Gene fusions involving ALK, ROS1, RET, and NTRK are now established targets in NSCLC, for which highly effective and well-tolerated kinase inhibitors are the preferred initial therapy. A growing body of evidence suggests fusions in NRG1 (neuregulin 1) will emerge as yet another relevant genomic target. NRG1 fusions are rare events, present across tumor types and seen in about 0.3% of NSCLC cases.1 They tend to be mutually exclusive with other oncogenic driver mutations. Physiologically, NRG1 serves as a ligand for ERBB3 (HER3). Fusions in NRG1 can tether the ligand to the membrane in proximity to ERBB3, which promotes heterodimerization, usually with ERBB2 (HER2), thus triggering a familiar downstream signaling cascade. There is rising interest in NRG1 fusions because of new therapeutic strategies that have shown early signals of efficacy. However, challenges in developing NRG1-targeted therapeutics include the relative rarity of NRG1 fusions, suboptimal detection rates with some sequencing platforms, and limited clinical data to draw from.
The eNRGy1 Global Multicenter Registry is a collaborative effort to characterize NRG1 fusions in lung cancer.2 Twenty-two centers across nine countries reported outcomes for 110 patients with lung cancer harboring an NRG1 fusion. Similar to other actionable targets, NRG1 fusions were more common in patients with no smoking history and in adenocarcinoma histology. However, there was some diversity in patient demographics; for example, 43% reported some smoking history. Invasive mucinous adenocarcinoma is a subtype of NSCLC that is enriched for NRG1 fusions, but the majority of cases in the eNRGy1 registry were identified in non-mucinous adenocarcinoma.
NRG1 fusions feature many unique gene partners, most commonly CD74 in lung cancer, and the clinical relevance of this pairing is not yet clear. It is important to note that the vast majority of NRG1 fusions in the eNRGy1 Global Multicenter Registry were detected using RNA-based testing. NRG1 is a very large gene, and less than 0.3% of it is coding.3 The large intronic regions make NRG1 a challenging gene to cover with DNA-based testing. RNA-based next-generation sequencing has a clear advantage in sensitivity for identifying fusions in NRG1. The immunophenotype of NRG1-fusion–positive NSCLC was also reported in this registry. High expression of PD-L1 was rare (4%); 72% of cases had no PD-L1 expression. Tumor mutation burden was also collected and was notably low.
One striking result from the eNRGy1 Global Multicenter Registry was the poor performance of standard therapy in NRG1-fusion–positive NSCLC. In evaluable patients treated with platinum-doublet chemotherapy, primarily pemetrexed-based, the response rate was only 13%, with a median PFS of 5.8 months. Post-platinum taxane therapy offered a response rate of only 14%, with 71% experiencing disease progression as their best response. Similar to other driver-positive lung cancers, immunotherapy was not particularly effective; 60% of patients experienced progression as their best response, and median PFS was 3.6 months. Chemotherapy–immunotherapy combinations did not fare better, with median PFS limited to 3.3 months.
Because the downstream signaling of NRG1 fusions is typically mediated by ERBB2, agents targeting that pathway can be effective, and in fact, multiple responses to the oral pan-HER kinase inhibitor afatinib have been previously reported.4 ,5 In the eNRGy1 Global Multicenter Registry, 20 patients with NRG1-fusion–positive NSCLC received afatinib, and 25% (n = 5) achieved a partial response. The median PFS was only 2.8 months, but the range extended beyond 2 years. Although there are no approved targeted therapies available for NRG1-fusion–positive NSCLC, there are several ongoing clinical trials, including studies of afatinib (NCT02693535); a monoclonal antibody targeting HER3 (seribantumab; NCT04383210);and a bispecific antibody targeting HER2 and HER3 (zenocutuzumab; NCT02912949). Zenocutuzumab was recently granted U.S. Food and Drug Administration Fast Track designation for tumors harboring an NRG1 fusion.
Detection of actionable targets in advanced NSCLC prior to treatment decisions is critical to proper management; its importance cannot be overstated. When a target, such as a gene fusion, is present and detected, it guides patients and oncologists toward a matched targeted therapy. It also guides clinicians away from immunotherapy, which in large part is less effective in this population. The same strategy likely holds true for NRG1 fusions, which seem to respond poorly to immunotherapy and to most standard therapies, highlighting the need for new treatment options for this molecular subset. While we await results from ongoing trials, detection of NRG1 fusions is an important first step. The rarity of these molecular events makes it difficult to justify single-gene testing, but NRG1 is now incorporated into the RNA component of several commercially available next-generation sequencing (NGS) panels. Further characterization of NRG1 fusion biology and treatment will be another important advance for precision oncology.
- 1. Jonna S, Feldman RA, Swenson J, et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res. 2019;25:4966-4972.
- 2. Drilon A, Duruisseaux M, Han JY, et al. Clinicopathologic features and response to therapy of NRG1 fusion-driven lung cancers: The eNRGy1 Global Multicenter Registry. J Clin Oncol. 2021. [Epub ahead of print].
- 3. Falls DL. Neuregulins: functions, forms and signaling strategies. Exp Cell Res. 2003;284(1):14-30.
- 4. Cheema PK, Doherty M, Tsao MS. A case of invasive mucinous pulmonary adenocarcinoma with a CD74-NRG1 fusion protein targeted with afatinib. J Thorac Oncol. 2017;12(12):e200-202.
- 5. Cadranel J, Liu SV, Duruisseaux M, et al. Therapeutic potential of afatinib in NRG1 fusion-driven solid cancers. Oncologist. 2021;26(1):7-16.