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NRG1 Fusion–positive Lung Cancers are Molecularly, Pathologically, and Clinically More Heterogeneous than Previously Thought

Findings from the eNRGy1 global multicentre registry
08 Jun 2021
Lung and other thoracic tumours;  Personalised medicine

The goals of the eNRGy1 global multicentre registry are to characterise the features of NRG1 fusion–positive lung cancers and elucidate the clinical activity of systemic therapy in a centrally curated real-world database of patients with these rare cancers. Dr. Alexander Drilon of the Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, US and thoracic oncology investigators, who formed the registry, reported that NRG1 fusions have a diversity of fusion partners. They recommend detection should focus on the inclusion of RNA-based sequencing, which maximises the likelihood of fusion identification. They also reported on 2 June 2021 in the Journal of Clinical Oncology that NRG1 fusion–positive cancers typically do not express PD-L1 and have a low tumour mutational burden (TMB), which is consistent with poor response to immunotherapy. Furthermore, responses to chemotherapy or targeted therapy with afatinib are underwhelming. Therefore, development of novel therapeutics for these cancers is an unmet need.

Activating fusions involving ALK, ROS1, RET, NTRK1-3 result in constitutive kinase domain activation that drives downstream pathway signalling, promoting lung cancer cell proliferation and survival. These fusions match patients to highly active targeted therapies.

NRG1 fusions are a relatively recent addition to this list of fusion oncogenes. Structurally, these alterations are distinct from the aforementioned fusions. The transmembrane chimeric oncoprotein contains the epidermal growth factor (EGF) or EGF–like binding domain of NRG1, a known ligand of ERBB3. Binding of the oncoprotein to ERBB3 results in the formation of heterodimers between ERBB3 and other ERBB family members, thereby activating oncogenic signalling and cancer growth. Of these heterodimers, ERBB3-ERBB2 is the most transforming; therapeutic targeting of these fusions has centred on the inhibition of ERBB3 and/or ERBB2.

The authors wrote in the study background that although NRG1 fusions were first discovered in lung cancers in 2014, the clinical, pathologic, and molecular features of these cancers are yet to be comprehensively characterised in a large series. In addition, the activity of many systemic therapies in this molecularly enriched cohort of patients has not been well described. They formed the eNRGy1, global multicentre consortium of thoracic oncology investigators to contribute data on patients with NRG1 fusion–positive lung cancers to a central registry.

From June 2018 to February 2020, a consortium of 22 centres from 9 countries in Europe, Asia, and the US 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 hybridisation. Anonymized clinical, pathologic, molecular, and response according RECIST v1.1 data were centrally curated and analyzed.

Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and non-metastatic (71%) phenotype predominated in 110 patients with NRG1 fusion–positive lung cancer, further diversity, including in smoking history (43%) and histology (43% non-mucinous and 6% non-adenocarcinoma), was elucidated.

RNA-based testing identified most fusions (74%). Molecularly, 6 (of 18) novel 5’ partners, 20 unique EGF 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%) and modest progression-free survival (PFS, 5.8 and 4.0 months).

Consistent with a low PD-L1 expressing (28%) and low TMB (median 0.9 mutations/megabase) immunophenotype, the activity of chemo-immunotherapy and single-agent immunotherapy was poor with 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 median PFS of 2.8 month.

The authors commented that comprehensive sequencing to identify NRG1 fusions should capture molecularly heterogeneous events and not be biased toward particular clinical or pathologic features. To develop novel therapeutic strategies, stakeholders should prioritise research into the underexplored biology of NRG1 fusion–positive tumours and the development of rationally designed drugs.

The study was supported by the National Cancer Institute at the US National Institutes of Health.

Reference

Drilon A, Duruisseaux M, Han J-Y, et al. Clinicopathologic Features and Response to Therapy of NRG1 Fusion–Driven Lung Cancers: The eNRGy1 Global Multicenter Registry. JCO; Published online 2 June 2021. DOI: 10.1200/JCO.20.03307.

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