Background: Prior studies have demonstrated clinical benefit with rechallenging the RAF pathway in melanoma with prior exposure to BRAF inhibitors. Purpose of this study was to explore antitumor activity and outcomes of BRAF aberrated solid tumors retreated with RAF inhibitors (RAFi). Methods: Between January 2010 and November 2022, 44 pts with BRAF alterations [V600E (42); V600K (1); K601Q (1)] who received RAFi as monotherapy or in combination were rechallenged with a second RAFi with or without other therapies at a single tertiary cancer center. All received therapy as part of standard of care or investigational (INV) regimens. Primary objectives: objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) on rechallenge. Results: Median age: 54.5 (25-76) with predominantly Caucasian pts (36; 82%) and males (26; 59%). Tumor types: melanoma (16; 36%), colon (10; 23%), thyroid (4; 9%); brain (4; 9%) and others (10; 23%). Median treatment duration was 7 months (m) for first RAFi (RAF1i) and 2.8m with second RAFi (RAF2i) while median time to RAF2i was 3.3m. Best ORR to rechallenge with RAF2i was partial response (PR) (8; 18.1%), stable disease (SD) (16; 36%) and progressive disease (PD) (20; 45.4%) with 5 PR + 6 SD >6m. PRs were seen in thyroid (1 anaplastic; 2 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma and 1 anaplastic astrocytoma with median duration of response for 2.5m. Of the 36 pts who discontinued RAF1i due to PD, 14% responded (6 PR) to RAF2i. Among 16 pts who had CR or PR on RAF1i, 5 pts had PR with RAF2i. In RAF2i group, of all pts achieving PR (n = 8), 5 pts had other intervening therapies prior to RAF2i (immunotherapy [IO]; kinase inhibitors; chemotherapy; INV) while 3 had no interim therapies and both factors did not have significant impact on survival for RAF2i (p=0.2). 5 responders received combination with MEKi, while 1 had MEKi + IO and 2 had monotherapy. ORR did not significantly differ between combination and monotherapy group in RAF 2i (p=0.056). At median follow up of 20m, median OS and PFS from rechallenge was 15.5m and 2.7m. 9 pts had genomic testing post RAF1i (3 tumor;7 blood) with no new acquired aberrations and persistence of BRAF V600E mutation. Independent prognostic factors for survival at rechallenge compared to RAF1i included inferior outcomes with male gender (HR: 3.05; p=0.0089), presence of metastatic sites (HR: 3.12; p=0.036), ECOG (1 vs. 0 or 2; HR: 3.50; p<0.001) while rechallenge with combination RAF2i had a worse survival impact compared to RAF2i monotherapy (PFS: 11.6m vs 2.7m; HR: 3.6; p=0.00145). These findings need to be cautiously inferenced due to small sample size. Conclusions: Rechallenge with RAFi(s) resulted in a clinically meaningful benefit in >50% pts on efficacy (>6m in 25%) and survival outcomes. Further prospective studies are warranted to validate these findings and expand re-challenging targeted therapy options in tumor-agnostic BRAF-aberrated cancers.