NRG1 fusion-positive lung cancers: Clinicopathologic profile and treatment outcomes from a global multicenter registry.

9081 Background: NRG1 fusions are potentially actionable driver events enriched in NSCLCs, particularly invasive mucinous adenocarcinomas (IMAs). These fusions activate HER3/HER2, supporting the therapeutic use of HER3 and/or HER2 inhibitors, but optimal treatment strategies remain unclear. Methods: A global, multicenter network of thoracic oncologists (6 countries, 13 institutions) identified patients with pathologically confirmed NRG1 fusion-positive NSCLCs. Anonymized clinical/pathologic features and clinical outcomes were collected retrospectively. Best response to systemic therapy was determined (RECIST v1.1). PFS was calculated (Kaplan-Meier). Results: 80 NRG1 fusion-positive NSCLCs were identified. RNA-based sequencing identified 66% (n = 53/80), DNA-based sequencing 18% (n = 14/80), and FISH 16% (n = 13/80) of cases. The most common upstream partners were CD74 (45%), SLC3A2 (31%), and SDC (9%). Most patients were female (64%) and never smokers (58%). Histology was adenocarcinoma in 95% (IMA, 91%), squamous 4%, large cell neuroendocrine 1%. At diagnosis, most patients had non-metastatic disease (stage: I 33%, II 27%, III 18%, IV 22%). The lifetime frequency of brain metastases was 15%. 12 patients received the HER2 inhibitor afatinib for stage IV disease. PD was the best response in 55% (n = 6/11) of evaluable patients with 18% PR (n = 2/11) and SD 18% (n = 2/11); median PFS was 3.5 months (range 0.6-16.5 months). 19 patients received platinum-based chemotherapy; most patients had SD as their best response (47%, n = 8); PD 41% (n = 7), PR 12% (n = 2). PD-L1 was negative in the majority of tumors (79%, n = 26/33) and none had high PD-L1 expression (range 0-20%). No responses to single-agent anti-PD-1/L1 therapy were observed (PD n = 5/6, SD n = 1/6: nivolumab/atezolizumab). No responses to chemoimmunotherapy (carboplatin, pemetrexed, pembrolizumab) were observed (SD n = 4/5, PD n = 1/5). Conclusions: RNA-based testing is an important component of NRG1 fusion detection. Novel targeted therapeutic approaches are needed as overall outcomes with afatinib are poor. NRG1 fusion-positive NSCLCs do not highly express PD-L1 and outcomes with immunotherapy ± chemotherapy are poor.