Clinicopathologic Features and Response to Therapy ofNRG1Fusion–Driven Lung Cancers: The eNRGy1 Global Multicenter Registry

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.

The significance of the fusion partner gene genomic neighborhood analysis in translocation‐defined tumors

“…Drilon reported on 20 patients with NRG1 rearranged NSCLC treated with afatinib (Drilon et al, 2021 ). The clinical outcome data on progression‐free and overall survival are partly summarized in Figures 1 and 2 .…”

A panel of three serum microRNA can be used as potential diagnostic biomarkers for nasopharyngeal carcinoma

“… 23 In addition, a large number of studies have been conducted on NRG1 fusion as a carcinogenic driving factor for many tumor types, including nasopharyngeal carcinoma. 24 SH3BGRL2 is also considered by various studies to play a role as a key tumor suppressor in the occurrence of cancers, such as glioblastoma and clear cell renal cell carcinoma. 25 , 26 SYNPO2, also known as synapsin 2 or myopod, encodes an actin‐binding protein and has been characterized as a tumor suppressor for aggressive cancers.…”

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

“…Aside from the ALK, ROS1, NTRK , and RET rearrangements, fusions have been demonstrated with other genes and may be promising for new therapeutic strategies. Among these genes, NRG1 and NUT are of strong interest for future investigation and confirmation of results obtained with clinical trials or preclinical patient‐derived lung cancer models for a use in daily practice 93–98 . NRG1 fusions are present in a rare number of solid lung cancers, since the incidence is estimated to be between 0.1% and 0.4% of NS‐NSCLC 95,99 .…”

“…Among these genes, NRG1 and NUT are of strong interest for future investigation and confirmation of results obtained with clinical trials or preclinical patient-derived lung cancer models for a use in daily practice. [93][94][95][96][97][98] NRG1 fusions are present in a rare number of solid lung cancers, since the incidence is estimated to be between 0.1% and 0.4% of NS-NSCLC. 95,99 It is interesting to note that NRG1 fusions are present in more than 5% of histological subtypes of lung adenocarcinomas, the invasive mucinous lung adenocarcinomas.…”