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marcello Tiseo
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EP1.09 - Pathology (ID 199)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.09-11 - Lipoid Pneumonia Resembling Bilateral Lung Cancer: Be Aware of Nasal Decongestants! (Now Available) (ID 2378)
08:00 - 18:00 | Author(s): marcello Tiseo
- Abstract
Background
To describe a case of bilateral exogenous lipoid pneumonia mimicking lung cancer in a patient affected by obstructive sleep apnea syndrome treated with decongestants mineral oils.
Method
A 57 year-old male patient was referred to our surgical department for an incidental finding of a bilateral pulmonary mass during a chest X-ray made for chronic coughing. His past medical history was unremarkable; he was an everyday smoker with a 80pack/years and he was affected by obstructive sleep apnea syndrome. A chest CT and CT/PET scans was subsequently done and revealed the presence of a both pulmonary consolidations of the lower lobes bilaterally with increase in uptake of FDG (Fig. 1A-B): mediastinal lymph node was normal, no other lesions was found. Morphology of the lesions was strongly suspect for non small cells lung cancer, so the patient underwent a CT-guided lung biopsy.
Result
A percutaneous CT-guided lung biopsy was done in the right lower lobe. The histological examination was consistent with pulmonary adenocarcinoma with signet-ring cell features (Fig.1C): therefore, the patient was addressed to conventional chemotherapy. At that point, a multidisciplinary discussion was done: a careful revision of the chest CT-scan was carried out and focal areas of fat attenuation within the lung consolidations were observed. According to that finding, a diagnosis of lipoid pneumonia was hypothesized. A more careful questioning about patient’s medical history revealed the use of daily nasal decongestants during the last 4 years due to chronic rhinitis secondary to OSAS: the drug was composed of mineral oils. A further blind revision of the histological tissue samples was requested and confirmed the diagnosis of exogenous lipoid pneumonia. The patient was invited to discontinue the nasal oil decongestant. No other pharmacological treatment was started. Six months later, a chest CT-scan was performed but no significant changing of the pulmonary consolidations were observed (Fig. 1D). Currently, the patient is well and a reduction of chronic coughing was reported.
Conclusion
Exogenous lipoid pneumonia is a rare condition that might be misdiagnosed with lung cancer; for this reason it should be considered in the differential diagnosis of pulmonary consolidations, especially when occurring bilaterally. A precise medical history could be resolutive.
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.03 - CEA and CYFRA 21-1 as Prognostic Biomarkers of Benefit from Nivolumab and as a Tool in Treatment Monitoring in Advanced NSCLC (Now Available) (ID 1370)
10:30 - 12:00 | Author(s): marcello Tiseo
- Abstract
- Presentation
Background
To assess the role of pre-therapy levels of Carcinoembryonic antigen (CEA) and Cytokeratin-19 Fragments (CYFRA 21-1) as prognostic marker in advanced NSCLC patients treated with nivolumab, and their change as an early predictor of treatment outcome.
Method
This is a retrospective cohort study including all patients with stage IIIB – IV NSCLC who received nivolumab after first-line chemotherapy in 2 Italian institutions. Median Overall Survival (OS), Overall Response Rate (ORR), Disease Control Rate (DCR) and Time to Treatment Failure (TTF) were chosen as endpoints.
Result
100 patients were included. Cyfra 21-1 > ULN resulted correlated with OS (FIG.1A) both in univariate (HR 2.77, 95% CI 1.53 – 5.30, p 0.001) and multivariate analysis (HR 2.72, 95% CI 1.44 – 5.16, p 0.002). The only other factor correlated with OS in multivariate was ECOG PS (0-1 vs 2) (HR 5.46, 95% CI 3.07 – 9.91, p< 0.001) (Table 1).
ECOG PS (0-1 vs 2) and CYFRA 21-1 (≤ 3.5 vs > 3.5) where combined to create a prognostic score (FIG.1B). Median OS was 23.9 months for patients without risk factors, 6.3 months with one (HR 2.75, 95% CI 1.40 – 5.40 p 0.003) and 1.3 months with 2 risk factors (HR 14.50, 95% CI 6.35 – 33.09, p< 0.001).
Early 20% reduction after 3rd cycle was correlated with OS for CEA, HR 0.05 (95% CI 0.01–0.41), p 0,003 and borderline for CYFRA 21-1, HR 0.29 (95% CI 0.09 – 1.01), p 0.052. (FIG.1C-1D)
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ConclusionUnivariate
Multivariate
Covariate
HR (95% CI)
P value
HR (95%CI)
P value
ECOG PS 2 vs 0-1
5.40 (3.21 – 9.09)
< 0.001
5.46 (3.07 – 9.91)
< 0.001
Cyfra > vs ≤ ULN
2.77 (1.53 – 5.03)
0.001
2.72 (1.44 – 5.16)
0.002
Liver metastasis yes vs no
2.19 (1.26 – 3.78)
0.005
0.102
Neutrophil/lymphocyte ratio ≥ 4 vs < 4
1.99 (1.23 – 3.20)
0.005
0.105
KRAS mutated vs wild type*
0.39 (0.21 – 0.74 )
0.004
0.262
Bone metastasis yes vs no
1.75 (1.10 – 2.79)
0.018
0.362
Response to previous therapy yes vs no
0.51 (0.29 – 0.91)
0.023
0.376
CEA > vs ≤ ULN
1.41 (0.88 – 2-25)
0.150
0.418
Stage IV vs IIIB
1.63 (0.75 – 3.54)
0.22
0.449
Squamous vs non squamous
0.79 (0.48 – 1.28)
0.334
0.689
Smoker vs never smoker
0.88 (0.65 – 1.18)
0.386
0.694
Second-line vs third or more
0.94 (0.60 – 1.47)
0.77
0.843
Brain metastasis yes vs no
1.16 (0.66 – 2.04)
0.603
0.594
Our data suggests that Cyfra 21-1 pre-therapy assessment, both alone and in combination with other factors in a prognostic/predictive score, may provide clinicians with further information on the prognosis of patients treated with nivolumab.
CEA and CYFRA 21-1 repeated measures could be useful as an early surrogate marker of clinical benefit.
Further analysis are warranted to confirm these findings.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-16 - Molecular Signature in Malignant Pleural Mesothelioma (MPM). Preliminary Data of Rames Study (ID 254)
09:45 - 18:00 | Author(s): marcello Tiseo
- Abstract
Background
MPM is an uncommon cancer with limited therapeutic options and poor clinical outcomes. The relative rarity of these tumor has limited the identification of MPM-driver molecular as well as the development of specific drugs
Method
RAMES study evaluated the second-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo.
From December 2016 to July 2018 (end of enrolment), 164 patients (pts) were admitted to this study.
We evaluated by NGS the mutational profile of a panel of 34 genes (ACTB, ACTG1, ACTG2, ACTR1A, BAP1,CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6,-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53,TXNRD1, UQCRC1, XRCC6).
We reported the results of the first 87 pts (54%): hystotype was epithelioid in 70 pts (80%), biphasic in 14 pts (16%) and sarcomatoid in 3 pts (4%). Median age was 63 years (range 45-81). 70 pts were male (80%) and 17 pts were female (20%). In the present analysis, we included 55 pts in stage III (63%), 26 pts in stage IV (30%) and 6 pts whose stage was unknown. Median first-line PFS platinum/pemetrexed therapy was for 5.75 months (I.C. 95% 4.75-6.76). PFS was ≤6 months for 40 pts (49%), and 6 months for 41 pts (51%).
Result
187 functional somatic mutations were identified. Genomic alterations/patient were 1 gene in 29 pts (33%), 3 genes in 18 pts (21%) and ≥5 genes in 2 pts (2%). The most frequent somatic mutations were RDX in 35 pts (40%), MXRA5 in 20 pts (23%), BAP1 in 13 pts (15%) and ACTG 1 in 9 pts (11%). When patients were collated by stage, the most frequent mutations were: MXRA5 in 16 pts in stage III (29%), BAP1 in 5 pts in stage IV (19%) and RDX in 16 pts in stage IV (62%). The percentage of somatic mutations in patients with PFS as first-line chemotherapy for ≤6 and >6 months was 2.2 and 1.6 (p=0.032), respectively. The most frequent mutations/patient for ≤6 and >6 months PFS were: RDX in 14 pts (35%) with PFS < 6, RDX in 19 pts (46%) with PFS >6 and MXRA5 in 11 pts (27%) with PFS >6.
Conclusion
This preliminary data suggests a possible role that a genetic signature may play in distinguishing MPM with different clinical-pathological features. The results are expected to be clarified further in the second step of the study, which is ongoing.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-03 - Molecular Determinants for Lorlatinib Activity in ROS1 Positive NSCLC: Results of the Prospective PFROST Trial (ID 1566)
09:45 - 18:00 | Author(s): marcello Tiseo
- Abstract
Background
Lorlatinib, an ALK/ROS1 inhibitor, demonstrated activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.
Method
PFROST was a prospective phase II trial designed to include ROS1+ NSCLC refractory to crizotinib. Eligible patients were treated with lorlatinib at the daily dose of 100 mg until disease progression. Primary end point was response rate (RR). For all included patients pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.
Result
From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N=8; 36.4%), PS1 (N=14; 63,6%); The majority had brain metastases at baseline (N=15; 68.1%), were never smokers (N=13; 59.1%) and received lorlatinib as third line therapy (N=16; 72.7%). In all cases crizotinib was the last therapy line before lorlatinib. At the time of the present analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N=1) or partial (N=6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N= 1 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of radiological evidence of lorlatinib failure.
Conclusion
In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals developing secondary ROS1 mutations after crizotinib failure.
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P1.14-26 - ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma (ID 1860)
09:45 - 18:00 | Author(s): marcello Tiseo
- Abstract
Background
Clinical outcomes of ALK positive (ALK+) Non-Small-Cell Lung Cancer (NSCLC) and the identification of the most effective anaplastic lymphoma kinase inhibitor (ALKi) according to the specific ALK fusion variants are not well assessed. We retrospectively characterized fusion variant distribution in a cohort of ALK+ lung adenocarcinomas (ADC) with paired clinical data about treatments and outcomes.
Method
Diagnostic tumor tissue from advanced ALK+ (by FISH and/or IHC) ADC diagnosed from 2010 to 2018 and treated with single or multiple ALKis were collected (expanded cohort from Gobbini et al. Lung Cancer, 2017). The OncomineTM Solid Tumor Fusion Transcript Kit on an Ion PGM™ system and the Ion Reporter™ software were used to identify targeted ALK fusion gene products (ThermoFisher).
Result
Specific fusion variant transcripts were found in 34/55 (62%) of collected samples. As expected, EML4-ALK fusion transcripts were the most common (31/34 samples, 91%), but HIP-ALK transcripts were also detected (3/34 - 9%). Among EML4-ALK fusions the following variants were detected: V1 (n=11); V2 (n=2); V3a/b (n=12 ) V5a/b (n=5 ) and E6A19 (n=1). Patient median age was 60 year [range 36-85], 22 were male and 12 female. Three patients were current, 11 former and 20 never smokers. Crizotinib, alectinib, ceritinib, brigatinib and lorlatinib were the ALKis used. Independently of the therapy line, 12 patients received crizotinib only, while 22 patients received crizotinib followed by one or two other ALKis. Regardless of the type of transcript, those patients who received more than one ALKi had a better median overall survival compared to those receiving crizotinib only, as expected (74 vs 21 months, HR: 5.31; 95%CI: 1.464-19.26, log rank p=0.0006). Furthermore, a significant difference in the mean duration of the different ALKi treatment was found according to the ALK variants (Chi-square p<0.0001), suggesting a private ALKi efficacy profile for specific fusion variants. Finally, the 3 HIP-ALK cases showed a better outcome with respect the EML4-ALK variants (not reached vs 51 months).
Conclusion
Our analysis suggests that different ALK fusion variant might affect ALKi treatment duration in ALK+ lung ADC.
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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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P2.04-84 - NSCLC Survival Expectancy for Patients Treated with Docetaxel/Nintedanib in the SENECA Trial and Previous Immunotherapy (ID 807)
10:15 - 18:15 | Author(s): marcello Tiseo
- Abstract
Background
The phase IIb SENECA trial was an Italian real-world experience recently ended, which demonstrated similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients treated with second-line docetaxel/nintedanib, regardless the relapsing-time from end of first-line chemotherapy and the docetaxel schedule employed (weekly or q3wks), with a slightly higher toxicity-trend in the q3wks arm. During accrual period (January 2016-April 2018), no therapeutic alternative to the use of docetaxel was available for patients with recurrent nsNSCLC until April 2017, when the first immune-checkpoint inhibitor was approved and reimbursed in Italy in this setting. At that point, the study was amended allowing enrolment of patients previously treated with immunotherapy (IT). Because of the lack of data about the optimal therapeutic algorithm in this context, aim of the present evaluation is to investigate if survival expectancy of patients treated with docetaxel/nintedanib could positively influenced when previously treated with IT.
Method
In the SENECA trial, 212 nsNSCLC patients, progressing after first-line chemotherapy, were treated with docetaxel plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on 16 patients previously treated with IT and compares them to the rest of patient population. Survival analysis is performed using Kaplan Meier curves; Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are reported to compare the two groups.
Result
Patients treated with IT (2 combined with first-line chemotherapy, 14 alone) correspond to 7.5% of the entire study population; they were 9 males and 7 females, with a median age of 62.5 years, mainly current or former-smokers, with an ECOG-performance status 0 in 93.7% of cases. At the cut-off date (December 25th, 2018), after a median follow-up of 35.5 months, no significant differences appear between patients previously treated with IT and the other ones in terms of PFS (5.84 vs 4.31 months, respectively; HR 0.564 [95% CI 0.283-1.122], p-value=0.1029), and OS (9.37 vs 9.02 months, respectively; HR 1.108 [95% CI 0.393-3.123], p-value=0.8456). No significant differences have been observed also in disease-control rates (80.0% vs 66.7%, p-value=0.5436).
Conclusion
Despite this report does not show a greater survival expectancy for patients treated with docetaxel/nintedanib and previous IT, it's likely that the small sample size may affect this result. The longer PFS and greater disease-control rate are attractive hints for future evaluations with larger sample sizes, supposing a new therapeutic algorithm for recurrent nsNSCLC patients.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-02 - Exploring the Features of the Short and Long-Term Survivors for Lung Adenocarcinoma: A Single Center Experience (Now Available) (ID 2808)
10:15 - 18:15 | Author(s): marcello Tiseo
- Abstract
Background
The aim of this study was to identify an objective way to define a long-term survivors(LTS) and short-term survivors(STS) in patients with surgically resected lung adenocarcinoma (ADK), and secondly to find peculiar clinicopathological features in these two groups of patients.
Method
all patients who underwent major lung resection for lung ADK from 2000 to 2015 were studied.LTS and STS were extrapolated considering the overall survival(OS) and pathological tumour stage:the first and the fourth quartile of those patients with cancer-related death were considered for statistical analysis.
Result
from 600 ADK patients we found 79 STS and 77 LTS;clinico-pathologic baseline characteristics are presented in Table 1.Considering STS patients, smoking habit, histotype, tumour necrosis, pleural invasion and pathological stage were significantly associated with OS at univariate analysis (Fig.1). In LTS patients, smoking habit, neoadjuvant chemotherapy, tumour-infiltrated lymphocytes and pathological stage were significantly associated with OS (Fig.2).On multivariate analysis, smoking status, lymphoid infiltrate, pleural invasion and stage remained significantly associated with OS (Table 2).
Table 1
Variable
Full samplea
STS (N=79)a
LTS (N=77)a
p-value
Age at diagnosis (median)
68 (62-74)
68 (61-74)
69 (64-75)
0.301
Gender (M:F)
110:46 (70.5%:29.5%)
60:19 (24,1%:75,9%)
27:50 (35,1%:64,9%)
0.131
Smoking status
<0.001
Never smoker
23 (19,6%)
5 (6,8%)
18 (27,3%)
Smoker + Former smoker
117 (81,4%)
69 (93,2%)
48 (72,7%)
Other previous primary tumor
0.936
Yes
43 (27,6%)
22 (27,8%)
21 (27,3%)
No
113 (72,4%)
57 (72,2%)
56 (72,7%)
Side
0.079
Right
70 (44,9%)
30 (38,0%)
40 (51,9%)
Left
86 (55,1%)
49 (62,0%)
37 (48,1%)
Histotype
0.085
Lepidic
5 (3,2%)
0 (0,0%)
5 (6,5%)
Papillary
21 (13,5%)
11 (13,9%)
10 (13,0%)
Acinar
37 (23,7%)
16 (20,3%)
21 (27,3%)
Micropapillary
18 (11,5%)
8 (10,1%)
10 (13,0%)
Solid
75 (48,1%)
44 (55,7%)
31 (40,3%)
Grade
0.034
G1
2 (1,3%)
0 (0,0%)
2 (2,6%)
G2
23 (14,7%)
7 (8,9%)
16 (20,8%)
G3
131 (84,0%)
72 (91,1%)
59 (76,6%)
Lymphatic invasion
0.864
Yes
101 (64,7%)
51 (67,1%)
50 (65,8%)
No
51 (32,7%)
25 (32,9%)
26 (34,2%)
Blood invasion
0.128
Yes
47 (30,1%)
28 (36,4%)
19 (25,0%)
No
106 (67,9%)
49 (63,6%)
57 (75,0%)
Pleural invasion
0.439
PL0
78 (50,0%)
37 (46,8%)
41 (53,2%)
PL1
41 (26,3%)
24 (30,4%)
17 (22,1%)
PL2
20 (12,8%)
8 (10,1%)
12 (15,6%)
PL3
17 (10,9%)
10 (12,7%)
7 (9,1%)
Necrosis
0.419
Yes
70 (46,7%)
37 (50,0%)
33 (43,4%)
No
80 (53,3%)
37 (50,0%)
43 (56,6%)
Lymphoid infiltrate
0.787
Absent
57 (37,0%)
27 (35,1%)
30 (39,0%)
Mild
63 (40,9%)
34 (44,2%)
29 (37,7%)
Moderate
21 (13,6%)
9 (11,7%)
12 (15,6%)
Marked
13 (8,4%)
7 (9,1%)
6 (7,8%)
Neoadjuvant chemotherapy
0.371
Yes
11 (7,1%)
7 (8,9%)
4 (5,2%)
No
145 (92,9%)
72 (91,1%)
73 (94,8%)
Table 2
Variables
p-value.
HR
95% CI
Smoking Habit
0,003
2,317
1,325
4,052
Histotype
0,817
,951
,620
1,459
Tumor Necrosis
0,065
,667
,434
1,025
Limphoyd Infiltrate
0,024
1,598
1,063
2,402
Neoadjuvant CHT
0,160
,502
,192
1,313
Pleural Invasion
0,021
,421
,201
,879
Stage
0,002
,480
,305
,755
Conclusion
Our findings suggest that the unexpected survival of STS and LTS ADK-patients is determined by a concert of clinical and pathological features. Biological characterizazion of these kind of patients will likely improve the understanding of their unusual course.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-14 - Comparison of Molecular Testing Modalities for Detection of NRG1 Rearrangements in Invasive Mucinous Adenocarcinoma (ID 2179)
10:15 - 18:15 | Author(s): marcello Tiseo
- Abstract
Background
The NRG1 (Neureguline-1) fusion gene has been recently described as a new molecular feature of non small cell lung cancer (NSCLC), strictly related to invasive mucinous adenocarcinoma (IMA) subtype. Despite of NRG1 fusion partners, all Nrg1 chimeric ligands were predicted to retain the EGF-like domain of the wild-type NRG1 III-β3 isoform that produces oncogenic signals through ErbB2-ErbB3 heterodimers and leads to phosphorylation of ErbB3. To date, the NRG1 fusions were quite exclusively identified by RNA sequencing and only in few cases confirmed by fluorescent in situ hybridization (FISH) analysis, mainly due to the cellular features of IMA subtypes that produce interference in fluorescent signals detection. An accurate detection of NRG1 rearrangement/fusions in clinical tumor samples is actually demanded. In this study we compared the performance of two molecular testing approaches to detect NRG1 breaks in paraffin embedded formalin fixed (FFPE) IMA lung tissues.
Method
A total of 19 lung FFPE IMAs were screened by immunohistochemistry (IHC) to evaluate the expression of phosphorylated-ErbB3 (pErbB3) receptor. Samples positive for pErbB3 staining were tested by using by break-apart FISH to detect putative NRG1 rearrangements and RNA-targeted next generation sequencing (NGS) to identify fusion variants.
Result
Eleven cases showed an increased expression of pErbB3 in cancer cells compared to the adjacent non-involving bronchial epithelium which demonstrated a basal level staining of the protein. pErbB3 positive cases were investigated by FISH and showed <15% of rearranged nuclei (range 17-47%, mean 29%). In addition to the canonical signal split pattern, the FISH NRG1 assay reveals that cells also showed rearrangement patterns in form of isolated 3’ signals, thus indicating a strength analogy with ALK and ROS1 fusions, where a 5’ gene deletion was frequently observed. CD74-NRG1 fusion variant was identified by NGS analysis in four cases, whereas in three cases a 3’/5’ NRG1 imbalance was detected. For both approaches, we identified assay characteristics that likely contributed to false-negative results.
Conclusion
Our investigations confirm the usefulness of IHC/FISH combined approach for NRG1 broken tumors identification, but also highlight the crucial role of NGS to identify NRG1 functional chimeric transcripts. Such combined molecular testing should enhance the selection of NRG1-positive patients to include in clinical trials with specific compounds designed to inhibit the RTK downstream signal.
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P2.14-59 - Osimertinib in EGFR T790M Advanced NSCLC: Analysis of Uncommon/Complex EGFR Mutations in a Real-World Study (ASTRIS) (ID 1263)
10:15 - 18:15 | Author(s): marcello Tiseo
- Abstract
Background
The challenges of treating uncommon/complex EGFR mutations impact treatment decisions in clinical practice. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations and has demonstrated efficacy in NSCLC CNS metastases. ASTRIS is an ongoing, international, real-world study of osimertinib in EGFR T790M positive advanced NSCLC (NCT02474355). We report a subset-analysis of patients with uncommon/complex mutations.
Method
Patients with stage IIIB/IV T790M positive NSCLC previously treated with an EGFR-TKI were enrolled and received osimertinib 80 mg once-daily. Progression-free survival (PFS), clinical response and time to treatment discontinuation (TTD) were analysed in both full analysis set (FAS) and patients with uncommon/complex EGFR mutations. Uncommon mutation combinations included: T790M+G719X, T790M+S768I, T790M+ex20ins; complex mutations included T790M+two or more mutation(s).
Result
From 18 September 2015 to 15 October 2018 data cut-off, 3015 patients across 16 countries had received ≥1 dose of osimertinib (FAS), 53(2%) of these patients had uncommon/complex EGFR mutations. Baseline demographics between this patient subset and the FAS were similar (Asian: 55%/69%; female: 57%/64%; median age: 59 [30–80] years/62 [range, 27–92]; WHO performance status 2: 9%/11%, respectively). Baseline EGFR mutation status at enrolment of the FAS is shown in Table 1. Clinical outcomes appeared to be lower in the uncommon/complex mutation subset than in the FAS: response rate (measured in a FAS subset with ≥1 documented response assessment) was 50% [95% CI, 35.2, 64.8] in the uncommon/complex mutation group, and 57% [55.2, 58.9] in the FAS; median PFS was 8.1 [5.4, 10.1] and 11.1 [11.0, 12.0] months; median TTD was 9.0 [6.7, 11.5] and 13.5 [12.6, 13.9] months, respectively. Overall survival data are immature.
Conclusion
Whilst clinical outcomes appeared to be lower in the uncommon/complex mutation subset than the FAS, they were favourable and support use of osimertinib 80mg in this heterogeneous population.
