P1.01-59 Expanding Access to Large-Scale Genomic Mutational Analyses for Patients with Advanced NSCLC in Italy

In NSCLC, large-scale mutational analysis facilitates access to targeted treatments but is still not routinely employed due to significant technological barriers. The Alleanza Contro il Cancro (ACC) network of Italian Cancer Centers developed an affordable targeted sequencing panel for the identification of multiple genetic alterations with potential clinical utility, and designed a prospective multicentric trial to recruit 1000 newly diagnosed advanced NSCLC patients, aiming to i) compare panel performance against a set of externally validated biomarkers, including alterations in standard-of-care (EGFR, ROS1 and ALK) and non-standard-of-care (KRAS, BRAF, MET) biomarkers; ii) identify alterations in a large dataset of driver and potentially actionable genes; iii) correlate genotypes to survival outcomes and toxicity; iv) carry out ancillary studies on additional biomarkers and/or on specific patient groups (e.g. mutational burden, cfDNA, extensive characterization of immunotherapy-treated patients); v) build a centralized data repository for mutation interpretation and clinical recommendation. Through systematic literature mining and ad-hoc developed bioinformatic pipelines we identified: i) a set of 164 potentially actionable genes in solid tumors; ii) additional 18 genes with predicted driver function in NSCLC; iii) 70 actionable fusion transcripts; iii) 141 SNPs associated with pharmacogenomics markers. We designed a custom enrichment panel (∼800 kb target) and compared PCR- and hybridization-based enrichment on semiconductor or by-synthesis sequencing to be subsequently deployed in a large observational trial. Sequencing is decentralized, to allow rapid turnaround time, but raw and processed data are collected in a single informatic infrastructure for centralized quality control and continuous bioinformatic pipeline improvement. PCR/semiconductor sequencing was selected for deployment based on cost and feasibility (2-day, highly automated workflow). 182 patients have been enrolled to date (90% stage IV, 10% IIIB). Of 65 patients with treatment information available, 28 (43%) subsequently received immunotherapy and 13 (20%) targeted therapy. For 56 patients with complete sequencing data, EGFR and KRAS status was concordant in 9/10 and 38/41 cases; discordant cases are being validated with orthogonal methods. Clinically significant MET amplifications were called in 2/2 cases. Remaining target regions did not show pathogenic alterations. Multiple alterations in potentially actionable genes were identified. Large-scale sequencing is reliable, feasible and sustainable across multiple hospitals and provides clinically relevant results. The increased availability of genomic information may result in enhanced access to tailored therapies. Data and sample integration in centralized, shared repositories will allow multiple ancillary studies.