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Immunotherapy; Lung neoplasms; Tumor biomarkers Immunoteràpia; Càncer de pulmó; Biomarcadors tumorals Inmunoterapia; Cáncer de pulmón; Biomarcadores tumorales Background Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive. Patients and methods We assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). Results High SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10−5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort. Conclusions SCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs. This work was supported by Merck Healthcare KGaA, Darmstadt, Germany (Grant for Oncology Innovation to the Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain), Fundación Cientifica Asociación Española Contra el Cancer-AECC (grant number GCB14142170 to EF); the Catalan Government/AGAUR (2017–SGR–1738 to EF). Merck Healthcare KGaA reviewed the manuscript for medical accuracy only before journal submission.

8561 Background: MPM is an aggressive malignancy without curative treatment. ONCOS-102 is an oncolytic adenovirus expressing GM-CSF (Ad5/3-D24-GMCSF) with a clinically documented ability to stimulate local and systemic immune responses and re-modulate the tumor microenvironment, both as a monotherapy and in combination with anti-PD1 blockade. The study objectives included determining safety and tolerability, efficacy and immunological activation in repeat tumor biopsies, and correlations with clinical outcomes. Methods: Following a safety run-in of n = 6 pts, 25 patients were randomized to receive ONCOS-102 intratumorally under CT or US guidance at a dose of 3 x 1011 Virus Particles on Day 1, 4, 8, 36, 78 and 120, plus six cycles of P/C starting on Day 22, or control comprising six cycles of P/C only. Both treatment-naïve (1L) and previously treated patients (2L) were enrolled. Imaging was done at baseline, Day 43-64 and 127-148 and tumor biopsy were collected at baseline and at Day 36. Final survival analysis (n = 25) was performed after 30 mo follow up. Multiplex immunofluorescence for immune cell subsets, RNASeq and qPCR was performed on repeat tumor samples. Results: The most frequent adverse events were anaemia, neutropenia and asthenia reported by > 50% in both groups with more frequent reports of pyrexia and nausea in the experimental (exp) group. No difference in the rate of severe events (Gr 3/4 acc to NCI CTCAE vs 4.0) were observed. 30-month survival rate (n = 25) was 34.3 % vs 18.2 % (NS) with mOS of 19.3 mo (95% CI: 4.6, NA) vs 18.3 mo (95% CI: 3.1, 28.9) in the exp group vs control. For patients treated in the 1L setting, 30 mo survival was 33.3 % in the exp group (n = 8) and 0% in the control group (n = 6) with mOS of 25.0 months and 13.5 months, respectively (NS). mPFS was unchanged from prior cut-offs; 9.8 months in the exp group and 7.6 in the control (NS). ONCOS-102 + P/C induced a pronounced increase in tumor infiltration by CD4+, CD8+ and granzyme B expressing CD8+ T-cells as well as M1:M2 macrophage polarization in patients with disease control (n = 13) vs progressing patients (n = 3). The data from RNAseq and qPCR analysis will be presented. Conclusions: The addition of ONCOS-102 to P/C was well tolerated by MPM patients and resulted in numerically improved 30-month survival rate in the overall population, and improved mOS in chemotherapy-naïve patients, albeit not statistically significant. Substantial immunological activation in tumor associated with ONCOS-102 was demonstrated, correlating with clinical benefit. Further exploration of ONCOS-102 as a treatment option in MPM is warranted Clinical trial information: NCT02879669.

e20595 Background: MPM is an aggressive cancer associated with asbestos exposure. Chemotherapy has been a mainstay of therapy and recently immunotherapy has been associated with survival improvements. Chemotherapy and immunotherapy influence the tumor microenvironment and some reports have shown increased of TIL after chemotherapy in MPM. The purpose of this study was to determine dynamic changes in the tumor immune environment during mesothelioma evolution and after systemic therapies in paired samples. Methods: We examined 20 matched formalin-fixed paraffin embedded tissue samples from 10 patients (p) with MPM taken at diagnosis and at disease progression (follow-up), including untreated and treated with chemotherapy or immunotherapy. Tissue densities (number of cells/mm2) of key immune effector cells such as total lymphocytes (CD3), cytotoxic T cells (CD8), regulatory T cells (FOXP3) and monocytes/macrophages (CD163) were quantified by image analysis using multiplexed immunohistochemistry (IHC). PD-L1 expression in both tumor cells and immune cells was analysed by singleplex IHC and quantified using the CPS score. Results: Median age was 62 years (range 53-84), 7 p were male and all p presented epithelioid histology. Three matched samples belong to patients that did not receive any systemic treatment between biopsies and the other 7 pair of samples belong to patients treated with chemotherapy +/- immunotherapy. The median interval between paired biopsies was 12 m (3-33 m). Median overall survival was 27.8 months (1 m-NR). Median densities of T cells and macrophages in diagnostic and matched follow-up samples were: CD3+:982 vs 712; CD8+:422 vs 334, FOXP3+: 22 vs 25 and CD163+: 2086 vs 1706. Median PD-L1 CPS was 2.5 and 4 in diagnostic and follow-up samples, respectively. In p receiving treatment between sample pairs, the median densities in diagnostic and follow-up matched samples were: CD3+:979 vs 407; CD8+:467 vs 225, FOXP3+: 25 vs 15, CD163+: 1583 vs 1508, and PD-L1: 2 and 1. In p without any systemic treatment between sample pairs, the median densities were CD3+:1645 vs 2397; CD8+:376 vs 1605, FOXP3+: 19 vs 121, CD163+: 2102 vs 2377, and PD-L1: 3 vs 25. Conclusions: In our small series with paired samples from MPM p, we observed immune cells infiltration changes during MPM evolution with a trend towards a decrease after systemic therapy. Further investigation in tumor microenvironment in MPM to define the most appropriate time for immunotherapy is needed.