{"doi":"10.1016/j.esmoop.2025.105061","title":"Clinical outcomes of tumor-agnostic targeting of BRAF, tumor mutation burden-high, and RET","abstract":"BACKGROUND: We report the BRAF p.V600E (BRAF V600E) mutations, high tumor mutational burden (TMB-H), and RET fusions frequency/outcomes with genomically matched therapies (GMTs). To raise awareness about GMTs providing data from a real-world scenario, the KISMET project was created. In this article we report the characteristics and the outcomes of patients with advanced cancer harboring three different classes of molecular alterations: BRAF V600E mutations, TMB-H, and RET fusions. PATIENTS AND METHODS: We retrospectively assessed the prevalence of the three aforementioned agnostic targets among 10 893 patients who underwent next-generation sequencing (NGS) from February 2020 to May 2022. We evaluated the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) for GMT versus non-GMT in the three cohorts of patients with each specific alteration. RESULTS: BRAF V600E occurred in 6.5% (662/10 158) of patients, TMB-H in 11.2% (265/2369), and RET fusions in 0.6% (42/7105). GMT was given to 115 (72.3%) out of the 159 patients who started a new line of treatment after NGS testing: 65 of 85 with BRAF V600E mutations, 42 of 65 for TMB-H, and 8 of 9 for RET fusions. The ORR of GMT versus non-GMT was 55.6% versus 12.8% for all patients (P < 0.0001), 51% versus 17.6% for the BRAF V600E (P = 0.016), 57.6% versus 9.5% for the TMB-H (P = 0.004), and 75% versus 0% for RET fusions (P = 0.30). The mPFS for GMT versus non-GMT was 9.6 versus 3.7 months (P = 0.001), 9.2 versus 4.2 months (P = 0.08) for BRAF V600E, and 7.9 versus 3.7 months (P = 0.04) for TMB-H, respectively. For the eight patients with RET fusions who received RET inhibitors, the mPFS was 15.0 months. CONCLUSIONS: BRAF V600E, TMB-H, and RET fusion were found in a wide variety of advanced cancers. Improved oncological outcomes with tumor type-agnostic GMT support the value of integrating comprehensive NGS testing and GMT administration for the aforementioned targets.","journal":"ESMO Open","year":2025,"id":567374,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8729,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1471465,"name":"Edoardo Crimini","orcid":"0000-0002-1869-0607","position":1,"is_corresponding":false},{"id":1471757,"name":"V.R. Holla","orcid":null,"position":2,"is_corresponding":false},{"id":1948,"name":"Kenna Shaw","orcid":"0000-0002-6873-0793","position":3,"is_corresponding":false},{"id":1471758,"name":"A M Doefler","orcid":null,"position":4,"is_corresponding":false},{"id":576396,"name":"E. Campbell","orcid":null,"position":5,"is_corresponding":false},{"id":509890,"name":"Richard K. Yang","orcid":"0000-0003-0433-8626","position":6,"is_corresponding":false},{"id":89706,"name":"J. Bryan Iorgulescu","orcid":"0000-0003-1405-3667","position":7,"is_corresponding":false},{"id":490969,"name":"Kishan Patel","orcid":"0000-0002-8971-3482","position":8,"is_corresponding":false},{"id":762671,"name":"David D. McPherson","orcid":null,"position":9,"is_corresponding":false},{"id":232859,"name":"Jing Ning","orcid":"0000-0002-5289-331X","position":10,"is_corresponding":false},{"id":1293102,"name":"F. Meric-Bernstam","orcid":null,"position":11,"is_corresponding":false},{"id":1471759,"name":"D.D. Karp","orcid":null,"position":12,"is_corresponding":false},{"id":1292327,"name":"Arash Ronaghy","orcid":"0000-0001-8870-7139","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:56:44.340853Z","pmid":"40460677","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}