (75%). Seven patients had early stage and 9 patients had stage III-IV disease. Co-mutations with BRAFV600E were found in 13 patients. EGFR mutation was the most common co-mutation (62.5%) follow by co-mutation with KRAS (37.5%), MET exon14 splice-site (18.8%), and PIK3CA (6.3%) (Table1). Advanced-stage patients with KRAS and MET exon14 splice-site co-mutations with BRAFV600E had worse survival (10.4, 10.4 months) compared to patients with EGFR co-mutation (41.1 months). Survival of patients with single BRAFV600E is better than patients with other co-mutations (not reach vs 60.5 months) in all stages.
Table 1: Baseline characteristics of 16 patients with BRAFV600E mutation and their co-mutated gene including palliative treatment in stage IV patients
ConclusionPatient ID
Gender
Age
Smoking
status
Staging
Co-mutation
First line treatment
Second line treatment
Current status
OS
(mo)
EGFR
KRAS
MET
PIK3CA
1
Female
62
Never
IA
L858R
Alive
2
Female
73
Never
IA
Del19, L858R
G12D
Alive
3
Female
50
Never
IA
Del19
G12C, G12D, Q61R
Alive
4
Female
67
Never
IA
G719S
G12D
Alive
5
Female
62
Never
IB
G12S
Alive
6
Female
67
Never
IB
G719A, del19
Alive
7
Female
75
Never
IIA
Alive
8
Female
80
Ex-smoke
IIIA
G12D, G13S
C2888-1G>A*
Death
10.4
9
Male
63
Ex-smoke
IIIA
Alive
10
Female
75
Never
IV
C3028G>T*
Gemcitabine
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Death
7.9
11
Female
60
Never
IV
Del19
Carbo/Pac
Bevacizumab
Death
12.6
12
Female
59
Never
IV
L858R
C3028G>A*
Carbo/Pem
Erlotinib
Death
48.9
13
Female
89
Never
IV
L858R
Erlotinib
Osimertinib
Death
60.5
14
Male
74
Ex-smoke
IV
Del19
G12D, Q61L
H1047R
Carbo/Pac
Gemcitabine
Death
27.1
15
Female
58
Never
IV
Carbo/Gem
Carbo/Gem
Death
34.9
16
Male
71
Current smoke
IV
L858R
Gefitinib
Carbo/Gem
Death
41.1
Our data demonstrated high prevalence of BRAF V600E and coexisting-actionable mutations. BRAFV600E-mutated NSCLC are common in female and never-smoker. Co-mutations with other actionable-mutations patients showed worse survival compared to single BRAFV600E patients. Integrating the sensitive multiplex NGS method into the clinical practice will help broaden the opportunity for superior treatment efficacy in the future.
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ES14 - What First Line in Oncogene Addicted NSCLC (ID 17)
- Event: WCLC 2019
- Type: Educational Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Dolores Isla, Jessica Menis
- Coordinates: 9/08/2019, 15:15 - 16:45, Vancouver (2003)
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ES14.01 - First Line in EGFR Mutated Patients (Now Available) (ID 3230)
15:15 - 16:45 | Presenting Author(s): Thanyanan Reungwetwattana
- Abstract
- Presentation
Abstract
Precision medicine is currently applied for almost all cancer types, especially, in NSCLC which is the prototype of successful targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the first effective targeted drug found in NSCLC for treatment in EGFR-mutation positive patients. EGFR (also termed human epidermal growth factor receptor 1 [HER1] or ErbB1) is a member of the ErbB family of cell surface receptor tyrosine kinase1. It is a 170‑kDa RTK with an extracellular ligand‑binding domain, a transmembrane region and an intracellular tyrosine kinase. The RTKs form homodimers and heterodimers after binding to specific ligands, leading to autophosphorylation of tyrosine residues on the intracellular TK domain. This interaction recruits a diverse set of signal transduction cascades including the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR), signal transduction and transcription (STAT) transcription and RAS/RAF/ mitogen‑activated protein kinase (MAPK) proliferation pathway1. In 2004, somatic mutations in the TK domain of EGFR, found most frequently in adenocarcinomas from patients in Asia who were never or former smokers, were strongly correlated with sensitivity to EGFR-TKIs1. The prevalence of EGFR mutation in NSCLC patients is higher in Asian population compared to the other population (50-55% vs. < 20%). These mutations are mostly distributed in four exons (exon18 to exon21)2. In‑frame deletions of exon19 (44%; E746‑A750deletion) and L858R substitutions in exon21 (41%) are the most prevalent mutations associated with sensitivity to EGFR-TKIs. The point mutations in exon18 (G719C, G719S and G719A) and exon20 (V765A and T783A) are less frequent; 5% and 1%, respectively1.
Presence of the “classical” mutations in exon19 and 21 are the best predictive biomarker for the efficacy of EGFR-TKIs with superior response rate (RR) of 60-70%, progression‑free survival (PFS) of 9-18.9 months, and overall survival (OS) more than 2 years compared with conventional chemotherapy in patients with tumors harboring EGFR‑sensitive mutations making EGFR-TKI is the first-line treatment3. Currently, there are 3 generations of EGFR-TKIs approved in the market. The strategy of first-line treatment in EGFR-positive patients can be categorized into 2 strategies. The first one is treating by the single agent EGFR-TKIs. The first and second-generation EGFR-TKIs have the efficacy in term of PFS of 9-14.7 months in first-line treatment, but if starting with third generation EGFR-TKI, the PFS is longer (18.9 months)3-4. The ORR is similar either starting with 1st, 2nd, or 3rd generation EGFR-TKIs (60-70%). The acquired resistance could be occurred after 9-14 months of treatment by 1st and 2nd-generation EGFR-TKIs and the majority of resistance mechanism is T790M (50-60%) which is now we have the 3rd-generation EGFR-TKI for overcoming this resistance. Moreover, the other bypass tracts (MET amplification, BRAF, HER2 mutation etc.)5 could be the mechanism of resistance as well and we have the potential targeted drugs in the clinical studies which some of them will be approved in the near future. The mechanism of resistance if we start the 1st-line treatment with 3rd-generation EGFR-TKI is different from the previous one. Recently, exploratory data from FLAURA study was reported. They found no T790M detected in the patients whom had progressive disease after 1st-line treatment with 3rd-generation EGFR-TKI. The most common detected acquired resistance genes in the blood were C797S and MET amplification. The other mechanism included HER2 amplification, PIK3CA and RAS mutations. Furthermore, the 3rd-generation EGFR-TKI has the significant strong evidence of better in survival outcome and CNS response in patient whom had the CNS metastases disease6. The second strategy is starting 1st-line treatment with the combination therapy. The recent studies reported in ASCO2018 and ASCO2019 showed the longer PFS (16-19 months) in combination of 1st- generation EGFR-TKI and anti-angiogenesis agents and also longer PFS (16-20 months) in combination of 1st-generation EGFR-TKI with doublet platinum-based chemotherapy compared to single agent 1st-generation EGFR-TKI.7-9 Definitely, there were more adverse events for the combination treatment. The rate of occurring T790M as the acquired resistance and the CNS efficacy are the issues to concern for the combination treatment (Figure 1). The most proper sequence of the treatment in EGFR-positive NSCLC is needed to explore more in the clinical studies. It has pros and cons in each approach and it depends on several factors such as; the patients’ performance status, the location of tumor (CNS metastases?), types of EGFR mutations, acquired resistance, toxicities, treatment after progression, cost of treatment and the reimbursement issue in each country.
In summary, EGFR mutation is the crucial oncogenic-driven mutation in NSCLC with effective EGFR-TKI treatment making the patient has good quality of life (QOL) even though they have the advanced-stage disease. The journey of treatment in this group of patients is still underway of development and it is the good prototype for the other targeted drugs development in the clinical studies. I believe that there will be the other effective novel targeted treatments for NSCLC approved in the near future which would improve the long-term survival and QOL for patients.
References:
1. Salomon DS, et al. Crit Rev Oncol Hematol 1995
2. Lynch TJ, et al. N Engl J Med 2004
3. Reungwetwattana T, et al. Journal of Carcinogenesis 2013
4. Soria JC, et al. N Engl J Med 2018
5. Papadimitrakopoulou V, et al. ESMO Congress 2018
6. Reungwetwattana T, et al. J Clin Oncol. 2018
7. Furuya N, et al. ASCO Congress 2018
8. Nakamura A, et al. ASCO Congress 2018
9. Nakagawa K, et al. ASCO Congress 2019
Figure 1: The survival outcome of each approach for EGFR-positive NSCLC
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-78 - PD-L1 Expression as a Prognostic Marker for Non-Small Cell Lung Cancer in Distinct Mutational Status (ID 2927)
10:15 - 18:15 | Author(s): Thanyanan Reungwetwattana
- Abstract
Background
Programmed death-ligand 1 (PD-L1) expression is widely used as the predictive biomarker for immunotherapy treatment in NSCLC whereas their role as a prognostic marker is limited.
Method
Seventy-nine FFPE tissues (stage I-IV) during 2012-2017 were retrieved for Next Generation Sequencing (NGS) and immunohistochemistry (IHC) staining. PD-L1 expression was performed using 22C3 Ab. Positive-PD-L1 was defined by tumor proportion score (TPS) >1%. Targeted mutations and fusion genes were analyzed by Lung Cancer Panel 45 Genes and Targeted RNAscan Panel on NGS, respectively. Variants from NGS with coverage of higher than 1000X, cutoff ≥3% alternate variant frequency were considered positive. The cutoff was validated by Real-time PCR. Clinical data correlation was analyzed.
Result
Thirty-one patients (39%) had stage I-II and 48 patients (61%) had stage III-IV disease. Mean age was 62.5 years old. Fifty-one patients (65%) were female and 55 patients (70%) were never-smoker. A majority of the patients (83.6%) were negative-PD-L1. All of the 13 PD-L1 positive patients were in stage III-IV, suggesting the increased likelihood of PD-L1 expression in advanced disease (p = 0.014). No difference in age, sex, smoking status, histological subtypes, and mutational status were seen between PD-L1 positive and negative group.However, PD-L1 negative was associated with a trend toward better survival (Table1). Subgroup analysis in stage IV patients with common EGFR mutations revealed PD-L1 positive status as a significant negative prognostic factor with HR of 3.00 (95% CI: 1.17, 7.73; P-value=0.023), whereas positive-PD-L1 patients with the other mutations showed a trend of worse survival outcome.
Table 1: Cox regression analysis of prognostic factors associated with overall survival of NSCLC patients
ConclusionPrognostic factors
Follow up time
(100 person-month)
Death
Median survival
(mo)
Univariate analysis
Multivariate analysis
No.
Rate (95% CI)
HR (95% CI)
p-value
Adjusted HR (95% CI)
p-value
Age
1.00 (0.98, 1.03)
0.893
-
Sex
0.250
Male
8.71
18
2.07 (1.30, 3.28)
22.8
1.43 (0.79, 2.59)
0.243
-
Female
21.14
28
1.32 (0.91, 1.92)
53.9
1
-
PDL1
0.002
Negative (<1%)
28.05
35
1.25 (0.90, 1.74)
53.9
1
1
Positive (≥1%)
1.80
11
6.09 (3.38, 11.00)
7.1
3.52 (1.73, 7.16)
0.001
1.88 (0.83, 4.22)
0.128
Stage
<0.001
I-II
19.20
6
0.31 (0.14, 0.70)
NR
1
1
III-IV
10.65
40
3.76 (2.75, 5.12)
20.1
11.09 (4.26, 28.87)
<0.001
10.03 (3.67, 27.41)
<0.001
Smoking status
0.011
Never smoker
24.04
28
1.16 (0.80, 1.69)
76.2
1
1
Ex-smoker
4.55
10
2.20 (1.18, 4.09)
20.1
1.70 (0.82, 3.52)
0.154
1.02 (0.47, 2.23)
0.962
Current smoker
1.26
8
6.33 (3.17, 12.66)
8.7
3.76 (1.68, 8.41)
0.001
1.70 (0.74, 3.88)
0.208
EGFR
0.825
Mutation
22.99
35
1.52 (1.09, 2.12)
31.9
0.93 (0.47, 1.83)
0.824
-
No mutation
6.87
11
1.60 (0.89, 2.89)
33.5
1
-
ALK
0.869
Positive
2.28
3
1.32 (0.43, 4.09)
NR
1.11 (0.33, 3.78)
0.867
-
Negative
16.50
19
1.15 (0.73, 1.81)
76.2
1
-
KRAS
0.051
Mutation
13.12
12
0.91 (0.52, 1.61)
NR
0.53 (0.27, 1.03)
0.062
-
No mutation
16.73
34
2.03 (1.45, 2.84)
31.1
1
-
Number of co-MT
0.045
< 1000
11.84
27
2.28 (1.56, 3.33)
22.8
1
1
≥ 1000
18.02
19
1.05 (0.67, 1.65)
57.6
0.55 (0.30, 0.99)
0.047
1.22 (0.61, 2.41)
0.574
Positive-PD-L1 is significantly associated with advanced disease and a trend toward unfavorable prognosis. The detrimental effect of PD-L1 is significant in stage IV patients with common EGFR mutations. A confirmatory study with a larger sample size would better identify the prognostic benefit of PD-L1 status in vast subsets.
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P2.11 - Screening and Early Detection (ID 178)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.11-25 - Pre- and Post-Surgery Metabolomic Profiles in Early-Stage NSCLC Patients (ID 2476)
10:15 - 18:15 | Author(s): Thanyanan Reungwetwattana
- Abstract
Background
Finding biomarkers to detect cancer at its early stage is of importance. Since metabolic reprogramming is a hallmark of cancer, oncometabolite is thus a promising target.Progress in cancer metabolomics opens the door for large scale screening of cancer-specific metabolites that could be future applied for subclinical stage detection and novel therapeutic targets.
Method
Seventy paired pre- and postoperative plasma samples of early-stage NSCLC patients who had completed curative surgery during 2015-2018 with ≥ 3 months disease free were retrieved. Demographic and Clinical data were collected. All samples were subjected to targeted metabolomics analysis using AbsoluteIDQ® p180 Kit on ESI 5500 LC-MS/MS System equipped with 1260 Series HPLC, according to the manufacturer's instruction.Multivariate analysis including PCA and OPLS-DA were used to identify the difference between pre- vs post-operative sample set. T-test was used to confirmed if the metabolites significantly different among groups at the univariate level (p < 0.05).
Result
Of the 70 patients, 31 (44.3%) were male and 39 (55.7%) were female. Median age was 63 years old (23 - 85). Majority of them were never-smokers (64.3%). Adenocarcinoma was the most common histology (91.4%). EGFR mutation was tested in 34 (48.6%) patients, of which, 22(64.7%) of them were positive. Metabolomic analysis revealed tryptophan as the most statistically significant change, together with other amino acids, carnitines, biogenic amines, and lipids (Table1). Besides glutamate, all metabolites increased postoperatively.Metabolites with VIP scores (Variable Importance in Projection) ≥ 1.5, including tryptophan, lysophosphatidylcholine-acyl C16:0, lysophosphatidylcholine-acyl C18:0, and carnitine, were assembled together for a predictive model which will be presented at the congress.
Table 1: Metabolites with significant difference between pre- and post-surgery in early-stage NSCLC patients
ConclusionMetabolite (ng/ml)
Pre operation (N=70)
Post operative (N=70)
Fold change
p-value
VIP score
Mean
SD
Mean
SD
Amino acid
Glutamate
17,449.31
7,808.80
10,192.53
5,294.28
-0.374
<0.001
1.21
Glutamine
87,406.56
22,839.10
104,994.00
26,276.52
0.324
<0.001
0.77
Arginine
10,869.44
5,082.21
16,101.94
8,220.61
0.481
<0.001
0.79
Asparagine
5,023.79
1,294.80
7,630.93
2,343.85
0.663
<0.001
1.34
Tryptophan
6,921.41
1,579.37
13,189.77
4,105.45
0.992
<0.001
1.70
Acrylcarnitine
carnitine (C0)
4,680.23
1,292.54
7,263.51
2,136.29
0.657
<0.001
1.50
Biogenic amine
Creatinine
7,262.43
2,410.21
10,529.83
4,070.33
0.536
<0.001
1.14
Kynurenine
363.42
126.06
571.91
232.05
0.723
<0.001
0.82
Sphingolipid
SM C16:1
8,837.49
2,290.28
10,875.53
2,970.15
0.290
<0.001
1.33
SM C20:2
178.18
60.77
205.47
66.55
0.304
0.005
0.43
Phosphatidylcholine
lysoPC a C16:0
26,863.83
6,420.81
45,877.36
13,732.55
0.774
<0.001
1.67
lysoPC a C16:1
740.24
287.44
1,256.99
588.67
0.842
<0.001
1.33
lysoPC a C17:0
303.24
90.78
521.36
200.39
0.853
<0.001
1.45
lysoPC a C18:0
8,449.64
2,593.82
14,854.50
5,047.03
0.885
<0.001
1.60
lysoPC a C18:2
6,818.04
2,466.61
11,990.73
4,760.87
0.965
<0.001
1.37
We identified a distinct cluster of significant metabolic biomarkers associated with early-stage NSCLC. Tryptophan is the most significant one that associated with cancer metabolome. These would be potential biomarker profile for early-stage NSCLC detection.Larger cohort is needed to be validated.
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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 | Author(s): Thanyanan Reungwetwattana
- 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.
