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Narumol Trachu
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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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P37.22 - Unique Characterization of KRAS Mutation in Non-Small Cell Lung Cancer in Thai Population (ID 3460)
00:00 - 00:00 | Presenting Author(s): Narumol Trachu
- Abstract
Introduction
KRASmutations were considered as poor prognostic marker and non-targetable until the recent development of AMG-510, an inhibitor specific for KRASG12Cmutation. Thus, in this study, we aimed to characterize the clinical and molecular characteristics between KRASG12Cand non- KRASG12Cpopulations using NGS.
Methods
Tissue archives of stage I-IV NSCLC patients during 2012 and 2015 were retrieved for DNA extraction. Samples were then analyzed by NGS with Qiagen GeneRead Human Lung Cancer Panel 45 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 were collected for survival analysis.
Results
Of the 159 FFPE samples, 45 (28.3%) harbored KRASmutations. Eleven (24.4%) of the KRAS-mutant samples were G12C(Table 1) and 34 (75.6%) werenon-G12C. The median age of patients with KRASG12Cand non-KRASG12Cwere 61.5 and 64 years old, respectively. KRASG12Cwas significantly associated with tobacco consumption (P=0.027) and tended to occur more in male (P=0.07) (Table 2). Interestingly, the non-G12C population was significantly associated with the presence of other co-driver mutations such as AKT1, EGFR, andMET, in which, EGFRwas the most prevalent, comprising 61.8 % (n=21) of the population. No significant survival differences (both progression-free survival and overall survival) were found between KRASG12Cand non-KRASG12C.
Table 1: Baseline Clinical Characteristics of 11 patients with KRASG12Cmutation
ID
Age
(yrs)
Sex
Stage at diagnosis
Smoking
Co-mutated gene
Treatment
Status
OS (mo)
KRAS
BRAF
EGFR
Early
palliative
1
50.2
F
T1bN0M0
IA
never smk
G12C G12D Q61R
V600E
del19
-
alive
2
44.6
F
T1aN0M0
IA
never smk
G12C
neg
neg
-
alive
3
29.7
F
T2bN0M0
IIA
never smk
G12C G12D
neg
neg
Cis/vnb
alive
4
73.3
M
T2aN2M0
IIIA
ex-smk
G12C
neg
neg
-
alive
5
75.8
M
T4N2M0
IIIB
ex-smk
G12C
neg
neg
Cb/pem
Gefitinib
Dead
17.2
6
71.4
M
T4N3M0
IIIB
ex-smk
G12C
neg
neg
Cb/pem
alive
7
54.8
M
TxN3M1
IV
current smk
G12C
neg
neg
-
Dead
3.5
8
71.1
M
T3N3M1
IV
current smk
G12C
neg
neg
Cb/pem
Dead
22.1
9
66.8
M
T3N0M1
IV
ex-smk
G12C
neg
neg
Cb/pac
Dead
27.2
10
72.9
M
T3N2M1
IV
ex-smk
G12C
neg
neg
Cb/pac
Loss f/u
11
67.6
M
T4N3M1
IV
ex-smk
G12C
neg
neg
-
Dead
0.7
Table 2: Baseline Characteristic of KRASmutation Patients
ConclusionCharacteristics
(n, %)
Total
(n=45)
KRAS subtype
p-value
G12C
(n=11)
non-G12C
(n=34)
Mean age ± SD, yrs
63.5 ± 12.0
61.6 ± 14.8
64.1 ± 1.9
0.567
Gender
0.069
Male
22 (48.9)
8 (72.2)
14 (41.2)
Female
23 (51.1)
3 (27.3)
20 (58.8)
Stage at diagnosis
0.417
0
1 (2.2)
0 (0)
1 (2.9)
I
16 (35.6)
2 (18.2)
14 (41.2)
II
5 (11.1)
1 (9.1)
4 (11.8)
III
6 (13.3)
3 (27.3)
3 (8.8)
IV
17 (37.8)
5 (45.5)
12 (35.3)
Smoking status
0.027
Never-smoker
26 (57.8)
3 (27.3)
23 (67.7)
Ex-smoker
16 (35.5)
6 (54.5)
10 (29.4)
Current smoker
3 (6.7)
2 (18.2)
1 (2.9)
Co-mutation
AKT1
6 (13.3)
0 (0)
6 (17.6)
0.311
BRAF
6 (13.3)
1 (9.1)
5 (14.7)
1.000
EGFR
22 (48.9)
1 (9.1)
21 (61.8)
0.004
MET
5 (11.1)
0 (0)
5 (14.7)
0.313
PIK3CA
1 (2.2)
0 (0)
1 (2.9)
1.000
ROS1
2 (4.4)
0 (0)
2 (5.9)
1.000
No. of mutated gene
0.002
1
19 (42.2)
10 (90.9)
9 (26.5)
2
13 (28.9)
0 (0)
13 (38.2)
3
10 (22.2)
1 (9.1)
9 (26.5)
4
3 (6.7)
0 (0)
3 (8.8)
We identified that G12C subgroup was associated with smoking and the absence of other actionable co-mutations. Longer survival was associated with the presence of EGFRco-mutation, possibly due to the EGFR-TKI. KRASG12Cmutation is one of the crucial oncogenic driven mutations which would effects the survival outcomes. Promising targeted therapy will be useful for treating this group of patient.
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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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P76.39 - Acquired Resistance Mechanisms in T790M-Positive Advanced NSCLC Tested by Non-Invasive Molecular Testing (NIMT) and Their Clinical Relevance (ID 1803)
00:00 - 00:00 | Author(s): Narumol Trachu
- Abstract
Introduction
There is currently limited knowledge of resistant mechanisms after failure of Osimertinib treatment in T790M-positive NSCLC in Asia. We used Non-Invasive Molecular Testing (NIMT) to explore the acquired resistant mechanisms to Osimertinib and their clinical relevancies.
Methods
This study was performed from January 2016 to December 2019 in T790M-positive NSCLC patients who received Osimertinib after failure of 1st/2nd generation EGFR-TKI treatment in Ramathibodi Hospital lung cancer database. We included patients who had plasma samples before treatment and at disease progression. The paired plasma samples were analyzed for resistant mechanisms by NGS (Thermofisher Pancancer 52 genes) then correlated with clinical outcomes.
Results
The 100 plasma samples from 50 patients were included (17 Males; 33 Females). The median age was 63.5 year-old. The majority of patients were non-smoker (82%) and adenocarcinoma (98%). Types of preexisting mutations were exon 19 deletion (60%), and exon 21 L858R (32%). Most of the patients used Osimertinib as 2nd-line treatment (68%). The response rates were 52% PR, 34% SD, and 14% PD. Nineteen patients (38%) developed more than one resistant alteration. The T790M-loss was most commonly found (50%), followed by PIK3CA (14%), EGFR C797S / HER2 / FGFR2 mutation (10% of each mutation) and EGFR (L792F, P848L/Q)/ BRAF/ RET/ KIT mutation (8% of each mutation), MET mutation (6%), MET exon 14 skipping (4%), MET amplification (2%) and small cell transformation (2%), and so on. EGFR C797S was found only in T790M-maintained patients. The median time to treatment failure (TTF) for taking Osimertinib in all patients was 9.3 mo. The patients with T790M-loss tended to have shorter TTF than the patients with T790M-maintained [median TTF 6.0 vs 10.1 months (mo), P=0.21]. Patients who developed T790M-maintained with C797S had tended of shorter OS compared to T790M-maintained without C797S (11.0 vs 15.2 mo). Furthermore, patients with T790M-loss together with other co-mutations had shorter TTF compared to patients with T790M-loss without other co-mutations (4.1 vs. 10.6 mo, adjusted HR 5.38, P=0.07) (Figure1). The patient who had brain metastasis before using Osimertinib significantly related to T790M-loss and patient who developed brain progression was related to BRAF mutation.
Conclusion
There were heterogeneous mechanisms of acquired resistance to Osimertinib in T790M-positive NSCLC. The patient with T790M-loss tended to have poorer survival compared to T790M-maintained patients. C797S and T790M loss with other co-mutation are the important factors affected the survival outcomes in this group of patients.
