Purpose: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B RAF alterations in lung cancer., Patients and Methods: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements., Results: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10 , DOCK4, and TRIM24 . BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A , TP53 , and STK11 alterations ( P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated., Conclusion: This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK , and exceed that of ROS1 or RET . This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR AF alterations represent a subgroup of lung cancers in which targeted therapy should be considered., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Yuri SheikineConsulting or Advisory Role: Foundation MedicineDean PavlickNo relationship to discloseSamuel KlempnerConsulting or Advisory Role: Lilly, Boston Biomedical, Celgene, Astellas Pharma Speakers' Bureau: Foundation Medicine Research Funding: Leap Therapeutics (Inst)Sally E. TrabuccoEmployment: Foundation Medicine Research Funding: Foundation Medicine Travel, Accommodations, Expenses: Foundation MedicineJon ChungEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineMark RosenzweigEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineKai WangNo relationship to discloseVamsidhar VelchetiHonoraria: Novartis, Foundation Medicine, Merck, Bristol-Myers Squibb, Genentech, Roche Consulting or Advisory Role: Clovis Oncology, Genentech, Bristol-Myers Squibb, Merck, Celgene, Foundation Medicine, AstraZeneca, MedImmune, Genoptix, Amgen, Takeda Research Funding: Genentech (Inst), Trovagene (Inst), Eisai (Inst), OncoPlex Diagnostics (Inst), ALkermes (Inst), NantOmics (Inst), GEnoptix (Inst), Altor BioScience (Inst), Merck (Inst), Bristol-Myers Squibb (Inst), Atreca (Inst), Heat Biologics (Inst), Leap Therapeutics (Inst) Travel, Accommodations, Expenses: AstraZeneca/MedImmune, Eisai, Foundation Medicine, MerckGarrett M. FramptonEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineNir PeledConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, Roche Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, RocheMolly MurrayEmployment: Foundation MedicineYoung Kwang ChaeConsulting or Advisory Role: Foundation Medicine, Boehringer Ingelheim, Biodesix, Counsyl, AstraZeneca, Guardant Health Speakers' Bureau: Merck, Genentech, Roche Travel, Accommodations, Expenses: HanmiLee A. AlbackerEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineLaurie GayEmployment: Foundation Medicine Stock and Other Ownership Interests: Gilead Sciences, Foundation MedicineHatim HusainConsulting or Advisory Role: AstraZeneca, Abbvie, Foundation Medicine Speakers' Bureau: AstraZeneca, Merck, Bristol-Myers Squibb Research Funding: Pfizer (Inst) Travel, Accommodations, Expenses: AstraZeneca, Merck, Bristol-Myers Squibb, Foundation Medicine, AbbvieJames SuhEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineSherri MillisEmployment: Foundation MedicineVenkataprasanth ReddyEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Travel, Accommodations, Expenses: Foundation MedicineJulia ElvinEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineRyan J. HartmaierEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Patents, Royalties, Other Intellectual Property: Nfe2L2 exon 2 and/or exon 3 loss from work conducted at Foundation Medicine (provisional patent filed) (Inst)Afshin DowlatiConsulting or Advisory Role: Abbvie, Stemcentrx, Ariad Research Funding: Lilly (Inst), ImClone (Inst), Amgen (Inst), Bristol-Myers Squibb (Inst), OncoMed (Inst), EMD Serono (Inst), MedImmune (Inst)Phil StephensEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineJeffrey RossEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Honoraria: Pfizer, EMD Merck Serono Research Funding: Foundation MedicineTrever BivonaStock and Other Ownership Interests: Driver Honoraria: Novartis, AstraZeneca, Array BioPharma, Revolution Medicine Consulting or Advisory Role: Revolution Medicine, Array BioPharma, Novartis, AstraZeneca Speakers' Bureau: Novartis Research Funding: Ignyta, Revolution MedicineVincent MillerEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Patents, Royalties, Other Intellectual Property: Receive periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer CenterShridar GanesanEmployment: Merck (I) Stock and Other Ownership Interests: Ibris, Inspirata, Merck (I) Consulting or Advisory Role: Inspirata, Novartis Patents, Royalties, Other Intellectual Property: I hold two patents for digital imaging that may be licensed to Ibris and Inspirata Travel, Accommodations, Expenses: InspirataAlexa SchrockEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineSai-Hong OuHonoraria: Pfizer, Roche Pharma AG, Genentech, Roche, ARIAD, Takeda, Novartis, AstraZeneca, Foundation Medicine Consulting or Advisory Role: Pfizer, Roche, Genentech, Novartis, AstraZeneca, Takeda, ARIAD, Foundation Medicine Speakers' Bureau: Genentech, AstraZeneca, Takeda, ARIAD Research Funding: Pfizer (Inst), Roche Pharma AG (Inst), AstraZeneca (Inst), MedImmune (Inst), Clovis Oncology (Inst), ARIAD (Inst), Ignyta (Inst), Peregrine Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Astellas Pharma (Inst), Chugai Pharma (Inst)Siraj AliEmployment: Foundation Medicine Stock and Other Ownership Interests: Exelixis, Blueprint Medicines, Agios Patents, Royalties, Other Intellectual Property: Patents via Foundation Medicine; patents via Seres Health on microbiomes in non-neoplastic disease (I), (© 2018 by American Society of Clinical Oncology.)