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Background: Biomarker-driven trials have led to multiple FDA tissue-agnostic approvals. We aimed to explore the clinic-genomic landscape of alterations currently actionable by tissue-agnostic targeted therapies. Methods: We mined AACR Project GENIE to extract data about three molecular targets currently on the list of FDA tissue-agnostic approvals (RET fusions, NTRK fusions, and BRAFV600E mutations). Results: Among 137401 patients in GENIE database (153,834 samples), 4506 samples harbored BRAFV600E mutations (3%), 390 had NTRK fusions (0.3%), and 375 had RET fusions (0.2%) (Table 1). Cancers with BRAFV600E mutations included melanoma (n=1278; 28%), CRC (n=1120; 25%), thyroid cancer (n=845; 19%), glioma (n=359; 8%), NSCLC (n=300; 7%); and multiple other tumor types (n=1882; 42%). The most frequent co-occurring alterations were TERT and TP53. NTRK fusions were observed in breast cancer (n=42; 11%), glioma (n=37; 10%), thyroid cancer (n=37; 10%), soft tissue sarcomas (n=34; 9%), and NSCLC (n=32; 8%); among others (n=208; 53%). The most common fusion partners were ETV6, TPM3, and LMNA and most frequent co-occurring mutations were TP53 and TERT. RET fusions were seen in NSCLC (n=208; 56%), thyroid cancer (n=88; 24%), CRC (n=15; 4%), breast cancer (n=11; 3%), and gastroesophageal cancer (n=8; 2%); among others (n=45; 12%). Common fusion partners were were KIF5B, CCDC6, and NCOA4 and most frequent co-occurring alterations were TP53 and SETD2. Conclusions: BRAF, RET and NTRK alterations are prevalent across multiple tumors. Although rare, together they are found in around 3.4% of all human cancers. Further analysis of co-occurring TP53, TERT and SETD2 alterations and their impact on response to targeted therapies is warranted, in order to tailor personalized treatments for patients harboring these alterations. Table 1: Tissue spectrum of activity for anticancer drugs with tissue-agnostic approvals Approved Alteration Most Common Diagnoses Prevalence in Literature Prevalence in Disease Specific Analysis Approved Drug(s) Tissue Agnostic FDA Approval Year Tissue Agnostic ORR from Clinical Trials NTRK Fusions Breast Cancer 0.08-0.13% 0.3% Larotrectinib; Entrectinib 2018 (Larotrectinib); 2019 (Entrectinib) ORR: 75% and DOR: NR (Larotrectinib); ORR: 57% and 12mDOR: 45% (Entrectinib) Glioma 0.55% 0.4% Thyroid Cancer 2.22-2.28% 1.7% Soft Tissue Sarcoma 0.68-1.17% 0.8% NSCLC 0.16-0.23% 0.1% Salivary Gland Cancer 79.6-84.9% 3% CRC 0.26-0.35% 0.2% Gastroesophageal Cancer N/A 0.4% Pancreatic Cancer 0.30-0.34% 0.3% Melanoma 0.36-0.54 0.2% RET Fusions NSCLC 2% 0.9% Selpercatinib 2022 ORR: 44% and DOR: 24.5m Thyroid Cancer 5-10% 4.1% CRC Citation Format: Mohamed A. Gouda, Blessie E. Nelson, Lars Buschhorn, Adam Wahida, Vivek Subbiah. Landscape of 4,506 pan-cancer samples harboring BRAFV600E mutations, and NTRK/RET Fusions from 137,401 adult patients with cancer: Clinical implications for tissue agnostic therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1173.