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Background: Fusion involving anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET) or ROSproto-oncogene 1, receptor tyrosine kinase (ROS1), neurotrophic receptor tyrosine kinase 1 (NTRK1)and neuregulin 1 (NRG1) are present in lung cancer (LC) and represent important biomarkers fortargeted therapies. However, little is known about the RNA expression levels of some of these genesregardless of fusions. Methods: We used a custom nCounter panel (NanoString Technologies) designed to detect fusionsand mRNA expression levels of ALK, ROS1, RET, NTRK1 and NRG1 in formalin-fixed paraffin embedded(FFPE) samples. RNA was purified from lung cancer tumor samples and analyzed with the panel. Thecounts corresponding to the 3' probes were normalized using the geometrical mean of thehousekeeping genes and then added to evaluate total mRNA expression levels. Cut-off values for veryhigh expression levels were established as the average counts in all samples (s.) studied for each geneplus three times the standard deviation. Results: A total of 580 LC s. from two different institutions were retrospectively analyzed for ALK,ROS1, RET and NTRK1 mRNA levels. Very high levels of ALK mRNA were found in 76 s. (13%). Of them,69/76 were also positive for EML4-ALK fusions and 61/76 had adenocarcinoma histology (ADC). OneALK-translocated patient with a sample with low levels of ALK mRNA did not respond to therapy.Twenty-two s. (3.8%) showed very high levels of ROS1 mRNA and 17/22 were ADC. In contrast withALK, only 4/22 had a concomitant ROS1 fusion. Among the remaining 16 s. with very high levels ofROS1 mRNA, 11 were ALK or EGFR positive and two were wt for the more common lung ADC geneticalteration. Regarding RET, very high expression levels were found in 11 s. (2%), only one of themshowed a RET fusion. Among the remaining 10 s., 6 presented neuroendocrine features and only 2were ADC. Regarding NTRK1, 4 s. showed very high expression levels of mRNA and only one of themwas positive for NTRK1 translocation. Finally, 116 LC s were analyzed for NRG1; very high mRNA levelswere detected in 2 cases, none of them translocated. Conclusions: Very high expression of ALK mRNA in NSCLC is associated with EML4-ALK translocations.In contrast, a significant number of fusion negative patients show high ROS1, RET and NTRK1 mRNAvery high levels. Further research is warranted to determine the clinical relevance of this finding. Citation Format: Cristina Aguado, Cristina Teixido, Ana Gimenez Capitan, Elba Marin, Ruth Roman, Sonia Rodriguez, Irene Moya, Roxana Reyes, Nuria Viñolas, Santiago Viteri, Andres Aguilar, Rafael Rosell, Noemi Reguart, Miguel Angel Molina-Vila. Comprehensive, large scale analysis of ALK, ROS1, RET, NTRK1 and NRG1 transcripts in lung cancer reveals over-expressing, potentially targetable patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 469.

There is growing evidence supporting that long-term survival of neoadjuvant chemo-immunotherapy for locally advanced NSCLC patients can be achieved. However, some patients invariably progress within the short-term. Identification of patients at high risk of progression is needed to achieve a better control of the disease. Concentrations of baseline ctDNA have been shown to be of prognostic significance. Patients and methods 42 pre-treatment plasma samples from the NADIM clinical trial (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab, were analyzed by NGS, using the Oncomine Pan-Cancer Cell-Free Assay™ (Thermo Fisher Scientific®). Variant calling, annotation and filtering were performed on the Ion Reporter (v5.14) platform using the OncomineTagSeq Pan-Cancer Liquid Biopsy workflow (v2.3). The final variant matrix was obtained from vcf files as generated from Ion Reporter (v5.14) platform and applying an internal pipeline (R-code is available upon request). Progression disease was evaluated by RECIST criteria V1.1. Results A total of 116 variants were detected in 88.10% (N=37) of the plasma samples collected before neoadjuvant treatment. The average number of variants detected per sample was 3.13. The most frequently mutated genes were TP53, which accounts for 59.52% of the detected variants, followed by PIK3CA (30.95%), MAP2K1 (30.95%), APC (23.81%), MTOR (9.52%) and KIT (9.52%). Patients in whom a GNA11 mutation was detected in the plasma sample by NGS showed worsen progression free survival (PFS) (HR: 14. 95%; CI: 2.6-71, P-value with Fold Discovery Rate correction: 0.019). Finally, ctDNA levels at Mutant Allele Frequency (MAF) below 1% at baseline were associated with improved PFS (P=0.025). At 30 months, PFS was 80.30% for these patients compared with 58.33% in patients with ctDNA levels ≥ 1%. Conclusions Molecular profiling of liquid biopsies collected before neoadjuvant chemo-immunotherapy using NGS can identify patients at high risk of progression who might require more aggressive adjuvant treatment in order to achieve a better control of the disease. Citation Format: Mariano Provencio, Roberto Serna-Blasco, Ernest Nadal, Amelia Insa, M. Rosario Garcia-Campelo, Diego Pereiro Corbacho, Manuel Domine, Margarita Majem, Delvys Rodriguez-Abreu, Alex Martinez-Marti, Javier de Castro, Manuel Cobo, Guillermo Lopez-Vivanco, Edel del Barco, Reyes Bernabe, Nuria Viñolas, Isidoro Barneto, Santiago Viteri, Eva Pereira, Ana Royuela, Marta Casarrubios, Clara Salas, Edwin R Parra, Ignacio Wistuba, Virginia Calvo, Raquel Laza-Briviesca, Bartomeu Massuti, Alberto Cruz-Vermudez, Atocha Romero. High levels of baseline ctDNA constitute a poor prognostic factor in progression-free survival in patients receiving neo-adjuvant chemo-immunotherapy: Results from NADIM clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 560.

Antibody targeting of the immune checkpoint receptor PD1 produces therapeutic activity in a variety of solid tumors, but most patients exhibit partial or complete resistance to treatment for reasons that are unclear. In this study, we evaluated tumor specimens from 65 patients with melanoma, lung nonsquamous, squamous cell lung or head and neck cancers who were treated with the approved PD1-targeting antibodies pembrolizumab or nivolumab. Tumor RNA before anti-PD1 therapy was analyzed on the nCounter system using the PanCancer 730-Immune Panel, and we identified 23 immune-related genes or signatures linked to response and progression-free survival (PFS). In addition, we evaluated intra- and interbiopsy variability of PD1, PD-L1, CD8A, and CD4 mRNAs and their relationship with tumor-infiltrating lymphocytes (TIL) and PD-L1 IHC expression. Among the biomarkers examined, PD1 gene expression along with 12 signatures tracking CD8 and CD4 T-cell activation, natural killer cells, and IFN activation associated significantly with nonprogressive disease and PFS. These associations were independent of sample timing, drug used, or cancer type. TIL correlated moderately (∼0.50) with PD1 and CD8A mRNA levels and weakly (∼0.35) with CD4 and PD-L1. IHC expression of PD-L1 correlated strongly with PD-L1 (0.90), moderately with CD4 and CD8A, and weakly with PD1. Reproducibility of gene expression in intra- and interbiopsy specimens was very high (total SD

This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression-free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.-7.1]; Pem+Cis, 1.5 months [1.3-2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775.

BACKGROUND Anaplastic lymphoma receptor tyrosine kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), and ret proto-oncogene (RET) fusions are present in 5%–7% of patients with advanced non–small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, but they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting. METHODS Formalin-fixed, paraffin embedded (FFPE) samples from 108 patients with advanced NSCLC were analyzed with an nCounter-based assay and the results compared with FISH, IHC, and reverse transcription PCR (RT-PCR). Data on response to fusion kinase inhibitors was retrospectively collected in a subset of 29 patients. RESULTS Of 108 FFPE samples, 98 were successfully analyzed by nCounter (91%), which identified 55 fusion-positive cases (32 ALK, 21 ROS1, and 2 RET). nCounter results were highly concordant with IHC for ALK (98.5%, CI = 91.8–99.7), while 11 discrepancies were found compared with FISH (87.5% concordance, CI = 79.0–92.9). For ROS1, nCounter showed similar agreement with IHC and FISH (87.2% and 85.9%), but a substantial number of samples were positive only by 1 or 2 techniques. Of the 25 patients deriving clinical benefit from fusion kinase inhibitors, 24 were positive by nCounter and 22 by FISH. CONCLUSIONS nCounter compares favorably with IHC and FISH and can be used for identifying patients with advanced NSCLC positive for ALK/ROS1/RET fusion genes.

Long intergenic noncoding RNA-p21 (lincRNA-p21) is a long noncoding RNA transcriptionally activated by tumor protein p53 (TP53) and hypoxia inducible factor 1 alpha subunit (HIF1A). It is involved in the regulation of TP53-dependent apoptosis and the Warburg effect. We have investigated the role of lincRNA-p21 in NSCLC.LincRNA-p21 expression was assessed in tumor and normal tissue from 128 patients with NSCLC and correlated with time to relapse and cancer-specific survival (CSS). H23, H1299, and HCC-44 cell lines were cultured in hypoxic conditions after silencing of lincRNA-p21. The TaqMan human angiogenesis array was used to explore angiogenesis-related gene expression. Levels of the protein vascular endothelial growth factor A were measured by enzyme-linked immunosorbent assay in the cell supernatants. Angiogenic capability was measured by human umbilical vein endothelial cell tube formation assay. Microvascular density in tumor samples was analyzed by immunohistochemistry.LincRNA-p21 was down-regulated in tumor tissue, but no association was observed with TP53 mutational status. High lincRNA-p21 levels were associated with poor CSS in all patients (p = 0.032). When patients were classified according to histological subtypes, the impact of lincRNA-p21 was confined to patients with adenocarcinoma in both time to relapse (p = 0.006) and CSS (p0.001). To explain the poor outcome of patients with high lincRNA-p21 expression, we studied the role of lincRNA-p21 in angiogenesis in vitro and observed a global downregulation in the expression of angiogenesis-related genes when lincRNA-p21 was inhibited. Moreover, supernatants from lincRNA-p21-inhibited cells were significantly less angiogenic and had lower levels of secreted vascular endothelial growth factor A than controls did. Finally, tumor samples with high lincRNA-p21 levels had higher microvascular density.Our findings suggest that lincRNA-p21 affects outcome in patients with NSCLC adenocarcinoma through the regulation of angiogenesis.

Objectives To investigate the capacity of a trained dog to identify LC in patients with malignant SPN. Methods We collected 90 exhaled gas samples from 30 patients with SPN (3 samples/patient). As controls we used 61 healthy volunteers and 18 COPD patients without SNP or LC, in each of whom we collected 5 exhaled gas samples (n = 395). The dog (Blat, a 4-year-old crossbreed between a Labrador Retriever and a Pitbull) and the methodology used were the same as previously reported by our group (see: https://drive.google.com/open?id=1R4mOtOtuZkTeb5iOEEv0K9r2kHKlPhWd ). Results Of 30 patients with SPN, Blat recognized 27 of them as positive for LC and 3 as negative for LC. These results fully matched post-surgical pathological results. Sensibility was 0.97, Specificity 0.99, Positive Predictive value 0.97 and negative predictive value 0.99. The AUC of the ROC curve was 0.985. Conclusions Trained dogs can identify accurately the malignant origin of SPN. It is now time to develop technology that can match canine olfaction and facilitate the implementation of this diagnostic approach in the clinic.

Since tumor-draining pulmonary vein blood (PV) is enriched in tumor-secreted products, we hypothesized that it would also be enriched in tumor-derived exosomes, which would be important in the metastasis process. We characterized exosomes from PV of 61 resected non-small cell lung cancer (NSCLC) patients to evaluate its potential as relapse biomarkers. Exosomes were characterized using transmission electron microscopy, western blot and nanoparticle tracking analysis and we examined time to relapse (TTR) and overall survival (OS). Differences between PV and peripheral vein were found. PV was enriched in smaller exosomes than the paired peripheral vein (p = 0.01). Moreover, PV exosome size mode was able to identify relapsed patients (Area under the curve [AUC] = 0.781, 95%CI: 0.6641&ndash, 0.8978), in whom exosome size was smaller (&lt, 112 nm, p &lt, 0.001). The combination of PV exosome size and N (lymph node involvement) showed an AUC of 0.89 (95%CI: 0.80&ndash, 0.97). Moreover, smaller PV exosome size was associated with shorter TTR (28.3 months vs. not reached, p &lt, 0.001) and OS (43.9 months vs. not reached, p = 0.009). Multivariate analyses identified PV exosome size and stage as independent prognostic markers for TTR and OS. PV exosome size is a promising relapse biomarker after surgery that can add valuable information to clinical variables.

Background HOTTIP, a long non-coding RNA located in the HOXA cluster, plays a role in the patterning of tissues with mesodermal components, including the lung. Overexpression of HOXA genes, including HOTTIP, has been associated with a more aggressive phenotype in several cancers. However, the prognostic impact of HOTTIP has not yet been explored in non-small-cell lung cancer (NSCLC). We have correlated HOTTIP expression with time to relapse (TTR) and overall survival (OS) in early-stage NSCLC patients. Methods Ninety-nine early-stage NSCLC patients who underwent surgical resection in our center from June 2007 to November 2013 were included in the study. Mean age was 66; 77.8% were males; 73.7% had stage I disease; and 55.5% had adenocarcinoma. A validation data set comprised stage I-II patients from The Cancer Genome Atlas (TCGA) Research Network. Results HOTTIP was expressed in all tumor samples and was overexpressed in squamous cell carcinoma (p = 0.007) and in smokers (p = 0.018). Patients with high levels of HOTTIP had shorter TTR (78.3 vs 58 months; p = 0.048) and shorter OS (81.2 vs 61 months; p = 0.023) than those with low levels. In the multivariate analysis, HOTTIP emerged as an independent prognostic marker for TTR (OR: 2.05, 95%CI: 1–4.2; p = 0.05), and for OS (OR: 2.31, 95%CI: 1.04–5.1; p = 0.04). HOTTIP was validated as a prognostic marker for OS in the TCGA adenocarcinoma cohort (p = 0.025). Moreover, we identified a 1203-mRNA and a 61-miRNA signature that correlated with HOTTIP expression. Conclusions The lncRNA HOTTIP can be considered a prognostic biomarker in early-stage NSCLC. Electronic supplementary material The online version of this article (10.1186/s12890-019-0816-8) contains supplementary material, which is available to authorized users.

The WORLD07 study was a female-specific database, to prospectively characterise the clinical, histological, molecular and treatment-related features in Spanish women with lung cancer. Data were collected from patients' medical records and patient interviews from October 2007 to December 2012. A total of 2,060 women were analysed: median age, 61.3 years; white, 98.6%; postmenopausal, 80.2%; and no smokers, 55% including never smokers and ex-smokers. A family history of cancer was found in 42.5% of patients, 12.0% of patients had had a previous history of cancer (breast cancer, 39.7%). Most patients (85.8%) were diagnosed of non-small-cell lung cancer (NSCLC), most commonly reported with adenocarcinoma (71.4%), which was stage IV at diagnosis in 57.6%. Median overall survival (OS) for the entire population was 24.0 months, with a 1- and 2-year survival rate of 70.7% and 50.0% respectively. Median OS in patients with small-cell lung cancer was 18.8 months versus 25.0 months in patients with NSCLC (p = 0.011). Lung cancer appears to be a biologically different disease in women. By collecting prospective information about characteristics of women with lung cancer attending university hospitals in Spain, we hope to highlight the need to develop strategies based on gender differences and influence future healthcare policy.

Objectives: Concomitant chemo-radiation is the standard treatment for unresectable stage III non-small cell lung cancer (LA-NSCLC), The aim of this study was to assess the safety and efficacy of oral vinorelbine and cisplatin (OVP) compared with etoposide and cisplatin (EP), both in combination with radiotherapy, in this setting. Material and methods: An open-label, randomized phase II trial was undertaken including 23 hospitals in Spain. Adults with untreated unresectable stage III NSCLC were randomizedl:1 to receive: oral vinorelbine (days 1 and 8 with cisplatin on day 1 in 3-week cycles; 2 cycles of induction, 2 cycles in concomitance) or etoposide (days 1-5 and 29-32 with cisplatin on days 1 and 8 in 4-week cycles; 2 cycles in concomitance). Both groups received concomitant radiotherapy 2 Gy/day (66 Gy). The primary endpoint was progression free survival (PFS). Results: One hundred and forty patients were enrolled. Sixty-nine patients received OVP and 71 received EP. Globally adverse events grade 3/4 per cycle were fewer in the vinorelbine arm (19.4%) than in the etoposide arm (62.6%) (p < 0.001). One patient (1.5%) in the OVP arm and 12 pts (17.6%) in the EP arm presented esophagitis grade 3/4 (p = 0.002). Median PFS was similar in both groups (10.8 [95% CI 7.7-13.8] and 9.6 months [95% CI 4.4-14.8]; p = 0.457, respectively). Preliminary median overall survival was 30 months in the OVP arm and 31.9 months in the EP arm (p = 0.688). Conclusions: Our findings show that OVP could be considered a standard combination with similar efficacy and better safety profile for the treatment of LA-NSCLC patients.

Background The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumor immunity and resistance to multiple therapies including CPIs. Bemcentinib is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods This PhII trial enrolled 48 advanced lung adenocarcinoma pts with progression on or after 1 prior line of PLT-based chemotherapy. Primary endpoint was ORR according to RECIST 1.1. Additional endpoints included efficacy according to biomarker expression, DCR, PFS, OS and safety. Tumor biopsies were analyzed for AXL by IHC, and PD-L1 expression (22C3 pharmDx). Additional biomarker analysis was also performed. Results In May 2019, Cohort A was fully recruited: median age 65 (range 39-82) yrs, 61% male, 76% smokers or ex-smokers. Pts had completed a median of 3 treatment cycles. 15 pts were ongoing. Out of 32 pts with available PD-L1, 17 (53%) had TPS 50%. Out of 33 patients with available AXL IHC, 19 (58%) expressed AXL on their tumors. Among pts who had at least 1 evaluable post-baseline scan: ORR was 10/38 (26%) overall, 6/16 (38%) in AXL positive pts (compared to 2/13 (15%) in AXL negative pts), and 7/30 (23%) in pts with TPS 0-49%. 12-mo OS was 54% overall (2 pts lost to follow up). mOS overall was 12.2 mos (95% CI 6.2 – NR). In pts with AXL positive tumors, mOS was 12.2 mos (2.0 – NR) and in AXL negative 12.7 mos (5.6 – NR). In PD-L1 negative pts, mOS was 12.4 mos (5.6-NR). Most common TRAEs (occurring in > 10% of pts) were transaminase increases (35%), asthenia/fatigue (30%), diarrhea (26%), nausea (13%), anemia (11%), and decreased appetite (11%). All cases of transaminase increase were reversible and resolved. 13 pts (28%) had TRAEs grade > 3, all of which were resolved or resolving at the time of writing. No treatment-related deaths were reported. Conclusions The combination of bemcentinib and pembro was well tolerated and showed promising efficacy in previously treated IO-naive NSCLC pts, particularly in those with AXL positive disease, including PD-L1 negative pts. mOS of > 12 mos is favorable compared with historical references in the NSCLC second-line setting. Clinical trial identification NCT03184571. Legal entity responsible for the study BerGenBio ASA. Funding BerGenBio ASA. Disclosure J.M. Trigo Perez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Blueprint Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Guardant Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Medscape; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Touchtime. A. Helland: Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: PierreFabre; Speaker Bureau / Expert testimony: Pfizer. E. Arriola: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. R. Garcia Campelo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim. J. Spicer: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Bayer; Honoraria (institution), Research grant / Funding (institution): BerGenBio ASA; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): BMS; Honoraria (institution), Research grant / Funding (institution): Curis; Honoraria (institution), Research grant / Funding (institution): Genmab; Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (institution), Research grant / Funding (institution): Starpharma; Honoraria (institution), Research grant / Funding (institution): Taiho; Shareholder / Stockholder / Stock options: IGEM Therapeutics. R.J. Holt: Full / Part-time employment: BerGenBio ASA. J.B. Lorens: Leadership role, Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Full / Part-time employment: BerGenBio ASA. M. Shoaib: Advisory / Consultancy, Full / Part-time employment: BerGenBio ASA. A. Siddiqui: Advisory / Consultancy, Full / Part-time employment: BerGenBio ASA. E.V. Schmidt: Full / Part-time employment: Merck Sharp & Dome. M.J. Chisamore: Full / Part-time employment: Merck Sharp & Dome. M.G. Krebs: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Achilles Therapeutics; Advisory / Consultancy: Octimet; Advisory / Consultancy: Janssen; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BerGenBio ASA. All other authors have declared no conflicts of interest.

3060 Background: Genetic profiling (GP) is essential not only for understanding tumor biology but also helps to identify potential genes for targeted therapies. At the same time, selected CT provide an individual genomic profile panel during the pre-screening phase. Here, we demonstrate our experience using these panels. Methods: We selected 14 CT from our Early Drug Development Clinical Trial Unit at Hospital Clinic of Barcelona that included analysis of gene panels in tumor (Foundation One, ArcherDX, Therascreen and Sophia Genetics) or plasma (Resolution Bioscience ctDx). These panels analyzed mutations, fusions, amplifications, microsatellite instability (MSI) and tumor mutational burden (TMB), among others. We collected information about types of cancers, molecular alterations and therapies chosen according to the results of GP. The platform OncoKB (Chakravarty JCO PO, 2017) was used to define genes with potential target therapies and levels of evidence (LE) for those targets (from LE 1 –FDA-recognized biomarker predictive of response to an FDA-approved drug- to LE 4 –Compelling biological evidence supports the biomarker as being predictive of response to a drug). Descriptive statistics were used. Results: From March 2017 to January 2021 we analyzed samples from 410 patients (pts) with CNS (19.3%), urothelial (18.3%), prostate (17.6%), breast (15.4%), ovarian (9.3%), esophageal and gastric (5.4%), colorectal (4.4%), pancreas (2.7%), endometrial (2.4%), cholangiocarcinoma (1.2%), cervix (1%), HNSCC (1%), renal (1%), lung (0.5%), liver (0.2%) fallopian tube (0.2%) and paraganglioma (0.2%). 352 pts (85.8%) had at least 1 genetic alteration. The most frequently altered genes were TP53 (153 pts, 46.2%), INSR (19 pts, 22.8%), TERT (76 pts, 22%), CDKN2A (65 pts, 19.9%), FAM175A (11 pts, 19.3%), CDKN2B (54 pts, 18.1%), MLL2 (53 pts, 17.7%), PTEN (52 pts, 16%), MTAP (45 pts, 15.7%), PIK3CA (52 pts, 15%) and ATM (55 pts, 14.4%). TMB ranged from 0 to 76.9 mut/Mb (median 2.5 mut/Mb). MSI was found in 3 pts (1.5%). 196 pts (47.1%) had an OncoKB LE 1 alteration, 105 pts (25.6%) if we restrict the options to their specific cancer type. 16 pts (3.9%) received a matched therapy: 6 pts received an off-label drug, 6 pts were included in the same CT for which the pre-screening was performed and 4 pts were included in a different CT. Additionally, 13 pts (3.2%) received a matched therapy either with OncoKB LE 4 (5 pts received an off-label drug and 3 were included in a different CT) or not included in OncoKB (8 pts included in the same CT of the pre-screening). As a whole, 29 pts (7.1%) received a matched drug according to their genomic results. Conclusions: Comprehensive gene panel testing offered through CT allows the identification of targets to enroll pts, although the recruitment was 1.5%. However, 7.1% of the pts received a matched therapy due to the molecular information of these gene panels.

Introduction: COVID-19 pandemic has drastically changed the management of patients with cancer The prioritization of the healthcare towards COVID-19 patients could interfere with the initial diagnosis, resulting in delayed treatment and worse outcome We aimed to study the incidence of lung cancer new diagnosis, severity and clinical outcomes during Covid-19-period (during-COVID) compared to the same period in 2019 (before-COVID) Methods: Bicenter retrospective cohort study of newly diagnosed non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients before (Jan-Jun/19) and during COVID-19 (Jan-Jun/20) in Spain Clinical data were collected We primarily assessed the difference on new lung cancer cases between both periods, and the disease severity considering: Performance status (PS), stage and any significant complication at diagnosis Secondarily, we assessed the 30 days-mortality rate, progression-free survival (PFS) and overall survival (OS) by period Results: 162 newly diagnosed lung cancer patients (68% NSCLC and 32% SCLC) were enrolled, with median age of 66 years, 70% were male, 33% smokers, 25% with PS ≥2 Advanced disease was diagnosed in 50% of NSCLC and 61% SCLC;13% of NSCLC harbored driver alterations During-COVID, the number of new cases diagnosed decreased by 38% (43 NSCLC;19 SCLC), compared to before-COVID period (67 NSCLC;33 SCLC) More symptomatic cases were new diagnosed during vs before-COVID The Table 1 summarized clinical data and complications of new lung cancer cases by period and histology In NSCLC population diagnosed during-COVID, we observed more respiratory symptoms at diagnosis (30% vs 23% before-COVID) with mainly locally-advanced/advanced disease (82% vs 76% before-COVID) Among the cases hospitalized, the mortality during-hospitalization was 44% (2/9) vs 17% before-COVID In SCLC population diagnosed during-COVID, respiratory symptoms were more common (32% vs 24% before-COVID), but no more aggressive disease observed in terms of stage, complications and hospitalizations Among the 4 cases hospitalized at diagnosis, none died during-hospitalization vs 18% before-COVID (2/11) Overall, during-Covid the mOS was 6 7 months [95% CI, 5 4-not reached] vs 7 9 months [95% CI, 4 7-12] before-COVID In NSCLC, the 30-days mortality was 49% vs 25% before-COVID;in SCLC, it was 32% vs 18% before-COVID Updated data and treatment outcomes will be presented in the meeting [Formula presented] Conclusion: Lung cancer diagnosis has been affected during the COVID-19 pandemic with fewer cases diagnosed and more symptomatic disease compared to 2019, which seems to be associated with worse outcomes This study is still ongoing Keywords: NSCLC, SCLC, COVID-19

We have previously identified six serum tumor markers (TMs) (carcinoembryonic antigen, carbohydrate antigen 15.3, squamous cell carcinoma-associated antigen, cytokeratin-19 fragment, neuron-specific enolase, and pro-gastrin-releasing peptide) related to the presence of lung cancer (LC).To validate their individual performance in an independent cohort, and to explore if their combined assessment (≥1 abnormal TM value) is a more accurate marker for LC presence.We determined these six TMs in 3,144 consecutive individuals referred to our institution by their primary care physician because of the clinical suspicion of LC.LC was excluded in 1,316 individuals and confirmed in 1,828 patients (1,563 with non-small cell LC and 265 with small cell LC). This study validated the previously reported performance of each individual TM. We also showed that their combined assessment (≥1 abnormal TM) had a better sensitivity, specificity, negative predictive value, and positive predictive value (88.5, 82, 83.7, and 87.3%, respectively) than each TM considered individually and that it increased the diagnostic performance (area under the curve) of a clinical model that included tumor size, age, and smoking status. In patients with radiographic nodules less than 3 cm, the negative predictive value of the TM panel was 71.8%, hence providing some support for a more conservative diagnostic approach. Finally we identified two TMs (neuron-specific enolase and pro-gastrin-releasing peptide) that differentiate the risk of non-small cell LC from that of small cell LC.The combined assessment of a panel of six serum TMs is a more accurate marker for LC presence than these same TMs considered individually. The potential of these TMs in the diagnostic and screening settings deserves further research.

Phlegmasia cerulea dolens (PCD) is a rare presentation of deep vein thrombosis (DVT) which clinically mimicks arterial ischemia and is caused by extensive thrombotic occlusion of the venous outflow of a major vein of an extremity. DVT is a common and potentially life-threatening complication in patients with lung cancer. We report the case of a patient who developed PCD in an upper limb while receiving anticoagulation treatment with low-molecular-weight heparin (LMWH) for recurrent venous thromboembolism (VTE) events at presentation of EML4-ALK translocated metastasic lung adenocarcinoma. Crizotinib therapy was associated not only with response of metastatic lesions but with a dramatic improvement of cancer-associated hypercoagulability. To our knowledge, this is the first case reporting PCD in an ALK-rearranged advanced NSCLC patient.

Background: NANCI is an intergenic long non-coding RNA (lncRNA) located in the genomic region of the NKX2-1 gene. It is essential for buffering NKX2-1 expression (also known as TTF-1), lung epithelial cell identity, and tissue homeostasis. To date, there is no prognostic information for NANCI or the NANCI-NKX2-1 duplex in non-small cell lung cancer (NSCLC). Methods: NANCI and NKX2-1 expression was assessed by TaqMan assays in paired tumor (TT) and normal tissue (NT) of 73 stage I NSCLC resected patients. The cohort was molecularly characterized including TP53, EGFR and KRAS mutational status. Results: NANCI expression was higher in TT (p Conclusion: In our cohort the NANCI-NKX2-1 is an independent OS marker in stage I NSCLC. Funding: AECC-Catalunya 2017

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%–84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r ¼ 0.91) with the ORR following antiPD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low ¼ 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Background New patterns of response to ICIs were recently described, including hyperprogressive disease (HPD) and pseudoprogression (PsPD). However, there is a lack of unanimous criteria about its definition. HPD predictors have not been identified. We aim to characterize predictive variables and related outcomes of patients (pts) treated with ICIs experiencing rapid tumor surge at our institution. Methods We performed a retrospective analysis of 210 pts treated with mono or dual ICI or ICI plus chemotherapy (CHT), from November 2013 to October 2018. Two CT scans before ICI and 1 CT scan while treatment was required and assessed according to RECIST 1.1. Tumor growth rate (TGR) at baseline, during ICI and its variation per month (ΔTGR) were calculated. HPD was defined as ΔTGR ≥ 2-fold. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method and compared between HPD and not HPD using the log-rank test. Results 187 pts were eligible, 23 pts died before tumor assessment. Mean age 63 (37-83), male 75%, performance status (PS) ≤1 88%. Non-small cell lung cancer (NSCLC) 62%, urothelial carcinoma 23% and kidney carcinoma 15%. Treated in phase3 31%. Two or more prior treatment lines (TL) 24%, ICI monotherapy 85% (nivolumab 49%, pembrolizumab 28%, atezolizumab 22%) and 11% combined with CHT. More than 3 metastatic sites 28%. At first evaluation 29 pts (15.5%) had progressive disease: 18 pts (10%) met HPD criteria; while 11 pts (6%) had ΔTGK Conclusions In our multitumor cohort, HPD occurs in 10% of pts treated with ICIs and is associated with worse OS, mostly in NSCLC. Further work is needed to better characterize this population. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure L. Ghiglione: Travel / Accommodation / Expenses: Kyowa Kirin; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Rovi; Travel / Accommodation / Expenses: Leo Pharma; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Lilly. C. Cabrera Galvez: Advisory / Consultancy: Pfyzer; Advisory / Consultancy: Roche ; Advisory / Consultancy: Boehringer ; Advisory / Consultancy: Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb. O. Reig: Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Ipsen. N. Vinolas: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Viphor Pharma; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Pierre Fabre. A. Prat: Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Nanostring Technology ; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Oncolytics Biotech ; Honoraria (self), Speaker Bureau / Expert testimony: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Puma ; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. B. Mellado: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb. N. Reguart: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche ; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AbbVie; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis ; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly ; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Aztra Zeneca ; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Guardiant Health ; Research grant / Funding (self): Instituto Carlos III ; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

Background NKX2–1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2–1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2–1: miR-365, which targets NKX2–1; and miR-33a, which is downstream of NKX2–1. We have examined the effect of NKX2–1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR. Methods mRNA and miRNA expression was determined using TaqMan assays in 110 early-stage NSCLC patients. TP53, KRAS, and EGFR mutations were assessed by Sanger sequencing. Results NKX2–1 expression was upregulated in never-smokers (P = 0.017), ADK (P

Background: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Patients and methods: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. Results: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had

The WORLD07 study characterizes lung cancer in Spanish women. This analysis investigated lung cancer features in never-smoking women. Of 2072 women recruited, 2035 were analyzed. Patient characteristics and demographics were similar for current/former smokers and never smokers. Among never smokers, 38.3% were exposed to passive smoking. Non-small-cell lung cancer was the most common type (78.8% of current/former smokers and 96.1% of never smokers) and adenocarcinoma the most common histology (69.1% and 83.4% respectively). There was a high incidence of lung cancer in Spanish never-smoking women and a high proportion (about 50%) had mutant epidermal growth factor receptor.

The WORLD07 project is a female specific database to assess the characteristics of women with lung cancer. WORLD07 database sets up in 2007, and prospectively stores clinical characteristics, treatment, outcome, and follow-up of lung cancer women. All women with epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) were selected for this analysis. From October 2007 to December 2012, a total of 1775 NSCLC women were recruited. EGFR mutation was identified in 34.4% of patients. Upfront EGFR tyrosine kinase inhibitor (TKI) reported a response rate of 60%, a median progression-free survival of 11.7 months, and median overall survival of 23.0 months. EGFR TKI, EGFR-mutation type, and smoking status did not impact in the outcome of treated women. Prevalence of EGFR mutation in women with NSCLC is higher than overall population with NSCLC. Efficacy of EGFR TKI in this real-world setting is similar to that previously reported.

Background Immunotherapy has become the main therapy in advanced NSCLC patients, but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described peripheral blood immune cells parameters as response biomarkers. In our study, we described the effect of neo-adjuvant chemo-immunotherapy treatment in Complete Blood Count (CBC) and Peripheral blood mononuclear cells phenotype, as well as, the association of these parameters with pathological response. Methods 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response: complete (pCR), mayor ( 10% viable tumour, pIR). Results Absolute numbers of Leucocytes, Eosinophil, Monocytes, Neutrophils, Haemoglobin and Platelets from hemograms were significantly reduced after treatment. However, no changes were observed for Lymphocytes, Basophils, LDH levels or the lung immune prognostic index (LIPI). Additionally, post-treatment neutrophil-to-lymphocyte (NLR), myeloid-to-lymphoid lineage (M:L) and platelets-to-lymphocytes (PLR) ratios were decreased. Remarkably, from all the CBC absolute numbers and ratios, only PLR variation showed differences between pCR and pIR. On the other hand, percentages of T cells, B cells, NK cells and macrophages did not vary after treatment, however activation of CD4 T cells and NK cells were significantly downregulated after treatment, associated to pCR. Also, PD-1 expression on T and NK cells pre-treatment was higher on pCR compared to pIR, reaching statistical significance only on CD4 T cells. Conclusions In our study, we described predictive biomarkers of response to treatment. A higher decrease on PLR post-treatment is associated to pIR. Moreover, higher expression of PD-1 pre-treatment in CD4 T cells, as well, as a reduced activation on CD4 T cells and NK cells, after treatment are associated to pCR. Clinical trial identification NCT 03081689; EudraCT 2016-003732-20. Legal entity responsible for the study Spanish Lung Cancer Group. Funding BMS. Disclosure M. Provencio: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Boehringer. All other authors have declared no conflicts of interest.

Background In resected non-small cell lung cancer (NSCLC) considerable recurrence rates has been reported (30%). Tumor secretes small extracellular vesicles known as exosomes, which plays a role in the metastasis process. Pulmonary tumor-draining vein blood has proved to be better source than peripheral vein to analyze the prognosis impact of exosomes (Navarro A, et al. Cancers 2019). LincRNA-p21 is a long non-coding RNA which upregulation in tumor tissue induced by hypoxia was related to poor prognosis in NSCLC (Castellano JJ. et al. JTO 2016). We aimed to evaluate the presence of lincRNA-p21 in exosomes and its potential as prognosis biomarker in resected NSCLC patients. Methods H23 and H1299 NSCLC cell lines were cultured in exosome-free medium 48h under normoxic/hypoxic conditions. LincRNA-p21 was inhibited using a siRNA and quantified using a TaqMan assay. Exosomes were purified by ultracentrifugation and characterized by electron microscopy, western blot and Nanosight. LincRNA-p21 was analyzed in exosomes from pulmonary tumor-draining vein, obtained during surgery, from 54 NSCLC patients. Results LincRNA-p21 was present in exosomes showing 18 times more representation than in their origin cells. Under hypoxic conditions exosomal lincRNA-p21 was upregulated in both cell lines (p Conclusions Tumor exosomes carry LincRNA-p21, which increases under hypoxia, and its analysis in tumor-draining vein arises as a promising prognosis marker. Legal entity responsible for the study The authors. Funding SAF2017-88606-P (AEI/FEDER, UE). Disclosure All authors have declared no conflicts of interest.

9098 Background: AXL is an RTK implicated in epithelial-to-mesenchymal transition and as a resistance mechanism to multiple therapies including anti-PD1. Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy in the pre-clinical setting. Methods: This is a Phase II single-arm, two-Stage study with bemcentinib (200mg/d) and pembrolizumab (200 mg/q3wk) for previously treated, IO naïve pts (n = 48 in total) with Stage IV lung adenocarcinoma. The primary endpoint was ORR according to RECIST 1.1 with pre-defined minimum requirement for 18% RR in the first Stage (n = 24) to proceed to Stage 2. Secondary endpoints included DCR, PFS, OS and safety. Tumour biopsies were analysed for PD-L1 (22C3 pharmDx), AXL, and infiltrating immune cells. Results: Stage 1 completed enrolment in Apr ‘18. As of Feb ‘19, 38 pts (24 and 14 in Stage 1 and 2, respectively) have been dosed with the combination; median age 66 (range 39-79) yr, 59% male, all previously received one prior line of platinum-based chemotherapy or a licensed EGFR/ALK-directed therapy. The most common TRAEs (occurring in > 15% of pts) were transaminase increases (37%), diarrhoea (29%), and asthenia (17%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments. At time of writing, Stage 1 had met the efficacy threshold to proceed to Stage 2 with continued enrolment. Among 29 pts evaluable for response 7 PRs were reported (24%). For AXL positive pts (10/21 with available biopsies), ORR was 40%. PD-L1 status was known for 5 responders: 4 pts (80%) were PD-L1 negative or weakly positive. In Stage 1, mPFS was 4.0 months (95% CI 1.9 – NR) and 5.9 months in AXL positive pts (n = 10; 3.0 - NR). mOS was not mature. Conclusions: Overall, bemcentinib in combination with pembrolizumab was well tolerated and promising clinical activity was seen, particularly in pts with AXL positive disease. Updated results will be reported at the meeting, incl 12-month OS for Stage 1 and preliminary efficacy of Stage 2. Clinical trial information: NCT03184571.

e20026 Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (< 10% viable tumour) and incomplete response (> 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.

8509 Background: Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months and complete pathologic response with conventional chemotherapy (CT) is no more than 9%. Methods: A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC adult patients with CT plus IO as a neoadjuvant treatment: three cycles of Nivolumab (NV) 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After complete neoadjuvant therapy, tumor assessment is performed prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present final data on all patients included in this study that underwent surgical assessment. Results: At the time of submission, 46 pts had been included and 41 had undergone surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts withdrew from the study preoperatively due to progression or toxicity. 41 surgeries had been performed and all tumors were deemed resectable, with R0 resection in all cases. 34 pts (83%) achieved major pathologic response (MPR) (CI 95% 71-95%), and 24 (71%) of them had a complete pathologic response (CPR) (CI 95% 54-87%). Downstaging was seen in 90% (CI 95% 81-100%) of cases. By RECIST, 29 pts (71%) (CI 95% 56-85%) had partial response and 3 (7%) (CI 95% 0-16%) complete response. Conclusions: This is the first multicentric study to CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a high complete pathologic response rate that has never been seen previously and unsuspected by RECIST criteria. Preliminary correlative analyses in blood samples are included in a separate abstract. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.

Lung cancer incidence is decreasing worldwide among men but rising among women due to recent changes in smoking patterns in both sexes. In Europe, the smoking epidemic has evolved different rates and times, and policy responses to it, vary substantially between countries. Differences in smoking prevalence are much more evident among European women reflecting the heterogeneity in cancer incidence rates. Other factors rather than smoking and linked to sex may increase women's susceptibility to lung cancer, such as genetic predisposition, exposure to sex hormones and molecular features, all of them linked to epidemiologic and clinical characteristics of lung cancer in women. However, biological bases of sex-specific differences are controversial and need further evaluation. This review focuses on the epidemiology and outcome concerning non-small cell lung cancer in women, with emphasis given to the Spanish population.

NKX2-1, a key molecule in lung development, is strongly expressed in lung cancer, especially in adenocarcinoma patients. Recently, two microRNAs interacting with NKX2-1 have been described: miR-365 that down-regulate NKX2-1; and miR-33a that is directly upregulated. To date, in non-small cell lung cancer (NSCLC) contradictory prognostic information about NKX2-1 and its microRNAs has been described. Aim: Elucidate the prognostic role of NKX2-1 and its microRNAs in resected NSCLC patients. Methods: mRNA and microRNA expression was determined using TaqMan assay in 142 NSCLC patients. The cohort was molecularly characterized including mutational status of TP53, EGFR and KRAS. Results: Locally advanced stages (III) had higher NKX2-1 expression than early stages (I-II) (p=0.002). High NKX2-1 expression was associated with longer disease-free survival (DFS) only in early stages (p=0.0389). Regarding to TP53 status, NKX2-1 was significantly downregulated in TP53-mutated patients (p=0.0087). Interestingly, TP53-WT patients with high expression of NKX2-1 had longer overall survival (OS) (p=0.0274) and longer DFS (p=0.00276). A negative correlation between NKX2-1 and miR-365 was found (r=-0.342, p Conclusions: In our cohort NKX2-1 impacts prognostic in early stage NSCLC particularly in patients without TP53 mutation, but no prognostic value was confirmed for its associated microRNAs. Supported by PFR Hospital Clinic de Barcelona, Becario SEPAR 2015, Mutual Medica 2015.

Anaplastic lymphoma receptor tyrosine kinase (Formalin-fixed, paraffin embedded (FFPE) samples from 108 patients with advanced NSCLC were analyzed with an nCounter-based assay and the results compared with FISH, IHC, and reverse transcription PCR (RT-PCR). Data on response to fusion kinase inhibitors was retrospectively collected in a subset of 29 patients.Of 108 FFPE samples, 98 were successfully analyzed by nCounter (91%), which identified 55 fusion-positive cases (32nCounter compares favorably with IHC and FISH and can be used for identifying patients with advanced NSCLC positive for