Clinicopathologic Features and Response to Therapy of NRG1 Fusion-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.

FIG 1.

Clinicopathologic features. (A) The frequency of metastasis to selected anatomic sites is shown for patients with NRG1 fusion–positive lung cancers. (B) The histologic subtypes of 103 NRG1 fusion–positive adenocarcinomas are shown. These are divided into invasive mucinous adenocarcinomas, noninvasive mucinous adenocarcinomas, and other subtypes. (C) Kaplan-Meier curves of OS are shown for stage I (blue), stage II (red), stage III (green), and stage IV (orange) disease at diagnosis. The median duration of follow-up was 32 months (range, 1-179 months). NR, not reached; OS, overall survival; U, undefined.

FIG 2.

Molecular features. (A) The primary assay that identified the NRG1 fusion in cancers from 110 patients in this registry is divided into RNA-based (blue) and DNA-based (red) assays. Below each corresponding bar, a list and number of the individual assays are shown. (B) A Circos plot of the various NRG1 fusions detected and their corresponding upstream partners is shown. The intensity of the red bars in the inner circle represents the frequency of each fusion event, with darker bars representing more common fusions and lighter bars representing less common fusions. (C) The frequency of upstream partners is shown. The most common 5′ partners—CD74, SLC3A2, SDC4, and FGFR1—are shown individually, whereas less common partners are aggregated into other partners (green). (D) When known, the exon that precedes the 5′ breakpoint is shown in green along with the frequency of each event. Exons and exon numbers are abbreviated as eX (e for exon and X for exon number), and events that occur in more than 10 fusions in aggregate are in boldface. The structure of the corresponding 3′ NRG1 gene is shown, with the first exon shown after the breakpoint noted above each blue bar. EGF domains are depicted as orange boxes. EGF, epidermal growth factor; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; PCR, polymerase chain reaction.

FIG 3.

Immunophenotype. (A) Of the 110 patients with NRG1 fusion–positive lung cancers, PD-L1 status was known in 46 patients as shown in the pie chart on the left. Of these 46 patients, PD-L1 expression is divided into 0%, 1%-49%, and ≥ 50%, the frequencies of which are shown in the pie chart on the right. The size of the pie graphs relative to each other is not scaled to the total size of the corresponding populations. (B) Violin plots of TMB in mutations per megabase are shown for patients with NRG1 fusion–positive lung cancers compared with those that harbor ALK, ROS1, RET, or NTRK1/2/3 fusions and those whose lung cancers do not harbor these alterations (gray). The circles and black bars indicate the median and 95% CIs, respectively. PD-L1, programmed death ligand-1; TMB, tumor mutational burden.

FIG 4.

Systemic therapy activity. Swimmer plots of the duration of therapy are shown. Best response to therapy is indicated by the blue (PR), red (SD), and teal (PD) bars. Note that no patients had complete responses. The duration of treatment for patients for whom best response could not be evaluated (such as those with nonmeasurable disease) is shown in orange. Plots are separated into patients who received (A) platinum-doublet chemotherapy (n = 18), (B) taxane-based chemotherapy after prior platinum-doublet chemotherapy (n = 9), (C) combination immune checkpoint inhibition and chemotherapy (n = 10), (D) single-agent immune checkpoint inhibition (n = 9), and (E) targeted therapy with the pan-ERBB family inhibitor, afatinib (n = 20). NE, could not be evaluated; PD, progressive disease; PR, partial response; SD, stable disease.