Clinicopathologic Features and Response to Therapy of NRG1 Fusion–Driven Lung Cancers: The eNRGy1 Global Multicenter Registry
Alexander Drilon
(1, 2)
,
Michaël Duruisseaux
(3, 4, 5)
,
Ji-Youn Han
(6)
,
Masaoki Ito
(7, 8, 9)
,
Christina Falcon
(1, 2)
,
Soo-Ryum Yang
(1, 2)
,
Yonina Murciano-Goroff
(1)
,
Haiquan Chen
(10)
,
Morihito Okada
(9)
,
Miguel Angel Molina
(7)
,
Marie Wislez
(11, 12)
,
Philippe Brun
(13)
,
Clarisse Dupont
(5)
,
Eva Branden
(14, 15, 16)
,
Giulio Rossi
(17, 18)
,
Alexa Schrock
(19)
,
Siraj Ali
(19)
,
Valérie Gounant
(20)
,
Fanny Magne
(21)
,
Torsten Gerriet Blum
(22)
,
Alison Schram
(1)
,
Isabelle Monnet
(23)
,
Jin-Yuan Shih
(24, 25)
,
Joshua Sabari
(26)
,
Maurice Pérol
(27)
,
Viola Zhu
(28)
,
Misako Nagasaka
(29, 30)
,
Robert Doebele
(31)
,
D. Ross Camidge
(31)
,
Maria Arcila
(1, 2)
,
Sai-Hong Ignatius Ou
(28)
,
Denis Moro-Sibilot
(32)
,
Rafael Rosell
(33, 34)
,
Lucia Anna Muscarella
(35)
,
Stephen Liu
(36)
,
Jacques Cadranel
(20, 37)
1
MSK2C -
Memorial Sloan Kettering Cancer Center [New York, NY, USA]
2 Weill Medical College of Cornell University [New York]
3 UCBL - Université Claude Bernard Lyon 1
4 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
5 Hôpital Louis Pradel [CHU - HCL]
6 National Cancer Center Korea
7 QTHI - Quironsalud Teknon Heart Institute [Barcelona, Spain]
8 IGTP - Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute
9 Hiroshima University
10 Fudan University [Shanghai]
11 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
12 Hôpital Cochin [AP-HP]
13 Lungenklinik Heckeshorn
14 Karolinska Institute
15 KUH - Karolinska University Hospital [Solna, Sweden]
16 Uppsala University
17 OIR - Ospedale "Infermi" di Rimini [Rimini, Italy]
18 S. Maria delle Croci Hospital
19 Foundation Medicine Inc
20 CHU Tenon [AP-HP]
21 Hôpital Nord-Ouest [Villefranche sur Saône]
22 HELIOS Klinikum Emil von Behring
23 CHI Créteil
24 National Taiwan University Hospital [Taipei]
25 NTU - National Taiwan University [Taiwan]
26 NYU Langone Medical Center - New York University Langone Medical Center
27 Centre Léon Bérard [Lyon]
28 UC Irvine - University of California [Irvine]
29 Wayne State University [Detroit]
30 St. Marianna University School of Medicine [Kanagawa, Japan]
31 University of Colorado Cancer Center [Aurora, CO, USA]
32 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
33 ICO-Girona - Catalan Institute of Oncology [Girona]
34 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
35 Fondazione IRCCS Casa Sollievo della Sofferenza - Laboratorio di Oncologia [San Giovanni Rotondo, Italy]
36 Georgetown University Medical Center
37 GRC 4 - Theranoscan - Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules
2 Weill Medical College of Cornell University [New York]
3 UCBL - Université Claude Bernard Lyon 1
4 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
5 Hôpital Louis Pradel [CHU - HCL]
6 National Cancer Center Korea
7 QTHI - Quironsalud Teknon Heart Institute [Barcelona, Spain]
8 IGTP - Institut d’Investigació Germans Trias i Pujol = Germans Trias i Pujol Research Institute
9 Hiroshima University
10 Fudan University [Shanghai]
11 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
12 Hôpital Cochin [AP-HP]
13 Lungenklinik Heckeshorn
14 Karolinska Institute
15 KUH - Karolinska University Hospital [Solna, Sweden]
16 Uppsala University
17 OIR - Ospedale "Infermi" di Rimini [Rimini, Italy]
18 S. Maria delle Croci Hospital
19 Foundation Medicine Inc
20 CHU Tenon [AP-HP]
21 Hôpital Nord-Ouest [Villefranche sur Saône]
22 HELIOS Klinikum Emil von Behring
23 CHI Créteil
24 National Taiwan University Hospital [Taipei]
25 NTU - National Taiwan University [Taiwan]
26 NYU Langone Medical Center - New York University Langone Medical Center
27 Centre Léon Bérard [Lyon]
28 UC Irvine - University of California [Irvine]
29 Wayne State University [Detroit]
30 St. Marianna University School of Medicine [Kanagawa, Japan]
31 University of Colorado Cancer Center [Aurora, CO, USA]
32 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
33 ICO-Girona - Catalan Institute of Oncology [Girona]
34 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
35 Fondazione IRCCS Casa Sollievo della Sofferenza - Laboratorio di Oncologia [San Giovanni Rotondo, Italy]
36 Georgetown University Medical Center
37 GRC 4 - Theranoscan - Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules
Alexander Drilon
- Fonction : Auteur
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- ORCID : 0000-0001-6806-9061
Michaël Duruisseaux
- Fonction : Auteur
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- ORCID : 0000-0003-1495-0966
Ji-Youn Han
- Fonction : Auteur
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- ORCID : 0000-0001-5033-0006
Christina Falcon
- Fonction : Auteur
- PersonId : 1424386
- ORCID : 0000-0001-9143-1639
Haiquan Chen
- Fonction : Auteur
- PersonId : 1424387
- ORCID : 0000-0001-7846-257X
Miguel Angel Molina
- Fonction : Auteur
- PersonId : 1424388
- ORCID : 0000-0001-8866-9881
Marie Wislez
- Fonction : Auteur
- PersonId : 1311560
- ORCID : 0000-0001-7518-7859
- IdRef : 089425774
Giulio Rossi
- Fonction : Auteur
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- ORCID : 0000-0001-8855-1218
Alexa Schrock
- Fonction : Auteur
- PersonId : 1424390
- ORCID : 0000-0003-0106-9096
Torsten Gerriet Blum
- Fonction : Auteur
- PersonId : 1424393
- ORCID : 0000-0003-1216-2157
Alison Schram
- Fonction : Auteur
- PersonId : 1424394
- ORCID : 0000-0002-6070-2413
Jin-Yuan Shih
- Fonction : Auteur
- PersonId : 1424395
- ORCID : 0000-0002-2854-5067
Joshua Sabari
- Fonction : Auteur
- PersonId : 1424396
- ORCID : 0000-0002-1556-1543
Maurice Pérol
- Fonction : Auteur
- PersonId : 1186643
- ORCID : 0000-0002-3296-423X
Viola Zhu
- Fonction : Auteur
- PersonId : 1424397
- ORCID : 0000-0002-9313-3253
Misako Nagasaka
- Fonction : Auteur
- PersonId : 1424398
- ORCID : 0000-0001-5308-615X
D. Ross Camidge
- Fonction : Auteur
- PersonId : 1424399
- ORCID : 0000-0003-3430-3213
Sai-Hong Ignatius Ou
- Fonction : Auteur
- PersonId : 1423219
- ORCID : 0000-0002-1764-4975
Rafael Rosell
- Fonction : Auteur
- PersonId : 1424400
- ORCID : 0000-0003-0817-3400
Stephen Liu
- Fonction : Auteur
- PersonId : 1424401
- ORCID : 0000-0002-4852-3914
Résumé
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.