Background: CRAF is a key mediator of oncogenic mitogen-activated protein kinase (MAPK) pathway reactivation following MEK or BRAF inhibition. LXH254 is a BRAF and CRAF inhibitor with antitumor activity in MAPK-driven tumor models. This Phase I dose-finding study of LXH254 in pts with advanced solid tumors harboring MAPK pathway alterations is evaluating safety/tolerability and preliminary antitumor activity (NCT02607813). Methods: Primary objective: characterize the safety/tolerability of single-agent LXH254 and identify a recommended dose (RD)/schedule for future study. Secondary objectives: characterize antitumor activity (per RECIST 1.1) and PK. Dose escalation was guided by a Bayesian model-based approach. Eligible pts had advanced, pretreated solid tumors with MAPK pathway alterations. Results: At data cut-off 4 Dec 2017, 75 pts were enrolled in 9 dose cohorts: 100 (n = 4), 200 (n = 4), 300 (n = 5), 400 (n = 6), 800 (n = 12), 1200 mg QD (n = 12), and 200 (n = 7), 400 (n = 12), 600 mg BID (n = 13). Pts (ECOG PS 0/1, 41% male, median age 57 yrs) had lung (n = 16), colorectal (n = 14), ovarian (n = 12), melanoma (n = 12), or other (n = 21) cancers. Median duration of exposure was 7.7 wks; 59/75 (79%) pts discontinued treatment, due to disease progression (49 pts [65%]), physician/pt decision (5 pts [7%]), death (3 pts [4%]), or AE (2 pts [3%]). Three DLTs were reported: platelet count decrease (Gr 4, 1 pt 1200 mg QD), pruritus and maculopapular rash (both Gr 3, 1 pt 600 mg BID). The most common ( > 15%) drug-related, any-Gr AEs were rash (dermatitis acneiform/rash/maculopapular rash, 53%), fatigue (20%), and nausea (20%). Gr ≥3 drug-related AEs occurred in 16% of pts, most frequently rash, myalgia, and increased lipase (2 [3%] pts each). Plasma peak drug concentration (C_max) and exposure (AUC) after QD/BID oral doses increased approximately dose-proportionally. There were two confirmed partial responses (with > 50% tumor size reduction) in pts with KRAS-mut and BRAF-mut cancers; stable disease was reported in 25/75 (33%) pts. Conclusions: Oral LXH254 was well tolerated, all AEs were manageable, and preliminary antitumor activity was observed. The study is ongoing to establish a RD/schedule, and further establish antitumor activity. Clinical trial information: NCT02607813