Lack of Targeted Therapies for NRG1 Fusion-Positive Advanced Solid Tumors Comes to Attention

David R. Spigel, MD

Driver alterations in neuregulin 1 (NRG1) fusions have recently come to light as a new target in patients with advanced or metastatic solid tumors. Multiple factors contribute to poor outcomes in this patients population with limited option for resolution. However, a few targeted agents are currently in development to potentially treat this group of patients with cancers harboring NRG1 fusions.¹

“NRG1 is a new actionable target in non–small cell lung cancer [NSCLC] and pancreatic cancer. This protein was discovered recently in 2014 in Germany. In this work, the fusion has been detected in EGFR- and KRAS-negative lung adenocarcinoma, specifically in a subtype of patients referred to as invasive mucinous adenocarcinoma,” said Michaël Duruisseaux, MD, a medical oncologist at Lyon Cancer Institute in France, during a prior interview with Targeted Oncology.

“Based on registry data, it seems that NRG1 may also occur in non-mucinous adenocarcinoma of the lung, and also in squamous carcinoma of the lung. Interestingly, NRG1 fusions are also detected in one-third to 50% of KRAS wild-type cancers, as well as cholangiocarcinoma, ovarian cancer, sarcoma, and [others],” Duruisseaux added.

In lung cancer specifically, NRG1 fusions are estimated to account for 0.8% of lung cancers overall and about 27% to 31% of all invasive mucinous adenocarcinomas (IMAs).

The Issue With Current Treatments for NRG1 Fusion–Positive Advanced Solid Tumors

The standard strategies for treating patients with advanced solid tumors that are NRG1 fusion–positive are chemoimmunotherapy or novel anti–PD-1 or anti–PD-L1 agents, according to David R. Spigel, MD, from a presentation at the 2020 North American Conference on Lung Cancer. The problem with utilizing these therapies is that response tends to be suboptimal for patients with NRG1 fusions.

Prior research showed that patients who have NRG1 fusion–positive advanced or metastatic solid tumors had worse overall survival (OS) compared with patients who did not have NRG1 fusions (P = .019). Additionally, patients with NRG1 fusions had shorter disease-free survival (DFS) compared with those who did not have NRG1 fusions (P = .013).^2,3

A multicenter registry study of patients with NSCLC performed in 2019 implied that patients with NRG1 fusions are not likely to derive benefit from existing treatments. For example, they do not benefit from novel checkpoint inhibition because PD-L1 is not commonly expressed in NRG1 fusion–positive NSCLC.³

Additionally, treatment with afatinib (Gilotrif) led most patients to progressive disease ([PD], 55%) whereas only 18% responded and another 18% had stable disease (SD). The median progression-free survival (PFS) with afatinib was 3.5 months (95% CI, 0.6-16.5).

The study also showed that patients with NRG1 fusion–positive lung cancer typically have poor outcomes on immunotherapy and chemotherapy. Of the 19 patients who received platinum-based chemotherapy, the best response was SD (47%), but PD was the second-best response (41%), and few patients had a partial response (12%). No patients in the study had responses to anti–PD-1 or anti–PD-L1 therapy.

Spigel, chief scientific officer; director, Lung Cancer Research Program; and principal investigator, Sarah Cannon Research Institute, also noted during his presentation that NRG1 fusions typically develop alone, independent of other known driver alterations.

It was determined that the most common NRG1 fusion partners include CD74, SLC3A2, SDC, and others. Because NRG1 produces proteins that belong to the NRG family of ligands with specificity fo HER3 and HER4, tumors with these aberrations can be treated with HER2/HER3 inhibitory monoclonal antibodies (mAbs), antibody-drug conjugates, EGFR tyrosine kinase inhibitors (TKIs), and HER2 TKIs.⁴

Knowing the issue with NRG1 fusions in patients with advanced solid tumors is one part of a multi-step process for treating these tumors properly moving forward. Next, Spigel analyzed the durability of response to novel and developing therapies, including anti-HER3 antibodies and pan-ERBB TKIs.

“NRG1 fusions are rare but recurrent oncogenic drivers occurring in ~0.2% of solid tumors and enriched in certain tumor subtypes such as the invasive mucinous adenocarcinoma subtype of the lung. Oncogenic gene fusions can be clinically actionable. This is well exemplified by ALK, ROS1, or RET fusions in NSCLC and NTRK fusions in advanced solid tumors, for which there are highly effective, FDA-approved targeted therapies available,” Jessica Jiyeong Lin, MD, attending physician, Center for Thoracic Cancer and Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital, told Targeted Oncology in an interview.

“For NRG1 fusions, there are currently no approved targeted therapies. Standard therapy for advanced tumors harboring NRG1 fusions remains chemotherapy and/or immunotherapy. Several clinical reports have demonstrated that NRG1 fusions are a viable, actionable target in tumors, with responses seen on inhibition of ERBB family members. We have an opportunity here to try and expand treatment option(s) for patients with tumors harboring these fusions.”

Durable Responses With Anti-HER3 and Pan-ERBB TKIs

Looking at clinical case data of patients with the IMA subtype, lung adenocarcinoma, and unspecified lung cancer subtypes with various types of NRG1 fusions, it was revealed that the most durable responses were observed with novel therapy and the pan-HER TKI, afatinib.1

The novel anti-HER3 agent GSK2849330 led to a 19-month duration of response (DOR) in patients with IMA who had CD74-NRG1 fusions. Afatinib had consistently long DORs in patients with lung adenocarcinoma ranging from 10 months to 12 months, which included patients with SDC4-NRG1, SLC3A2-NRG1, and CD74-NRG1 fusions. Patients with IMA and CD74-NRG1 fusions, as well as those with SDC4-NRG1 fusions, had DORs ranging from 5 months to more than 18 months.

Promising Agent Under Investigation in NRG1 Fusion-Positive Advanced Solid Tumors

The phase 2 open-label, multicenter, basket trial of the novel IgG2 mAb seribantumab is in the process of enrolling 75 patients with advanced solid tumors who have NRG1 fusions. The CRESTONE study (NCT04383210) will investigate the efficacy and safety of seribantumab in 3 cohorts.

“The preclinical data for seribantumab in NRG1 fusion–positive models have been encouraging, and we look forward to assessing its clinical efficacy in this trial. We hope through this trial to also continue to educate the community about this rare but important biomarker and the need to pursue appropriate testing in order to enable the identification of such biomarkers,” Lin stated.

In the first cohort (cohort 1), 55 patients who have not received prior treatment with any ERBB-targeted therapy will be enrolled. Cohort 2 will include up to 10 patients who have progressed after prior treatment, including prior ERBB-targeted therapy, and cohort 3 will enroll up to 10 patients who harbor NRG1 fusions without an EGF-like binding domain.

Each cohort will receive seribantumab intravenously in 3 stages: weekly induction infusions at 3 g for weeks 1-4 followed by 6 cycles for consolidation at 3 q every 2 weeks and then 3 g every 3 weeks as maintenance until progressive disease or toxicity. The schedule was designed to rapidly achieve steady levels and optimize exposure.

The primary end point being explored in this study is the objective response rate observed with seribantumab per RECIST v1.1 criteria and by both independent and central radiographical review. The secondary end points that will be investigated included DOR, safety, PFS, OS, and clinical benefit rates. The study’s exploratory end points include the clinical relevance of fusion partners, impact of previous therapies—including ERBB targeted therapies—and resistance mechanisms.

Currently, patients are being recruited from approximately 25 sites in the United States, which includes the Sarah Cannon Research Institute, Siteman Cancer Center, the Henry Hord Health System, and the Carbone Cancer Center. Eligible patients are those with a locally advanced or metastatic solid tumor with NRG1 fusions who have fresh or archived tumor sample, received at least on prior standard therapy, are 18 years of age or older, have an ECOG performance status of 0 to 2, and have a minimum of 1 measurable extra-cranial lesion. The study excludes patients who have a known actionable oncogenic driver mutation other than an NRG1 fusion.

As a fully human IgG2 mAb that inhibits HER3 and downstream pathways, seribantumab had rationale for use in NRG1 fusion–positive cancers. “Seribantumab is a monoclonal antibody targeting HER3, which results in the inhibition of NRG1-dependent HER3 activation, HER3-HER2 dimerization, and downstream signaling,” explained Lin. “The safety profile of seribantumab has already been assessed through prior monotherapy and combination studies, and the drug is well-poised to be evaluated for activity in an appropriately defined, targeted patient population as in CRESTONE.”

The phase 2 study of seribantumab in adult patients with NRG1 gene fusion–positive advanced solid tumors is currently enrolling patients and is expected to be completed by 2022.

Addressing the Unmet Need

Beyond this phase 2 clinical trial, oncologists still face the challenge of identifying the patients with NRG1 fusions and determining how certain fusion partners may help or interfere with novel therapies. As observed with afatinib in 2019, any type of NRG1 fusion had limited benefit from treatment and fusion partners did not appear to matter. However, experts like Duruisseaux believe more research is needed.

“First of all, the issue is to find of NRG1 fusion–positive patients because it is very difficult in terms of technology. The second step is to find a way to give the good drug in combination with afatinib [because] it seems that afatinib does not work for our NRG1-positive tumors. We need to find a way to test all of our patients, and then refer the patients to a specific trial,” he said.

_References:

_{1. Spigel D, Waqar SN, Burkard ME, et al. CRESTONE – clinical study of response to seribantumab in tumors with neuregulin-1 (nrg1) fusions – a phase 2 study of the anti-her3 mab for advanced or metastatic solid tumors (NCT04383210). Presented at: IASLC 2020 North America Conference on Lung Cancer Worldwide Virtual Event (NACLC 2020); October 16-17, 2020. Abstract 46.}

_{2. Shin DH, Lee D, Hong DW, et al. Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung. Oncotarget. 2016;7(43):}

_{69450-69465. doi:10.18632/oncotarget.11913}

_{3. Duruisseaux M, Liu SV, Han JY, et al. NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry. J Clin Oncol. 2019;37(suppl 15):9081. doi:10.1200/JCO.2019.37.15_suppl.9081}

_{4. Dimou A, Camidge DR. Detection of NRG1 Fusions in Solid Tumors: Rare Gold? Clin Can Res. 2019;25(16):4865-4867. doi:10.1158/1078-0432.CCR-19-1219}