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Updated: Nov 3, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter
Alexander Drilon1, Michael Duruisseaux2,3,4, Ji-Youn Han5
1Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
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.
Insights
The global eNRGy1 registry characterized NRG1 fusion-positive lung cancers, revealing greater diversity than previously known. Current therapies show limited efficacy, necessitating further research into NRG1-rearranged tumor biology for new treatments.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- NRG1 fusions are oncogenic drivers in various cancers, including lung cancer.
- Studying NRG1 fusions is challenging due to their rarity.
Purpose of the Study:
- To characterize NRG1 fusion-positive lung cancers using the largest and most diverse patient series to date.
- To establish the global eNRGy1 registry for this purpose.
Main Methods:
- Data from 110 patients with NRG1 fusion-positive lung cancer were collected from 22 centers across nine countries.
- Next-generation sequencing (DNA/RNA) and fluorescence in situ hybridization were used for molecular profiling.
- Clinical, pathologic, molecular, and response data were centrally curated and analyzed.
Main Results:
- A diverse patient population was identified, with variations in smoking history and histology.
- RNA-based testing identified the majority of fusions (74%), revealing novel partners and chimeric events.
- Chemotherapy, immunotherapy, and targeted therapy (afatinib) demonstrated limited efficacy, with low objective response rates and modest progression-free survival.
Conclusions:
- NRG1 fusion-positive lung cancers exhibit significant molecular, pathological, and clinical heterogeneity.
- Current cytotoxic, immune, and targeted therapies are largely ineffective against these tumors.
- Further investigation into NRG1-rearranged tumor biology is crucial for developing novel therapeutic strategies.
