While precision medicine is increasingly available, the first trials produced disappointing results, partly due to limitations of molecular profiling to mutational analyses. Here, we report a monocentric real-life experience of an integrative and interactive approach using a dedicated genomic platform for metastatic cancer patients in a situation of therapeutic failure. From October 2020 to May 2024, 1049 patients with cancers in a situation of treatment failure have been prospectively enrolled in the national program “France Médecine Génomique 2025”, 73 patients from Avicenne Hospital. Data from 20 patients with hepatocellular carcinoma were previously reported. We report here data from 27 among the remaining patients. For each patient, Sequencing Omics Information Analysis platform performed tumor and germline whole-genome, whole-exome sequencing, and RNAseq to receive tailored treatments. Tumor responses and survival data were systematically collected. Twenty-seven patients with locally advanced or metastatic cancers from twenty histological types received 32 treatment lines, 37.5% being ESCAT-I/II (high-proof efficacy level). 40% of lines were guided in part by transcriptomic analyses. Median treatment duration was 15.6 months, and median survival was not linked to ESCAT category. SeqOIA-tailored treatment outperformed previous lines, with a Growth Modulation Index≥ 1.33 for 70% of the patients. 69% of treatment lines were combined therapies, showing greater clinical benefit (86% vs. 54%, P   <  0.01) and longer survival than monotherapies (15.8 vs. 13.9 months, HR=0.77, P  = 0.01). Our monocentric real-life experience of interactive multidisciplinary care based on integrative genomic analyses improved survival of metastatic cancer patients using off-label combined personalized therapies.