Defining a Space for NRG1 Fusion–Positive Tumors in Lung and GI Cancers

A group of lung and gastrointestinal (GI) cancer experts gathered during a Frontline Forum event to discuss treatment options for NRG1 fusion–positive tumors. The panel covered how to best detect this gene through different assays using DNA or RNA, and updates in the therapeutic space.

The panel was led by Alexander I. Spira, MD, PhD, FACP, codirector of the Virginia Cancer Specialists Research Institute and director of the Thoracic and Phase I Program in Fairfax. He was joined by Teresa Macarulla, MD, PhD, a physician in the Medical Oncology Department at Vall d’Hebron University Hospital in Barcelona, Spain; Cindy Neuzillet, MD, PhD, HDR, head of the Gastrointestinal Oncology Unit and professor in the Department of Medical Oncology at the Curie Institute in Saint-Cloud, France; Joshua K. Sabari, MD, assistant professor of medicine and director of high reliability organization initiatives at NYU Langone Health in New York, New York; Alison Schram, MD, assistant attending physician at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York; and Eric Van Cutsem, MD, PhD, full professor at the University of Leuven and division head of Digestive Oncology at University Hospitals Gasthuisberg in Leuven, Belgium.

A Brief Overview of NRG1 Gene Fusions

To begin the conversation, the panel first discussed what NRG1 gene fusions were and how they applied to the lung and GI cancer space, respectively. The most common NRG1 fusion partner is CD74. It was noted that SLC3A2, VAMP2, RBPMS, WNR, and SDC4 may retain a membrane-bound EGF-like domain, which can retain the wild-type NRG1 III-β3 form. The oncogenic potential of CD74-NRG1 can be maintained by the other
fusions listed.^1,2

When looking into the background of NRG1 gene fusions, most notably the fusions occur in 0.5% of patients with cholangiocarcinoma and pancreatic ductal adenocarcinoma, respectively. For patients with non–small cell lung cancer, they occur in 0.3%. A total of 51% of women who are nonsmokers receive a diagnosis of mucinous subtype adenocarcinoma each year.

The panel agreed that they rarely see patients with NRG1 gene fusions. However, Schram from MSKCC said her institution is a referral center and has seen an uptick in these patients. Van Cutsem has stopped specifically screening for this and instead does a broad next-generation sequencing (NGS) panel.

Neuzillet said she does not do molecular screening regularly for those in the GI space. Her institution limits screening to KRAS and microsatellite instability testing. Spira said the difference between the United States and European countries regarding testing is that the United States may be more willing to include additional testing due to having fewer budget constraints, which is why more RNA testing is ordered.

“It’s a question of reimbursement. In the majority of countries in Europe, it’s not reimbursed through the NGS analysis in pancreatic cancer. For example, in our country, in Spain, we are doing it only in referral centers in which it’s paid by the center but not by the government,” said Macarulla.

In the United States when NGS testing gets billed, Sabari said it never gets sent to the patient. At NYU Langone, the institution's internal assay is utilized, which helps to cut down on costs. In France, Neuzillet said, it is not reimbursed at all, so it is hard to initiate that practice change of testing for specific genes.

Current Standard of Care

Next the panel focused on assays used to detect NRG1 gene fusions (Table 1).^3-6 Spira began with fluorescence in situ hybridization for DNA input. This is something that clinicians widely use, and it can be completed quickly with no restrictions on fusion partners. The multiplex polymerase chain reaction assay can be utilized to find fusion partners. It is a very sensitive and specific assay.

Schram highlighted the MSK-IMPACT test, which was developed to “detect exons in over 500 cancers associated with genes in DNA specifically.” This assay focuses on introns and genes that are known to have fusions so it can be more comprehensive. Assays that focus on RNA input look for the transcriptome and can detect NRG1 gene fusions more frequently because they do not rely on tiling introns.

“In our institution, because we know that MSK-IMPACT has that limitation, we do reflex RNA testing in all cases, where you don’t find a driver. For example, in pancreatic cancer, we’re not doing RNA [testing] in all our patients, but in any patient with KRAS wild-type pancreatic cancer, they do get RNA [testing] and you’ll find NRG1 fusions and FGFR fusions and other alterations, like ALK, etc. That also goes for lung cancer; if we don’t find a driver using DNA, we go to RNA. That’s the way that we improve our sensitivity,” said Schram.

Macarulla has found that it is more difficult to obtain RNA samples. More tissue is asked for in patients with pancreatic cancer because it is difficult to obtain these results. In Van Cutsem’s practice, the initial biopsy for pancreatic cancer is often cytology or a fine needle aspiration through endoscopic ultrasonography.

The immunohistochemistry assay is widely available, can be done quickly, and does not cost much money. These assays are used in different scenarios, but Spira asked his colleagues how ordering these tests differed between the United States and Europe.

As Schram works at MSKCC, she typically sticks with the MSK-IMPACT assay because she finds it covers all her needs and she has access to the raw data. When needing an assay for RNA, she goes with the Archer FusionPlex assay, even if it is not comprehensive. Sabari’s experience has included a wait time of 4 to 6 weeks if the tissue sample needs genome testing. To keep the sequencing in house, he orders FusionSeeker to help save some time.

In Spain, Macarulla uses the panel in her hospital for both DNA and RNA testing. In France, Neuzillet said they use an internal panel. She did bring to light that there is a program in France to give access to NGS testing to all patients, but currently it is only for frozen materials, which are not needed for fusion detection.

Treatment Options for the Population

The panel discussed 2 potential therapy options: zenocutuzumab and afatinib. They are currently novel therapeutic options that can help aid with NRG1 fusion–positive tumors in lung or GI cancers. The experts discussed efficacy rates from the phase 1/2 eNRGy trial (NCT02912949) and the eNRGy1 Global Multicenter Registry when deciding between different treatment options, with the data shown in Tables 2⁷and 3.⁸ 

Schram presented these data at the 2023 European Society for Medical Oncology meeting, which included all different histologies for patients with NRG1 fusion–positive tumors.⁹ “One of the questions that we had is whether zenocutuzumab could be effective in patients who had been previously treated with afatinib. If you look at the response rates, [they’re] comparable to [those of] the overall population so we don’t think that there’s much of a difference if you’ve had prior afatinib,” she said.

When looking at these data, Schram noted that the results are often compared with those of patients who have ALK, ROS, or EGFR mutations, but NRG1 is not comparable with those. By itself, this is a good option because there are no targeted therapies for this population, and it holds up well compared with chemotherapy.

“I think this [can be approved] in the frontline setting based on these data; it depends on how the FDA feels on this. This is a very small subset of patients with a very small population, and overall, whether you’ll get a broad agnostic approval across different diseases [or not], it’ll be interesting,” said Sabari. 

REFERENCES

1. Jonna S, Feldman RA, Swensen J, et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res. 2019;25(16):4966-4972. doi:10.1158/1078-0432.CCR-19-0160
2. Murayama T, Nakaoku T, Enari M, et al. Oncogenic fusion gene CD74-NRG1 confers cancer stem cell-like properties in lung cancer through a IGF2 autocrine/paracrine circuit. Cancer Res. 2016;76(4):974-983. doi:10.1158/0008-5472.CAN-15-2135
3. Laskin J, Liu SV, Tolba K, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020;31(12):1693-1703. doi:10.1016/j.annonc.2020.08.2335
4. Solomon BJ, Kim DW, Wu YL, et al. Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in ALK-mutation-positive non-small-cell lung cancer. J Clin Oncol. 2018;36(22):2251-2258. doi:10.1200/JCO.2017.77.4794
5. Drilon A, Somwar R, Mangatt BP, et al. Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov. 2018;8(6):686-695. doi:10.1158/2159-8290.CD-17-1004
6. Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014;20(12):1479-1484. doi:10.1038/nm.3729
7. Schram A, Macarulla T, Cleary J, et al. Durable efficacy of zenocutuzumab, a HER2 × HER3 bispecific antibody, in advanced NRG1 fusion–positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC). Ann Oncol. 2023;34(suppl 2):S895-S896. doi:10.1016/j.annonc.2023.09.2567
8. Cadranel J, Liu SV, Duruisseaux M, et al. Therapeutic potential of afatinib in NRG1 fusion–driven solid tumors: a case series. Oncologist. 2021;26(1):7-16. doi:10.1634/theoncologist.2020-0379
9. Schram A, Goto K, Kim D, et al. Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC). Presented at the European Society of Medical Oncology Congress 2023; Madrid, Spain, October 20-24, 2023. Abstract 1315MO