NRG1-fusion positive gastrointestinal tumours: afatinib as a novel potential treatment option

Abstract

Introduction: NRG1 encodes for neuregulin 1, a growth factor that binds HER3 and HER4 and activates ErbB signalling-pathways. NRG1 fusions are emerging therapeutic targets in multiple malignancies, including gastrointestinal tumours. Afatinib, an ErbB-family blocker, may be a treatment option for patients with tumours harbouring NRG1 fusions, as supported by preclinical and clinical evidence, including published case reports of two patients with cholangiocarcinoma and pancreatic adenocarcinoma. Both of these patients had NRG1-ATP1B1 fusions and achieved a partial response with afatinib, lasting 8 months and 3 months, respectively. Method(s): Here, we describe three new cases of afatinib treatment for NRG1 fusion-positive gastrointestinal tumours. NRG1 fusions were detected using Caris Molecular IntelligenceVR (Patient 1) and whole genome transcriptome analysis (Patients 2 and 3). Result(s): Patient 1, a 69-year-old, male ex-smoker with KRAS -mutated, right-sided metastatic colorectal cancer initially presented with gastrointestinal bleeding in June 2017. He underwent a right hemicolectomy and liver and lung metastasectomies after intolerance of FOLFOX and single-agent irinotecan. CarisVR profiling revealed a novel NRG1-POMK fusion not previously seen in colorectal cancer, and afatinib (30 mg daily) was initiated in September 2018. After initial stable disease, the patient progressed 4 months later but remains on afatinib treatment to date, and is currently receiving local therapies to the liver and a chest wall mass. He has occasional diarrhoea that responds to loperamide, and intermittent acneiform rashes. Patients 2 and 3, are both male, aged 55 and 59 years, respectively, with KRAS -wild-type metastatic pancreatic cancer. Patient 2 presented initially in 2016 with abdominal pain; his initial chemotherapy was gemcitabine and nab-paclitaxel, which was discontinued due to toxicity. Patient 3 presented in 2017 with abdominal pain and weight loss, and had multiple liver metastases; his initial chemotherapy was 5FU/irinotecan/oxaliplatin. Following progression on chemotherapy, NRG1-ATP1B1 fusions were detected in both patients as part of the Personalized Oncogenomics study (NCT02155621). Patient 2 initiated afatinib in Oct 2018, had a significant radiological response, and remains on afatinib after 5 months. Patient 3 initiated afatinib in March 2018; after an initial significant response, his tumour progressed after 5.5 months of afatinib treatment. Conclusion(s): These new findings add to an existing body of evidence suggesting that afatinib is a potential treatment option for patients with NRG1 fusion-positive gastrointestinal tumours. Further investigation of the potential therapeutic benefit of afatinib in gastrointestinal cancer and other cancer types is warranted.