Alexander Drilon1, Michael Duruisseaux2,3,4, Ji-Youn Han5, Masaoki Ito6,7,8, Christina Falcon1, Soo-Ryum Yang1, Yonina R Murciano-Goroff9, Haiquan Chen10,11, Morihito Okada8, Miguel Angel Molina12, Marie Wislez13,14, Philippe Brun15, Clarisse Dupont2, Eva Branden16,17, Giulio Rossi18,19, Alexa Schrock20, Siraj Ali20, Valérie Gounant21, Fanny Magne22, Torsten Gerriet Blum23, Alison M Schram9, Isabelle Monnet24, Jin-Yuan Shih25, Joshua Sabari26, Maurice Pérol27, Viola W Zhu28, Misako Nagasaka29,30, Robert Doebele31, D Ross Camidge31, Maria Arcila1, Sai-Hong Ignatius Ou32, Denis Moro-Sibilot33, Rafael Rosell34, Lucia Anna Muscarella35, Stephen V Liu36, Jacques Cadranel37. 1. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY. 2. Respiratory Department, Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France. 3. Anticancer Antibodies Laboratory, Cancer Research Center of Lyon, Lyon, France. 4. Université Claude Bernard Lyon UMR INSERM 1052 CNRS 5286, Université de Lyon, Lyon, France. 5. National Cancer Center, Korea, Goyang-si, South Korea. 6. Pangaea Oncology, Quiron-Dexeus University Institute, Barcelona, Spain. 7. Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain. 8. Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 9. Memorial Sloan Kettering Cancer Center, New York, NY. 10. Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China. 11. State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Thoracic Oncology, Fudan University, Shanghai, China. 12. Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain. 13. Université de Paris, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Paris, France. 14. Team Inflammation, Complement, and Cancer, and Oncology Thoracic Unit Pulmonology Department, AP-HP, Hôpital Cochin, Paris, France. 15. Department of Pneumology, Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Valence, France. 16. Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden. 17. Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden. 18. Local Health Authority of Romagna, Infermi Hospital, Rimini, Italy. 19. Local Health Authority of Romagna, St Maria delle Croci Hospital, Ravenna, Italy. 20. Foundation Medicine Inc, Cambridge, MA. 21. Department of Pulmonology, Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, France. 22. Hopital Nord Ouest Villefranche sur Saône, Gleizé, France. 23. Department of Pneumology, Klinikum Emil von Behring, Berlin, Germany. 24. Centre Hospitalier Intercommunal de Créteil, Créteil, France. 25. National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan. 26. New York University Langone Health Perlmutter Cancer Center, New York, NY. 27. Léon Bérard Cancer Center, Lyon, France. 28. Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology/Oncology, University of California, Irvine School of Medicine, Orange, CA. 29. Karmanos Cancer Institute, Wayne State University, Detroit, MI. 30. Division of Neurology, Department of Internal Medicine, St Marianna University, Kawasaki, Japan. 31. Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO. 32. Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA. 33. Clinique de Pneumologie, Pôle Médecine Aiguë Communautaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. 34. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain. 35. Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy. 36. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. 37. Department of Pneumology and Thoracic Oncology, Assistance Publique-Hopitaux de Paris, Tenon Hospital and GRC Theranoscan Sorbonne Université, Paris, France.
Abstract
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.
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.
Authors: A Drilon; I Bergagnini; L Delasos; J Sabari; K M Woo; A Plodkowski; L Wang; M D Hellmann; P Joubert; C S Sima; R Smith; R Somwar; N Rekhtman; M Ladanyi; G J Riely; M G Kris Journal: Ann Oncol Date: 2016-04-07 Impact factor: 32.976
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Authors: J Mazières; F Barlesi; T Filleron; B Besse; I Monnet; M Beau-Faller; S Peters; E Dansin; M Früh; M Pless; R Rosell; M Wislez; P Fournel; V Westeel; F Cappuzzo; A Cortot; D Moro-Sibilot; J Milia; O Gautschi Journal: Ann Oncol Date: 2015-11-23 Impact factor: 32.976
Authors: Hira Rizvi; Francisco Sanchez-Vega; Konnor La; Walid Chatila; Philip Jonsson; Darragh Halpenny; Andrew Plodkowski; Niamh Long; Jennifer L Sauter; Natasha Rekhtman; Travis Hollmann; Kurt A Schalper; Justin F Gainor; Ronglai Shen; Ai Ni; Kathryn C Arbour; Taha Merghoub; Jedd Wolchok; Alexandra Snyder; Jamie E Chaft; Mark G Kris; Charles M Rudin; Nicholas D Socci; Michael F Berger; Barry S Taylor; Ahmet Zehir; David B Solit; Maria E Arcila; Marc Ladanyi; Gregory J Riely; Nikolaus Schultz; Matthew D Hellmann Journal: J Clin Oncol Date: 2018-01-16 Impact factor: 44.544
Authors: Alexander Drilon; Romel Somwar; Biju P Mangatt; Henrik Edgren; Patrice Desmeules; Anja Ruusulehto; Roger S Smith; Lukas Delasos; Morana Vojnic; Andrew J Plodkowski; Joshua Sabari; Kenneth Ng; Joseph Montecalvo; Jason Chang; Huichun Tai; William W Lockwood; Victor Martinez; Gregory J Riely; Charles M Rudin; Mark G Kris; Maria E Arcila; Christopher Matheny; Ryma Benayed; Natasha Rekhtman; Marc Ladanyi; Gopinath Ganji Journal: Cancer Discov Date: 2018-04-02 Impact factor: 39.397