Abstract Background Activation of the mTOR pathway is associated with shorter overall survival (OS) in patients (p) with metastatic renal cell carcinoma (mRCC). This outcome could be reversed with mTOR inhibitors (mTORi). Methods We retrospectively analized by amplicon-seq mutations in mTOR, VEGF, and cell cycle pathways in 90 mRCC p who had received mTORi. A multivariate Cox model including sex, age, non-clear or sarcomatoide component, metastatic sites, IMDC subgroup, and line of mTORi was adjusted to isolate the effect of having mTORi mutations on progression-free survival (PFS), death form diagnosis (OS1) and death from mTORi treatment (OS2). Results We identified 33% of p having mutations in the mTOR pathway: mTOR (17.8%), PIK3CA (5.6%), PTEN (3.3%), TSC1 (5.6%) and TSC2 (4%). No mutations were found in AKT (AKT1, AKT2, AKT3). OS for favorable, intermediate and poor prognosis of the IMDC were 43.7, 22.2 and 8.7 months respectively. As summarized in the table, in the best adjusted model there were no statistically differences in the hazard ratios (HR) of PFS, OS1 or OS2, between patient with and without mutations (M/NotM). Four long-term responders to mTORi (> 7 years) harboured mutations in one or more genes of this pathway (p53, PTEN and mTOR). Upon progression one patient adquired an LRPB1 mutation. Table:975PAdjusted HR (Cox)PFSOS1OS 2M/NoM1.121.021.1895% CI0.67 – 1.890.61 – 1.690.63 – 2.21p0.6600.9460.607 Conclusions In a multivariate adjusted model in patients with mRCC treated with mTORi, we did not find the expected worse prognosis associated with mTOR mutations. This finding can be considered as an indirect signal of the effect of mTORi on PFS and OS in patients with mTOR mutations. Although, not the most effective treatment in the overall population, some patients with specific alterations in the mTOR pathway should be considered for an mTORi. Legal entity responsible for the study Vall d´Hebron Institute of Oncology. Funding Has not received any funding. Disclosure C. Suarez Rodriguez: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy: Eusa; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Sanofi-Aventis; Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution): Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Research grant / Funding (institution):, F. Hoffmann-La Roche LTD; Research grant / Funding (institution): Genentech INC; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Research grant / Funding (institution): Karyopharm Therapeutics INC; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Nanobiotix SA. J.A. Arranz Arija: Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pierre-Fabre; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen-Cilag. R. Morales Barrera: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Arog Pharmaceuticals, INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas Pharma.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A.; Research grant / Funding (institution): Bristol-Myers Squibb International Corporation (BMS); Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology, INC,; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: F. Hoffmann-La Roche LTD/Genentech,; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Advisory / Consultancy: Johnson and Johnson; Research grant / Funding (institution): Karyopharm Therapeutics INC.,; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Medimmune, Millennium Pharmaceuticals, INC.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: MSD; Research grant / Funding (institution): Nanobiotix SA,; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Puma Biotechnology; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi-Aventis; Research grant / Funding (institution): Pharma LTD; Research grant / Funding (institution): Teva Pharma S.L.U.; Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma. J. Puente: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eusa; Advisory / Consultancy: Sanofi-Aventis; Speaker Bureau / Expert testimony: Pierre-Fabre; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Kiowa; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Lilly. O. Reig: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Pfizer. L. Faez: Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Pfizer. A. González del Alba: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eusa; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: MSD. B. P. Valderrama: Honoraria (self), Advisory / Consultancy: Pierre-Fabre; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self): Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi-Aventis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Janssen-Cilag; Travel / Accommodation / Expenses: Pfizer. E. Gallardo: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommo