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Cristina Teixido
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-41 - Feasibility of EBUS-TBNA Cytologies for an Extensive Assessment of Predictive Biomarkers in Lung Cancer (Now Available) (ID 1640)
08:00 - 18:00 | Author(s): Cristina Teixido
- Abstract
Background
Clinical guidelines support the determination of several driver genes as well as PD-L1 to drive treatment decisions in non-small cell lung cancer (NSCLC). Endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) cytology specimens are useful for the initial diagnosis of NSCLC, although its capacity to provide enough material for a complete genotyping remains controversial. The aim of this study is to determine the yield of EBUS for a comprehensive multiplex genotyping in patients (pts) with suspected NSCLC.
Method
In this single-center, ongoing, prospective study, samples from mediastinal lymph nodes were obtained from pts undergoing EBUS-TBNA for lung cancer diagnosis/staging. Following malignant confirmation and appropriate cell content by rapid on-site evaluation, the study sample was obtained and formalin-fixed paraffin-embedded (FFPE). Three analytes were evaluated (DNA/RNA/protein). DNA and RNA were extracted and analyzed by Oncomine Solid Tumour panel (22 genes) and a customized nCounter panel (ALK, ROS; RET, NTRK, METDe14). Tumor Proportion Score (TPS) for PD-L1 protein expression was evaluated by an expert pathologist and scored into <1% (negative), 1-49% (weakly positive) and 50% (high).
Result
Twenty-five pts with NSCLC have been included and cytology samples of 20 of them molecularly characterized (5 still in progress). Overall, cytological analysis of EBUS-TBNA yield a complete characterization for the three analytes (DNA/RNA/protein) in 15 pts (75%). EBUS-TBNA sampling was sufficient for both, Nanostring and Oncomine evaluation, in a total of 18 pts (90%): 15 patients (83%) had any alteration detected by oncomine (TP53 61% [11/18],KRAS 44% [8/18], EGFRe 195.5% [1/18], BRAF V600E 5,5% [1/18], DDR2 5.5% [1/18], STK11 11% [2/18]) and 1 pt (5.5 %) by nanostring (METDex14). A total of 19 samples were sufficient for PD-L1 expression scoring (95%). TPS for PD-L1 expression was negative in 8 pts (42%), week in 4 (21%) and high in 7 pts (37%). Overall, half of the pts evaluated (10/20) would be potential candidates for an upfront personalized treatment strategy using targeted agents or immunotherapy.
Conclusion
EBUS-TBNA is a promising alternative source of material for NSCLC genotyping and allows the identification of pts candidates for personalized therapies.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-43 - Programmed-Death Ligand 1 Spectrum in a Large Cohort of Genetically Characterized Non-Small Cell Lung Cancer Patients (ID 1760)
09:45 - 18:00 | Author(s): Cristina Teixido
- Abstract
Background
Programmed-death ligand 1 (PD-L1) expression, assessed by immunohistochemistry (IHC), is used to select patients (pts) for checkpoint inhibitors. However, the pattern of PD-L1 expression across rare oncogenic alterations remains poorly characterized. We aimed to evaluate PD-L1 expression in a large dataset of pts with activating molecular alterations to define the potential responsiveness to immunotherapy.
Method
From 2016 to 2018, we prospectively characterized advanced NSCLC pts from a single institution. Tumor Proportion Score (TPS) for PD-L1 protein expression was evaluated by IHC (22C3 clone) using formalin-fixed paraffin-embedded tumor samples and scored into <1% (negative), 1-49% (weakly positive) and >=50% (high). DNA and RNA were extracted and analysed by Oncomine Solid Tumour panel (22 genes) and a customized nCounter-based panel (ALK, ROS1, RET, NTRK1, MET∆14). Associations between PD-L1 expression and the most prevalent driver alterations were assessed. Smoking habit and its possible relationship with PD-L1 expression was also appraised. Statistical analyses were performed using Kruskal-Wallis and Mann-Whitney tests.
Result
TPS for PD-L1 expression was available for a total of 140 patients (pts) fully genotyped. The cohort included: 36% women; 89% adenocarcinoma; 87% smokers. TPS for PD-L1 expression was negative (<1%), weak (1-49%) and high (>=50%) in 40%, 35% and 25% of pts, respectively. Actionable drivers were found in 84 pts (60%) being KRAS (n=43.31%) the most commonly detected, followed by EGFR (n=22.16%), BRAF (n=7.5%), MET∆14 (n=8.6%), ALK (n=3.2%) and ERBB2 (n=1, 1%). Thirty (21.4%) [ME1] pts harboured TP53 co-mutations. By comparing all genotyped cohorts, MET∆14 alteration was associated with higher PD-L1 expression levels compared with other subgroups (median TPS 58.62 vs 25.26, p=0.017[ME2] ). In addition, PD-L1 expression was also higher in pts harbouring any TP53 co-mutation than those with any alteration but TP53-WT (median TPS 41.53 vs 21.45, p=0.035). When KRAS-mut, BRAF-mut and EGFR-mut were evaluated separately, PD-L1 expression was higher in TP53 mutated tumors compared to TP53 WT only in BRAF-mut (p=0.028). Finally, no significant differences were found regarding patients’ smoking status (p=0.527).
Conclusion
Our results suggest differential expression of PD-L1 based on the presence of MET alterations and TP53 mutations and highlight the need of further characterizing PD-L1 expression across oncogenic alterations.
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P1.01-56 - Increased ROS1 and RET Transcripts in Fusion-Negative NSCLC Patients (ID 2477)
09:45 - 18:00 | Author(s): Cristina Teixido
- Abstract
Background
Fusion involving anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET) or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1) occur in non-small cell lung cancers (NSCLC) and are important biomarkers for targeted therapies. However, little is known about the RNA expression levels of these genes regardless of fusions.
Method
We used a custom nCounter panel (NanoString Technologies) designed to detect several genetic alterations, including fusions and mRNA expression levels of ALK, ROS1 and RET in formalin-fixed paraffin embedded (FFPE) samples. RNA was purified from NSCLC tumor samples and analyzed with the custom panel. The counts corresponding to the 3’ probes were normalized using the geometrical mean of the housekeeping genes and then added to evaluate total mRNA expression levels. Cut-off values for overexpression were established as the average counts for each gene plus two times the standard deviation.
Result
A total of 400 stage III-IV NSCLC patients (p) from two different institutions were retrospectively analyzed. Overexpression of ALK was found in 55 p (13.8%). Of them, 48 (87%) were also positive for EML4-ALK fusions. One ALK-translocated patient with low levels of ALK mRNA expression did not respond to therapy. Fifteen p (3.8%) showed ROS1 overexpression. In contrast with ALK, only three of them (15%) had a concomitant ROS1 fusion. Among the remaining 12 patients overexpressing ROS1, four were ALK positive, five harbored mutations in EGFR and three were non-smoker females with no known drivers. Regarding RET, high expression levels were found in 14 p (3.5%) and only one of them showed a RET fusion (7%). Among the remaining 13 p, three presented neuroendocrine features and seven were smoker or ex-smoker without other known drivers.
Conclusion
Overexpression of ALK mRNA in NSCLC is associated with EML4-ALK translocations. In contrast, a significant number of fusion negative patients show high ROS1 or RET mRNA levels. Further research is warranted to determine the clinical relevance 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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P2.03-17 - Optimization of an Ex-Vivo Preclinical Model for Drug Testing (ID 2385)
10:15 - 18:15 | Author(s): Cristina Teixido
- Abstract
Background
Predicting drug response in advanced lung cancer patients remains a major challenge. A promising approach to tackle this challenge is based on testing drugs in an ex-vivo preclinical model using cultured precision-cut fresh tumour slices, which maintain not only the tumour itself but also its microenvironment. However, even though different protocols have been reported for ex-vivo models with different time-windows in a growing list of cancer types, no standard protocols are currently defined in lung cancer. To address this limitation, we have begun to optimize a protocol for an ex-vivo preclinical model for drug testing in lung cancer, using samples from the standard in vivo model of bleomycin-induced lung fibrosis, which resembles the fibrotic stroma of non-small cell lung cancers.
Method
Bleomycin-induced fibrotic and control rat lungs were precision-cut with a tissue-chopper and cultured on cell culture inserts up to 12 days in a sterile setting. Two main variables were tested: the coating of the cell culture insert (bare or collagen-I coated), and the interaction with the culture medium (submerged or floating). Small lung pieces were collected at days 0, 2, 6, 9 and 12 and examined by hematoxylin-eosin staining to assess their integrity and viability.
Result
Tissue architecture was maintained equally well in all culture conditions up to 12 days. In contrast, cellular content appeared to decline after day 6; since only subsets of cells in the periphery of the explants remained viable at day 9-12. No contamination was detected at any culture time.
Conclusion
Our preliminary results suggest that our protocols for an ex-vivo preclinical model maintain the integrity and viability of lung cells and their microenvironment up to one week, which is comparable to time-windows previously reported in other cancer types. This time-window is expected to be sufficient to test drug responses, thereby underlying the potential of this preclinical model for drug testing as well as for the study of drug resistance mechanisms.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-22 - Programmed Death 1-mRNA Expression Predicts Benefit to Anti-PD1 Monotherapy in a Prospective Cohort of Advanced NSCLC (ID 1092)
10:15 - 18:15 | Presenting Author(s): Cristina Teixido
- Abstract
Background
Immunotherapy (IO) targeting PD1 or PD-L1 represents a new treatment option for patients (pts) with advanced non-small cell lung cancer (NSCLC). Besides PD-L1 IHC, other predictive biomarkers are being explored as potential predictors of outcomes. Our group has recently described an association between PD1-mRNA expression and response to IO in a retrospective multi-tumor dataset (Annals Oncol 2018). We aimed to corroborate these results in a prospective cohort of advanced NSCLC.
Method
We prospectively evaluated the expression of 7 immune-related genes (CD4, CD8, PD1, PDL1, IFNG, GZMM andFOXP3) and 5 housekeeping genes in formalin-fixed paraffin-embedded tumor samples obtained before anti-PD1 therapy using the nCounter platform (Nanostring Technologies). The study cohort included consecutive pts with advanced NSCLC, ECOG/PS 0-1, no targetable oncogenes, treated in the first or second-line setting with anti-PD1 monotherapy from June 2017 to January 2019. Associations between the expression of PD1 mRNA (as a continuous variable and using a previously defined pre-specified cutpoint) and response (complete and partial response) were assessed using logistic regression analysis. Kaplan-Meier method was used for survival analysis. PD-L1 IHC tumor cell expression was assessed using the 22C3 clone. Pearson correlation between PD-L1 IHC and PD1 mRNA was explored.
Result
A total of 43 pts were included (men 79%; adenocarcinoma 53%; nivolumab 55%; pembrolizumab 45%; first-line 30%; second-line 70%). Response occurred in 23% of pts and was significantly associated with PD1 (p=0.029) and FOXP3 (p=0.035) expression. Using the pre-established PD1 cutoff (Annals Oncol 2018), 37% and 63% samples were PD1-high and PD1-low, respectively. PD1-high was significantly associated with increased overall response rate (ORR) (43% vs 11%, OR=6.22 [CI=1.31-29.44], p=0.021) and progression-free survival (HR 0.36 [CI= 0.14-0.90], p=0.028) but not with overall survival (p=0.117). PD-L1 IHC expression was available in 35 cases, of which 46% had high (>=50%) expression levels. A moderate concordance (0.49) was observed between PD-L1 IHC and PD1-mRNA. In this subset analysis, high PD-L1 IHC was significantly associated with response (50% vs 11%, OR=8.50 [CI= 1.45-49.53], p=0.043). Importantly, when combining predefined high/low-sets for both biomarkers (PD-L1 IHC/PD1-mRNA), response was significantly increased in PD-L1-high/PD1-high compared to PD-L1-low/PD1-low (ORR 58% vs 0%, p=0.019).
Conclusion
PD1-mRNA expression is associated with response to anti-PD1 monotherapy and can increase the predictive ability of PD-L1 IHC. Further validation of these findings in pivotal clinical trials evaluating IO in advanced NSCLC pts seems warranted.
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P2.04-61 - Preliminary Report of a Multidisciplinary Task Group for the Study of Immune-Mediated Pulmonary Toxicity (ID 1647)
10:15 - 18:15 | Author(s): Cristina Teixido
- Abstract
Background
Immunotherapy (IO) is now the standard of care for many tumor types. However, it is not free of risks, being pulmonary toxicity one of the most relevant immune-related adverse event due to its severity. Differential diagnosis with other pulmonary complications such as infections or tumor dissemination further complicates its management.
Method
In order to raise awareness, gather information, and to discuss early management strategies in patients (pts) with immune-related interstitial lung disease (irILD), in 2017 we created a multidisciplinary task group comprised of pneumologists, pathologists, oncologists and radiologists. We herein report the main features of the first series of pts treated with IO who subsequently developed ILD, prospectively identified from a tertiary University Hospital over a period of two years (2017-2019), focusing on clinical presentation, radiological patterns, outcomes and therapeutic intervention.
Result
We identified a total of 23 pts with suspicion of irILD. Patients mainly received programmed cell death-1 (PD-L1) inhibitors (61%). Main characteristics are summarized in Table 1. ILD occurred more often in males, and former or current smokers (91%), with a median age of 62 years. The most common radiological pattern was the presence of ground-glass opacities (87%), followed by consolidations (61%). Forty-eight percent of the cases had grade 3 severity according to the Common Terminology Criteria for Adverse Events (CTCAE). Thirteen of the patients (57%) underwent a fibrobronchoscopy during the diagnostic period and a specific microorganism was isolated from BAL in three cases (13%) (Aspergillus fumigatus, cytomegalovirus and herpes type 1 virus). Ten pts (43%) underwent transbronchial biopsies being focal organizing pneumonia and desquamative changes the most common pathological patterns observed. Twenty patients (87%) received prednisone (1mg/kg/day) and thirteen of them (57%) also received antibiotic treatment.
ConclusionPatients (%)
Mean age (years)
61.63 ± 12.35
Gender
Male
19 (83%)
Female
4 (17%)
Smoking history
Current
2 (9%)
Never
7 (30%)
Former
14 (61%)
Type of cancer
Lung
8 (35%)
Kidney
5 (22%)
Skin
4 (17%)
Others*
6 (26%)
* Others: haemathologic, bladder, liver, sigma, urothelial, timic.
Immunotherapy
Nivolumab
8 (35%)
Pembrolizumab
6 (26%)
Durvalumab
2 (9%)
Others*
7 (30%)
* Others: Atezolizumab, Nivolumab+Ipilimumab, Atezolizumab+Daratumumab, Atezolumab+Bevacizumab, CX-072, Nivolumab/Nivolumab+Ipilipumab, Avelumab.
Immuno-mediated pulmonary toxicity is a rare but severe complication that carries a significant mortality. Due to their complexity, multidisciplinary approach is required to provide an adequate treatment and to guarantee early intervention.
