Genomic mutational landscape of solid tumors: Preliminary results from ROME trial

The Rome trial is a randomized phase II trial (NCT04591431). The aim is to evaluate the feasibility on large scale and the clinical utility of a tailored treatment (TT) in patients (pts) compared to standard of care (SoC) with solid tumors. Here we report the preliminary results of the molecular alterations detected during the screening phase. Centralized NGS was performed on both tumor tissue, collected within 6 months, and liquid biopsy from pts with refractory malignancies. Molecular alterations were evaluated by Molecular Tumor Board (MTB) using COSMIC, ClinVar, OncoKB and VarSome datasets. All pts with actionable genomic alterations were weekly discussed by the MTB. Genes with at least 10% frequency of mutation, microsatellite status (MS) and tumor mutational burden (TMB) were collected. From Oct 2020 to Apr 2022, 792 pts were enrolled from 40 italian hospitals. To date, we have complete mutational data of 482 patients. Molecular profiling was available both on tissue and liquid biopsy in 414 (86%) pts, while 13 and 53 had only tissue or liquid test available. 3138 genomic alterations were identified in 258 genes with a median of 7.9 alterations (0-35). The most frequent altered genes were: TP53 (57%), PIK3CA (21%), KRAS (28%), DNMT3A (22%), CDKN2A (19%), APC (16%), PTEN (12%), ARID1A (12%), ERBB2 (11%), NRAS (11%), ATM (10%), TET2 (11%). The most frequent altered pathways were TP53 (57%), RAS/RAF (47%), Cell cycle/cycline (38%), PI3KCA/AKT/MTOR (28%), Homologous Recombination system (20%). The most common actionable alterations with TT available in the ROME trial were: PIK3CA/AKT (24%), H-TMB/MSI (17%), FGFR1/2/3 (9%), EGFR (9%), BRAF V600/nonV600 (6%), JAK 1/2/3 (3%), NTRK1-3/ROS1 (2%), RET (2%), PTCH1 (1.5%), ALK (1%).17 pts were MSI (3.5%). Overall median TMB was 9.7 (0-458) while median TMB for MSS and MSI pts were 5.9 (0-35) and 96.0 (24-458), respectively. MSS pts with a TMB >10 mut/mb were 65 (13.5%). Actionable mutations were detected in 202 pts (43%) and 130 (27%) were randomized in the trial after the MTB discussion. ROME trial demonstrates the feasibility of extensive molecular profiling and discussion in MTB. Almost 30% of pts had molecular alterations for which a target strategy was available in the trial.