In an analysis from the global eNRGy1 registry for NRG1 fusion–positive lung cancers reported in the Journal of Clinical Oncology, Alexander Drilon, MD, and colleagues found greater than expected heterogeneity in characteristics of disease. Additionally, patients had poor responses to cytotoxic, immune, and targeted therapies.
The investigators stated, “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.”
Study Details
The study involved data on 110 patients with pathologically confirmed NRG1 fusion–positive lung cancer obtained between June 2018 and February 2020 from a consortium of 22 centers in 9 countries. Molecular profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (Response Evaluation Criteria in Solid Tumors version 1.1) data were centrally analyzed.
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.— Alexander Drilon, MD
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Key Findings
The anticipated disease phenotype consisting of never-smokers (57% of patients), mucinous adenocarcinoma (57%), and nonmetastatic disease at diagnosis (71%) was predominant among the 110 patients. However, heterogeneity of the disease profile was indicated by a history of smoking in 43% of patients and nonmucinous adenocarcinoma and nonadenocarcinoma histology in 43% and 6%, respectively.
RNA-based testing identified 74% of fusions, and DNA-based assays identified 26%. In molecular analysis, 18 unique upstream gene partners were identified, with 6 being novel 5’ partners (FGFR1, CADM1, F11R, FLYWCH1, KRAS, and PLCG2). A total of 20 unique EGF domain–inclusive chimeric events were identified and heterogeneous 5’/3’ breakpoints were observed.
Among 46 patients with known tumor PD-L1 status, expression was < 1% in 72%, 1% to 49% in 24%, and ≥ 50% in 4%. The median tumor mutational burden (TMB) was 0.9 mutations/megabase (mut/Mb; range = 0–2.6). Median TMB was lower than that found in cohorts of patients with ALK (1.8 mut/Mb; P = .03), ROS1 (2.6 mut/Mb; P = .0008), RET- (2.6 mut/Mb; P = .0006), and NTRK1/2/3- (4.9 mut/Mb; P = .003) fusion–positive lung cancers and in > 5,000 lung cancers without fusions involving ALK, ROS1, RET, or NTRK (5.9 mut/Mb; P < .0001).
Objective response rates were 13% with platinum doublet chemotherapy and 14% with postplatinum taxane-based chemotherapy, with median progression-free survival of 5.8 and 4.0 months, respectively. Objective response rates were 0% with chemoimmunotherapy and 20% with single-agent immunotherapy, with median progression-free survival rates of 3.3 and 3.6 months, respectively. Afatinib was associated with an objective response rate of 25%, independent of fusion type, and a median progression-free survival of 2.8 months.
The investigators concluded, “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.”
Dr. Drilon, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
