Epidermal growth factor receptor (EGFR)-mutation-positive non-small cell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p = 0.0407) and overall survival (hazard ratio of 2.23, p = 0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.

11504 Background: PD-L1 can be induced by oncogenic signals or up-regulated via INFG in a STAT1- and NFκB-dependent manner. STAT3 opposes STAT1-mediated anti-tumor immune responses. I kappa B kinase epsilon (IKBKE) is an interferon signaling inducer. We explored whether INFG expression in pre-treatment tumors is associated with to the efficacy of ICB in NSCLC and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE and STAT1 was also examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1 and PD-L1 mRNA were examined. PD-L1 protein expression in tumor and immune cells was evaluated (Ventana SP142 assay). Progression free survival (PFS) and overall survival (OS) were estimated. Results: 17 previously treated NSCLC patients received nivolumab; 71% lung adenocarcinoma, 71% male, 53% smokers, 35% KRAS mutant, 88% EGFR wild-type (wt). 21 previously treated melanoma patients received pembrolizumab; 67% male, 67% BRAF wt. PFS to nivolumab was significantly longer in NSCLC patients with high vs. low INFG expression (5.12 vs. 2mo, p = 0.0124). PFS to pembrolizumab was significantly longer in melanoma patients with high vs. low INFG expression (4.99 vs. 1.86mo, p = 0.0099). Significantly longer OS was observed for melanoma patients with high vs. low INFG expression (not reached vs. 3.10mo p = 0.0183). There was a trend for longer OS for NSCLC patients with high vs. low INFG expression (10.15 vs. 4.86mo, p = 0.0687). The other gene levels and PD-L1 protein levels in tumor and immune cells did not affect the outcome to ICB. IKBKE was positively correlated with INFG and PD-L1 expression (NSCLC Spearman’s ρ = 0.58 and 0.65; melanoma Spearman’s ρ = 0.61 and 0.59), and STAT3 expression was loosely anticorrelated with PD-L1 expression (NSCLC Spearman’s ρ = −0.21; melanoma Pearson’s ρ = −0.01). Conclusions: INFG is an important marker for qRT-PCR mediated prediction of response to ICB in NSCLC and melanoma patients. Further research is warranted in order to validate that INFG is more accurate than PD-L1.

Introduction: Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656). Methods:The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatindocetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response.Results: In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio ¼ 0.63, 95% confidence interval: 0.42-0.83, p ¼ 0.0080). PALB2 was also predictive of overall survival (hazard ratio ¼ 0.68, 95% confidence interval: 0.42-0.90, p ¼ 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive

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e14521 Background: Thestandard treatment for biliary tract cancer is gemcitabine plus platinum, but median progression-free survival (PFS) is only 5-8 months (m) (Valle et al, NEJM 2010). Gene expression or somatic mutations may influence the clinical phenotype, which will affect decisions on individualized treatment. Methods: We retrospectively analyzed tissue blocks from 54 advanced or metastatic cholangiocarcinoma, gallbladder or ampulllary cancer patients (p) treated with single-agent gemcitabine or gemcitabine plus carboplatin or cisplatin. Using RT-PCR, we analyzed the mRNA expression levels of oncogenes, tumor suppressors and DNA repair genes (BRCA1, RRM1, AEG-1, RAP80, SPINK1 and FBXW7) and correlated results with PFS, overall survival (OS) and response. In addition, FBXW7 hotspot mutations were assessed. Results: p characteristics: 72% females; median age, 60 (40-87). Only FBXW7 expression correlated with PFS and OS. When FBXW7 levels were dichotomized at the median value, PFS was 4.2 m for p with low levels vs 12.6 m for p with high levels (p=0.02). When FBXW7 expression was divided by terciles, PFS was 4.9 m for p in the lowest tercile, 7.6 for p in the intermediate tercile, and 26.9 m for p in the highest tercile (p=0.08). OS was 6.2 m for p in the lowest tercile, 8 m for p in the intermediate tercile, and not reached for p in the highest tercile. No other significant correlation was observed between expression levels of the other genes examined and PFS or OS. Only AEG-1 expression correlated with response (p=0.05). No FBXW7 hotspot mutations were detected. Conclusions: Although we did not find the FBXW7 hotspot mutations previously described in biliary tract cancer, FBXW7 mRNA expression significantly influenced PFS and OS. A separate cohort of p is being analyzed to validate the prognostic role of FBXW7.