Background: The MAPK pathway is frequently activated in different cancers. Inhibitors of different molecules across this pathway have been developed and approved including BRAF, MEK, and ERK inhibitors. However, limited data are available regarding response in patients with upstream RAS alterations. The interplay between RAS and downstream RAF/MEK/ERK has been commonly noted; although distinct conclusions have been debated. In this study, we aimed to explore possible associations between RAS status and therapeutic outcomes to RAF/MEK/ERK inhibition in patients with advanced solid tumors. Methods: We used MD Anderson Cancer Center (MDACC) CHIMERA platform to extract data of patients with advanced solid tumors who were treated with investigational protocols including RAF, MEK, and/or ERK inhibitors in the department of investigational cancer therapeutics at MDACC as part of early phase-clinical trials. We included only patients who had molecular testing annotated by MD Anderson Precision Oncology Decision Support (PODSS) team. Patients who did not complete 30 days of therapy and those who were unevaluable for response were excluded from analysis. Treatment given at cycle 1 day 1 was manually checked to exclude patients who received other drugs in combination protocols that are not inclusive of RAF, MEK, and/or ERK inhibitors, patients who received non-selective RAF, MEK, and/or ERK inhibitors, and patients who received RAS inhibitors. Results: We included 219 patients (107 males and 112 females) who received treatment with investigational RAF, MEK, and/or ERK inhibitors. The majority of patients (58%, n=127) had RAS wild type status. Patients without RAS mutations had higher response rate compared to patients with RAS alterations (18.1% vs 2.2%, p<0.001) (Table). Disease control rate (PR or SD) was also higher in patients with RAS wild-type status compared to patients with RAS alterations (70.1% vs 52.2%, p=0.007). Additionally, progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS) were significantly longer in patients without RAS mutations (median PFS 18 weeks vs 9 weeks, p<0.001; median TTF 19 weeks vs 10 weeks, p<0.001; and median OS 58 weeks vs 42 weeks, p=0.027). Conclusions: RAS alterations are associated with lower efficacy of RAF/MEK/ERK inhibitors. This can be further validated while controlling for potential confounding factors in multivariable analysis. Additional studies are needed to investigate if RAS mutations might confer inherent resistance to treatment with RAF/MEK/ERK inhibition.