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Purpose: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date., Methods: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed., Results: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS., Conclusion: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1 -rearranged tumor biology is needed to develop new therapeutic strategies., Competing Interests: Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicans' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerviewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, Verastem, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Michael DuruisseauxConsulting or Advisory Role: AstraZeneca, MSD Oncology, BMS, Pfizer, Roche, Takeda, Boehringer Ingelheim, Janssen Oncology, Amgen, AbbVieTravel, Accommodations, Expenses: Boehringer Ingelheim, Merck Sharp & Dohme Ji-Youn HanHonoraria: Roche, AstraZeneca, Bristol Myers Squibb, TakedaConsulting or Advisory Role: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Takeda, PfizerResearch Funding: Roche, Pfizer, Ono Pharmaceutical, Takeda Soo-Ryum YangConsulting or Advisory Role: Invitae Yonina R. Murciano-GoroffTravel, Accommodations, Expenses: AstraZeneca Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical, Nippon Kayaku, Chugai Pharma, Covidien, Johnson & Johnson, Daiichi Sankyo, Yakult Honsha, Lilly Japan, Nihon Medi-Physics, Pfizer, Mochida Pharmaceutical Co Ltd, Shionogi, Ono Pharmaceutical, Kyowa Hakko Kirin Miguel Angel MolinaEmployment: Pangaea OncologyResearch Funding: AstraZeneca, Merck Serono, In3Bio Marie WislezConsulting or Advisory Role: Boehringer Ingelheim, Roche, MSD Oncology, Bristol Myers Squibb, AstraZeneca, AmgenSpeakers' Bureau: Boehringer Ingelheim, Amgen, Roche, MSD Oncology, Bristol Myers Squibb, AstraZenecaTravel, Accommodations, Expenses: Roche, MSD Oncology Alexa SchrockEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation Medicine, Roche Siraj AliEmployment: EQRX (I), Foundation Medicine, EQRXLeadership: Incysus Inc, Elevation Oncology, Pillar BiosciencesStock and Other Ownership Interests: Exelixis, Merus NV, PfizerConsulting or Advisory Role: Azitra (I), Princepx Tx (I)Patents, Royalties, and Other Intellectual Property:Patents via Seres Health on microbiome in non neoplastic disease (I), Foundation Medicine Valérie GounantConsulting or Advisory Role: Bristol Myers Squibb, Takeda, Roche, AstraZeneca, Boehringer Ingelheim, Novartis, Chugai Pharma EuropeTravel, Accommodations, Expenses: Takeda, Roche, Pfizer Alison M. SchramResearch Funding: Merus, Kura Oncology, Surface Oncology, AstraZeneca, Lilly, Northern Biologics, Pfizer, Black Diamond Therapeutics, BeiGene, Relay Therapeutics Isabelle MonnetTravel, Accommodations, Expenses: MSD Oncology, Roche, Takeda, Pfizer Jin-Yuan ShihHonoraria: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Bristol Myers Squibb, Roche, Chugai Pharma, LillyConsulting or Advisory Role: Chugai Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Roche, AstraZeneca, Lilly, Takeda, CStone Pharmaceuticals, Janssen Oncology, Novartis, Pfizer, Ono Pharmaceutical, Merck Sharp & DohmeResearch Funding: RocheTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Chugai Pharma, Roche Joshua SabariConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Navire, Pfizer, Regeneron, Medscape, Takeda Maurice PérolConsulting or Advisory Role: Lilly, Roche/Genentech, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Amgen, Takeda, Chugai Pharma, Gritstone OncologyResearch Funding: AstraZeneca, Roche, Takeda, Boehringer IngelheimTravel, Accommodations, Expenses: AstraZeneca, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Chugai Pharma Viola W. ZhuStock and Other Ownership Interests: TP TherapeuticsHonoraria: AstraZeneca, Roche/Genentech, Takeda, Blueprint Medicines, XcoveryConsulting or Advisory Role: AstraZeneca, Takeda, TP Therapeutics, Roche/Genentech, XcoverySpeakers' Bureau: AstraZeneca, Roche/Genentech, Takeda, Blueprint MedicinesTravel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, Takeda, TP Therapeutics Misako NagasakaConsulting or Advisory Role: AstraZeneca, Caris Life Sciences, Daiichi Sankyo, Takeda, Novartis, EMD SeronoSpeakers' Bureau: Blueprint MedicinesResearch Funding: TempusTravel, Accommodations, Expenses: Anheart Therapeutics Robert DoebeleEmployment: Rain TherapeuticsLeadership: Rain TherapeuticsStock and Other Ownership: Rain TherapeuticsConsulting or Advisory Role: GreenPeptide, AstraZeneca, Roche/Genentech, Bayer, Takeda, Rain Therapeutics, Anchiano, Blueprint Medicines, Foundation Medicine, Guardant HealthPatents, Royalties, and Other Intellectual Property: Abbott Molecular for Patent PCT/US2013/057495, Rain Therapeutics, Genentech (Inst), Foundation Medicine (Inst), Black Diamond (Inst), Pearl River (Inst), Voronoi (Inst)Travel, Accommodations, Expenses: Rain Therapeutics, Roche/Genentech D. Ross CamidgeHonoraria: Roche, Takeda, AstraZeneca, Daiichi Sankyo, Bio-Thera, Ribon Therapeutics, Bristol Myers Squibb, Inivata, AbbVie, Apollomics, Elevation Oncology, EMD Serono, Helsinn Therapeutics, Lilly, Nuvalent Inc, Seattle Genetics, Turning Point Therapeutics, Kestrel Labs, Amgen Astellas BioPharma, Anchiano, Eisai, GlaxoSmithKline, Janssen, OnKure, Mersana, Pfizer, QiLu Pharmaceutical, SanofiResearch Funding: Takeda Maria ArcilaHonoraria: Invivoscribe, BiocartisConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance Technologies Sai-Hong Ignatius OuStock and Other Ownership Interests: Turning Point Therapeutics, Elevation OncologyHonoraria: Pfizer, Roche Pharma AG, Genentech/Roche, ARIAD/Takeda, AstraZenecaConsulting or Advisory Role: Pfizer, Roche/Genentech, AstraZeneca, Takeda, Jassen/JNJSpeakers' Bureau: AstraZeneca, Genentech/RocheResearch Funding: Pfizer, Roche Pharma AG, AstraZeneca/MedImmune, AstraZeneca, ARIAD, Revolution Medicines, Mirati Therapeutics, Jassen/JNJ Denis Moro-SibilotConsulting or Advisory Role: Roche/Genentech, Boehringer Ingelheim, Lilly/ImClone, Sanofi, Novartis, Amgen, Pfizer, AstraZeneca, Clovis Oncology, MSD Oncology, ARIAD, Bristol-Myers Squibb, Takeda, AbbvieResearch Funding: Abbvie (Inst), Boehr (Inst), Roche/Genentech (Inst), Bristol-Myers Squibb (Inst)Expert Testimony: MSD OncologyTravel, Accommodations, Expenses: Roche/Genentech, Lilly/ImClone, Pfizer, MSD Oncology, Bristol-Myers Squibb Lucia Anna MuscarellaTravel, Accommodations, Expenses: Boehringer Ingelheim Stephen V. LiuConsulting or Advisory Role: Genentech, Pfizer, Lilly, Bristol Myers Squibb, AstraZeneca, Takeda, Regeneron, G1 Therapeutics, Guardant Health, Janssen Oncology, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Inivata, PharmaMar, Daiichi Sankyo/UCB Japan, BeiGene, AmgenResearch Funding: Genentech/Roche, Pfizer, Corvus Pharmaceuticals, Bayer, Merck, Lycera, AstraZeneca, Molecular Partners, Blueprint Medicines, Lilly, Rain Therapeutics, Alkermes, Bristol Myers Squibb, Turning Point Therapeutics, RAPT Therapeutics, Merus, Debiopharm Group, Elevation OncologyTravel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, MSD Oncology Jacques CadranelHonoraria: AstraZeneca/MedImmune, Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Boehringer IngelheimConsulting or Advisory Role: AstraZeneca/MedImmune, Roche/Genentech, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, Merck Sharp & Dohme, Pfizer, Lilly, NovartisResearch Funding: Pfizer, Novartis, AstraZeneca/MedImmuneNo other potential conflicts of interest were reported.