Background: The Rome Trial is a randomized, prospective, multicenter, multi-basket, Phase II clinical trial (EudraCT n° 2018-002190-21; NCT04591431). The aim is to evaluate the efficacy of Tailored Therapy (TT) vs Standard of Care (SoC) in patients (pts) with metastatic solid tumors who received at least one and no more than two lines of treatment. Pts with a molecular alteration were discussed in a Molecular Tumor Board (MTB), assigned to one or a combination of the 20 available treatments, and randomized to TT or SoC. Methods: Tissue (collected within 6 months) and blood samples from pts with refractory solid tumors were analyzed centrally with next generation sequencing (NGS, FoundationOneCDx and FoundationOneLiquid). MTB discussed all screened pts with any actionable genomic alterations using common mutational database and ESCAT. Genomic data, MTB reports and treatment outcomes were collected. The 3 outcomes of the MTB were: A) assignment of a TT and randomization, B) screening failure (SF) C) SF for the trial but with relevant information from the genomic test. Outcome C was divided into 3 groups: 1) indication to receive a personalized standard treatment different from the planned one, 2) indication to access to another clinical trial/compassionate use/expanded access, 3) indication to perform a germline test (GT). Results: From Oct 2020 to Dec 2021, 497 pts were enrolled in 38 Italian accrual sites, 303 (61.0%) had relevant genomic alterations and were discussed to the MTB. Molecular profiling was determined both on tissue and liquid biopsy in 262/303 (86.5%) pts, while in 11 (3.5%) and 30 (10.0%) only on tissue or liquid, respectively. After applying clinical and molecular exclusion criteria and considering multiple actionable or resistance-conferring mutations (detected in 95 and 70 out of 303 patients): 135 pts (45%) were randomized (outcome A), 19 (30%) were SF (outcome B), and 78 (25%) SF but with an additional indication (outcome C). Of them, 14 patients (18%) were group 1 and 42 (54%) had indication to a target therapy outside from the trial (group 2). MTB suggested a GT to 60/303 pts (20%, group 3). To date, 8 out of 9 GT performed confirmed a germline mutation (4 BRCA1/2, 2 PALB2, 1 MUTHY, 1 ATM). Finally, 213 pts, 71% of those discussed to MTB and 43% of the entire screened population, were randomized or received at least one specific indication following the extended molecular assessment with NGS. Conclusions: We demonstrated the feasibility of screening a large numbers of pts from numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse to investigate combination targeted-therapy regimens. The Rome trial MTB, even when no actionable alterations were detected, provided a therapeutic and diagnostic indication with a potential impact on patient’s outcomes. Clinical trial information: NCT04591431.