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Miguel Angel Molina-Vila
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-31 - BRAF Mutations: Classes I, II and III in NSCLC Patients Included in the SLLIP Trial, Targeted Treatment According to Class (Now Available) (ID 897)
09:45 - 18:00 | Author(s): Miguel Angel Molina-Vila
- Abstract
Background
BRAF V600 mutations have been found in 2% of non-small cell lung cancer (NSCLC) patients, with FDA approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class 2, with intermediate to high kinase activity and RAS independence, or class 3, with impaired kinase activity, upstream signaling dependence and consequently sensitivity to receptor tyrosine kinase (RTK) inhibitors. Non-V600 tumors require combinatory therapy with RAF/MEK inhibitors and blockers of RTK signaling, like SHP2 (PTPN11) inhibitors.
Method
Plasma DNA of 185 newly diagnosed advanced lung adenocarcinoma patients was examined for BRAF and other mutations with a clinically validated cell-free DNA (cfDNA) assay (Guardant360, Guardant Health Inc. CA, U.S), and results were correlated with patient outcome. In addition, two NSCLC cell lines and one Triple Negative Breast Cancer (TNBC), H1395 (class 2 BRAF mutation), H1666 (class 3 BRAF mutation) and MDA-MB-231 (class 2 BRAF mutation) were treated with single or combined BRAF, MEK and SHP2 inhibitors and cell viability was assessed.
Result
BRAF mutations were found in 17/185 (9%) and BRAF amplification in five patients (3%). Three patients had BRAF V600E mutations (2%) and 14 patients non-V600 BRAF mutations (8%), including four class 2 and four class 3 mutations. Patients were treated with chemotherapy and/or immunotherapy, or targeted therapy for other co-alterations. PFS was 1.8, 6.1, 5.0, 5.3 and 5.3 months for Class 1, 2, 3, other BRAF, and BRAF amplification, respectively. These low survival rates indicate that new treatment options are urgently needed. In vitro results confirm sensitivity of class 3, and resistance of class 2 BRAF mutations to single SHP2 inhibition with RMC-4550 and SHP099, with similar results in TNBC and lung cancer cells. Combined dabrafenib and trametinib treatment indicated antagonistic effects, especially in the class 3 BRAF mutant cell line. Concomitant MEK and SHP2 inhibition was synergistic in both class 2 and 3 BRAF mutations.
Conclusion
It is evident that different classes of BRAF mutations require distinct treatments, which could even outweigh tumor type. Therefore, we should examine BRAF class in daily clinical practice. Upfront targeting of the MAPK signaling pathway combined with SHP2 inhibitors reveals synergistic interactions, and additional inquisition may pave the way for new treatment options in the most frequently found mutations in BRAF patients.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-56 - Copy Number Gains (CNGs) of Clinically Relevant Genes in Advanced NSCLC Patients (ID 2519)
10:15 - 18:15 | Author(s): Miguel Angel Molina-Vila
- Abstract
Background
Somatic copy number variations (CNV; i.e. amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies, such as amplified ERBB2 in breast cancer. In the case of NSCLC patients, MET alterations are receiving increasing attention as targets in precision medicine, and several clinical trials of anti-MET agents are ongoing. Routine testing for these potential targets on formalin-fixed paraffin embedded (FFPE) samples is mainly carried out by in-situ hybridization (FISH) approaches covering only a single gene of interest. Although this methodology is still the gold standard of CNV detection, it presents several drawbacks. Here we aimed to determine the potential of next generation sequencing (NGS) to simultaneously determine CNGs across many in FFPE samples
Method
FFPE biopsies from 140 stage IIIb-IV NSCLC patients (p) of our institution were prospective tested. Of them, 110 corresponded to samples at diagnostic and 30 after progression to targeted therapies. DNA was purified submitted to NGS using the 16-gene QIAact Lung Panel (Genereader®, Qiagen). Coverages for the genes analyzed were normalized using the total coverage of the panel. Cut-off values for CNVs were established as the average normalized coverage for each gene plus two times the standard deviation. Representative samples were analyzed by FISH
Result
Validation analyses in 8 cell lines showed 100% concordance between FISH and NGS for detection of EGFR, MET and ERBB2 amplifications. Among the 140 NSCLC p, MET was the gene showing a higher frequency of CNGs, followed by PIK3CA, NRAS, EGFR and KRAS (Table 1). In contrast, only one p was found to harbor a ROS1 CNG. Among the 17 samples with MET CNG (12%), 6 corresponded to p progressing to targeted therapies. In addition, 8 of the 17 samples with MET CNGs were submitted to FISH, 6 of them were positive and the remaining 2 samples had copy numbers higher than 3.5 by this technique. In the case of EGFR, CNGs were associated with sensitizing mutations, with 5 samples showing both alterations concomitantly. In contrast, PIK3CA, NRAS, ALK, BRAF, HER2, PDGFRA, KIT and MET CNGs were not associated with mutations (Table 1).
n CNG
%
n MUTANT
MET
17
12.1
0
PIK3CA
12
8.6
0
NRAS
10
7.1
0
EGFR
10
7.1
5
KRAS
10
7.1
2
ALK
8
5.7
0
BRAF
8
5.7
0
ERBB2
8
5.7
0
PDGFRA
6
4.3
0
KIT
6
4.3
0
ROS1
1
0.7
0
Conclusion
CNGs in clinically relevant genes are present in a significant percentage of advanced NSCLC patients and, except in the case of EGFR, are not associated with driver mutations. Further research is warranted to determine the clinical implications of this finding.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)
10:15 - 18:15 | Author(s): Miguel Angel Molina-Vila
- Abstract
Background
Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.
Method
This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.
Result
Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.
Conclusion
NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).
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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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P2.04-79 - High Rate of Immune Related Pneumonitis in Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 1061)
10:15 - 18:15 | Author(s): Miguel Angel Molina-Vila
- Abstract
Background
Treatment with anti PD-1/PD-L1 antibodies has demonstrated survival improvement in several malignancies, including non small cell lung cancer (NSCLC), but these therapies are not exempt from risks. Meta-analysis and clinical trials have reported immune related (ir) pneumonitis of any grade in 3-5% of patients treated with anti PD-1/PD-L1 antibodies, including grade 3 or higher in 0.8% to 1.8% of patients.
Method
We have retrospectively reviewed clinical reports from 125 cancer patients treated at our center with anti PD-1/PD-L1 antibodies (55 were treated with nivolumab, 27 with pembrolizumab, 33 with atezolizumab, 6 with avelumab, and 4 with durvalumab) from January 2016 to January 2019.
Result
Nineteen patients (15.2%) developed ir pneumonitis. Four (21%) patients had recurrent pneumonitis during tapering corticoesteroid dose after an initial improvement and finally died. Patient characteristics are summarized in Table 1. Median time to pneumonitis was 4 months (m) (range 1m to 9m). Twelve patients (9.6% %) had grade 3-5 and 7 patients (5.6 %) grade 1-2 pneumonitis. Nine (7.2 %) patients died from ir pneumonitis, including 4 patients with no tumor progression (1 had received only one cycle, and 3 patients had ongoing tumor response at 10m+, 12m+ and 30m+). Ir pneumonitis was more frequent with nivolumab (any grade 21.8 %, grade 3 or higher 18.2 %, including 7 fatal cases-12.7%-), while no patient treated with atezolizumab developed pneumonitis (Table 2).
Table 1 Total 19 Gender
Women, n (%)
7 (36,8%)
Age
Median (range)
63,4 (51-82)
Cancer type, n (rate)
NSCLC Adenoca
NSCLC Squamous
SCLC
Mesothelioma
13 (68,4 %)
4 (21%)
1 (5,3%)
1 (5,3%)
Line of therapy, n (rate)
Adjuvant
First line
Second or further line
1 (5,2 %)
8 (42,1%)
10 (52,6%)
Tumor Response, n (rate)
CR
PR
SD
PD
NE
2 (10,5%)
8 (42,1%)
5 (26,3%)
3 (15,8%)
1 (5,2%)
table 2 Drug,n patients treated Any Grade, n (%) Grade 3-5, n (%) Grade 5, n (%) Nivolumab, 55 12 (21,8%) 10 (18,2%) 7 (12,7%) Pembrolizumab, 27 3 (11,1%) 1 (3,7%) 1 (3,7%) Atezolizumab, 33 0 0 0 Durvalumab, 4 2 (50%) 0 0 Avelumab, 6 2 (33,3%) 1 (16,7%) 1 (16,7%) Total, 125 19 (15,2%) 12 (9,6%) 9 (7,2%)
Conclusion
In our experience, ir pneumonitis rate with anti PD-1/PD-L1 antibodies in lung cancer patients was 15.2%, including 7.2% of fatal complications. It suggests that previous clinical trials could have under diagnosed this serious complication. Further studies must be performed in order to specifically assess the rate of pneumonitis in patients treated with anti PD-1 and anti PD-L1 antibodies in lung cancer patients.
