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e20693 Background: Immune checkpoint inhibitors (ICIs) have revoluzionized the therapeutic paradigm for different types of cancer including NSCLC. Clinical benefit, however, is limited to a minority of patients. The only adopted predictive biomarker, PD-L1 IHC testing, suffers from some limitations. A better understanding of biomarkers associated with response to ICIs is needed. Here, we studied immune gene expression profile and association with clinical response to immunotherapy in advanced NSCLC patients (pts) treated with ICI. Methods: A total of 37 Formalin-fixed, paraffin-embedded (FFPE) samples from advanced NSCLCs were analyzed by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) (ThermoFisher Scientific) to measure the expression level of 395 genes associated with 36 functional groups including checkpoint pathways, lymphocyte regulation and cytokine interactions, using the Ion Chef and Ion Torrent PGM. Gene level differential expression analysis were performed with the Torrent Suite and Transcriptome Analysis Console (TAC) 4.0 Software. Gene network analysis based on Bayesian algorithm was performed by GeneMANIA database querying with the genes selected through mRNA expression analysis. Results: Among 37 FFPE samples only 18 showed more than 300 OIRRA detectable target genes. In this subgroup, gene expression analysis revealed 7 genes (CCR2, CRTAM, FASLG, SELL, TIGIT, TNFRSF4, and TP63) up-regulated and one gene (CXCL8) down-regulated (p-value < 0.05) in ICI-responders compare to ICI-no responders. Bayesian enrichment computational analysis of the eight gene expression signature showed a more complex network which involves other 10 genes (SIRPG, GZMK, XCL2, CD8A, CD2, IFNG, SIT1, TAGAP, PTPRC and GZMH), correlated with different functional groups. Three main immune-pathways were identified (p < 0.01) (T cell activation, leucocyte activation and migration) involving TIGIT, TNFRSF4, CCR2 and CXCL8 genes among the gene expression signature identified. Conclusions: Our results revealed an immune response gene expression signature of 8 genes differentially expressed between ICI and ICI-no responders. Cancer systems biology analysis approach strengthen our findings identifying an immune molecular network and confirm the correlation of the gene expression signature with relevant immune regulatory functions. If validated, our results may have an important role for the development of a robust test to select patients properly and predict immune response to enable precision immunotherapy.

e14057Background: About 21-62% of GBM patients (pts) access to 3rd line therapy. In this setting, there is no defined standard. In this study we evaluated the outcome of pts who received 3rd line t...

2040Background: Low grade gliomas (LGG) are a heterogeneous group of brain primary tumors. The EORTC and the RTOG criteria are the most valuable scores to evaluate risk factors and for treatment de...

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of advanced non-small cell lung cancers (NSCLCs) that harbour specific EGFR activating mutations. However, the efficacy of an EGFR-TKI is limited by the onset of acquired resistance, usually within one year, in virtually all treated patients. Moreover, a small percentage of EGFR-mutant NSCLCs do not respond to an EGFR-TKI, thus displaying primary resistance. At the present time, several mechanisms of either primary and acquired resistance have been elucidated, and new drugs are currently under preclinical and clinical development in order to overcome resistance to treatment. Nevertheless, there still remains much to be thoroughly investigated, as so far research has mainly focused on the role of proteincoding genes involved in resistance to EGFR-TKIs. On the other hand, in line with the data underscoring the relevance of non-coding RNAs in the pathogenesis of lung cancer and modulation of response to systemic therapies, microRNAs (miRNAs) have been supposed to play an important role in resistance to EGFR-TKIs. The aim of this review is to briefly summarise the existing relationship between miRNAs and resistance to EGFR-TKIs, and also focusing on the possible clinical applications of miRNAs in reverting and overcoming such resistance.

e18023 Background: Treatment with a reversible EGFR-TKI may benefit pts with EGFR WT advanced NSCLC, though to a much lesser extent than pts carrying an activating mutation in the EGFR gene. We assessed whether KRAS mutational status would help predict sensitivity to gefitinib or erlotinib in EGFR WT advanced NSCLC pts. Methods: Sixty-seven EGFR WT, advanced NSCLC pts treated with a reversible EGFR-TKI in any line setting were included. Pts were treated from May 2005 to March 2011 at the Medical Oncology of the Perugia Hospital. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results: Median age was 60 years (39-84); 52 pts (77.6%) were PS 0 or 1; 58 pts (86.6%) belonged to the non-squamous subtype and 22 pts (32.8%) were never-smokers. Eighteen pts (26.8%) were KRAS mutant (MUT), of which 14 pts at codon 12 (COD 12 MUT) and 4 pts at codon 13 (COD 13 MUT). Overall, 11 pts (16.4%) responded to treatment and 8 pts (11.9%) achieved stable disease, for a disease control rate of 28.3%. At a median follow-up of 25.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.9 and 29.5 months, respectively. When analyzed according to KRAS status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (N=18) compared with the EGFR WT/KRAS WT population (N=49) (1.6 vs. 3.0 months, respectively, p=0.04). However, no significant difference was observed between the two groups in terms of OS (18.0 vs. 34.8 months, respectively, p=0.42). Within the EGFR WT/KRAS MUT subrgoup a significantly longer PFS was reported for COD 12 MUT pts compared with COD 13 MUT pts (1.7 vs 0.7 months, respectively, p=0.04). Similarly, KRAS COD 12 MUT pts experienced a statistically significant superior OS compared with COD 13 MUT pts (36.2 vs 7.4 months, respectively, p=0.003). Conclusions: EGFR WT/KRAS MUT pts appear to be more resistant to treatment with a reversible EGFR-TKI, the greatest resistance occurring in COD 13 MUT pts. KRAS COD 12 MUT pts may represent a clinically distinct subgroup of KRAS mutants with a particularly favorable prognosis.

e19054 Background: Identification of oncogenic drivers has dramatically changed current therapeutic strategies for lung cancer, initiating the era of personalized therapy. "Pan-negative" NS non-sma...

e18101 Background: All mutated non-small cell lung cancer (NSCLC) patients (pts) previously treated with an EGFR reversibile inhibitor, develop, soon or later, resistance. Afatinib is a potent irreversible HER family inhibitor, with preclinical data suggesting activity against the resistance mutation EGFR T790M. From August 2005 to January 2011, in a retrospective observational study at our Division of Medical Oncology, we have evaluated 22 advanced NSCLC pts, who have been treated with Afatinib, after disease progression with Erlotinib or Gefitinib. Methods: 22 advanced NSCLC pts who have previously received a reversible EGFR-TKI (gefitinib or erlotinib), and subsequently have been treated with Afatinib in a different setting of their medical history, were included in the analysis. Afatinib was provided in an expanded access program by Boehringer. Results: Patients characteristics: median age 64 ys (34-85); PS 0-1; most of pts were never smokers (82%) with non-squamous histology. 12 pts (54%) had multi-metastatic sites at diagnosis, 4 of which (33%) had brain lesions. Nineteen pts (86%) were found to be EGFR mutated (15 patients with EGFR-sensitizing mutations at exon 19 and 21). No one was K-RAS mutated. Eighteen pts (82%) received Afatinib in a second line TKI setting and 4 pts (18%) in a third line. Overall, 4 pts (18%), 2 of which had a multi-metastatic disease at diagnosis, had a partial response to Afatinib and 11 pts (50%) achieved a stable disease. Of the 16 pts evaluable for response in the second line setting, median progression-free survival (PFS) was 5,2 months. Diarrhea and skin rash were the most common adverse events but a dose-limiting toxicity was observed in only three patients. Conclusions: Our experience confirmed Afatinib clinical activity in patients with acquired resistance to prior reversible TKI. The treatment has been well tolerated and there were no new or unexpected safety findings.

Background In this retrospective analysis we assessed whether KRAS mutation would affect the clinical outcome of EGFR WT advanced NSCLC pts treated with a first-line platinum-based chemotherapy. Moreover, the effect of specific mutant KRAS was evaluated. Methods One hundred and ninety-five EGFR WT, advanced NSCLC pts were included in the analysis. Study pts were treated at the Medical Oncology of the Perugia Hospital from Jan 2005 to March 2012. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results Median age was 60 years (29-81); 181 pts (92.8%) were PS 0 or 1; 155 pts (79.4%) belonged to the non-squamous subtype and 39 pts (20.0%) were never-smokers. Treatment was as follows: platinum + a third generation agent in 103 pts (52.8%); platinum + pemetrexed in 81 pts (41.6%); platinum-based doublet + bevacizumab in 11 pts (5.6%). Seventy-five pts (38.4%) were KRAS mutant (MUT), of which 60 pts at codon 12 (COD 12 MUT), 12 pts at codon 13 (COD 13 MUT) and 3 pts at codon 61 (COD 61 MUT). The most common amino acid changes found were: Gly12Cys (29 pts), Gly12Val (11 pts) and Gly13Cys (10 pts). In the whole study population, 69 pts (35.3%) responded to treatment and 62 pts (31.7%) achieved stable disease, for a disease control rate of 67.0%. At a median follow-up of 14 months (2-102), median progression-free survival (PFS) and overall survival (OS) were 6.2 and 21.6 months, respectively. When analyzed according to KRAS mutation status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (n = 75) compared with the EGFR WT/KRAS WT population (n = 120) [5.1 vs 6.6 months, respectively, P = 0.02; HR = 1.43 (95% CI, 1.05 to 1.95)]. Similarly, a significant difference was observed between the two groups in terms of OS [13.7 vs 26.1 months, respectively, P = 0.02; HR = 1.56 (95% CI, 1.06 to 2.30)]. In the EGFR WT/KRAS MUT subrgoup, OS for COD 12 MUT, COD 13 MUT and COD 61 MUT was 17.2, 10.2 and 8.0 months, respectively, P = 0.17. Multivariate analysis for PFS and OS confirmed that KRAS mutation was an independent predictor of poorer oucome. Conclusions EGFR WT/KRAS MUT pts appear to experience a less favorable prognosis compared with the EGFR WT/KRAS WT genotype, with a significant difference in clinical outcome according to the mutant codon of KRAS. Disclosure All authors have declared no conflicts of interest.