In the United States, pancreatic cancer is the fourth leading cause of cancer related death.¹ In 2023, approximately 64,050 people were diagnosed with pancreatic cancer and 50,550 deaths occurred from the disease.  When 2012 is compared to 2022, despite the approval of novel drug therapies, the 5-year pancreatic cancer survival rate remains low and unchanged at 12.8%.² 

On December 14, 2024, the US Food and Drug Administration (FDA) granted an accelerated approval to zenocutuzumab-zbco ​(Bizengri), an intravenous medication for the treatment of advanced, unresectable, or metastatic pancreatic adenocarcinoma or non-small cell lung cancer with a neuregulin 1 (NRG1) gene fusion. Zenocutuzumab blocks NRG1 fusion protein binding to HER2/HER3 receptors on the cell surface.³˒⁴ For this article, we will focus on pancreatic cancer. 

The pancreas is a gland in stomach area which produces proteins that break down and store energy from food.⁵ Pancreatic cancer is typically diagnosed in late stage and develops when cancerous cells form in the pancreas tissue; adenocarcinoma is the most common.⁶ Some risk factors for pancreatic cancer include smoking, obesity and an acquired mutation. Lack of biomarkers for early detection, drug resistance, rapid spread and late-stage diagnosis make pancreatic cancer difficult to treat.⁷˒¹²

Currently, treatment options for metastatic pancreatic cancer include chemotherapy (ex. oxaliplatin, Onivyde (liposomal irinotecan) and targeted therapy (ex. Keytruda (pembrolizumab) erlotinib, Vitrakvi (loratrectinib), Lynparza (Olaparib).⁸⁻¹² However, chemotherapy resistance and the small populations covered by targeted agents provide limited treatment options.¹³   

NRG1 fusion is a rare, acquired mutation found in less than 1% of solid tumors and 0.13% - 0.5% of pancreatic adenocarcinoma cases.⁷˒¹¹,¹⁴ RNA-based next generation sequencing is the best method to detect NRG1 fusion. The mutation causes continuous activation of HER2/HER3 pathway and leads to pancreatic cancer cell growth.  Pancreatic cancer with NRG1 gene fusion is resistant to current treatment options. ¹⁰˒¹¹  

The eNRGy study (NCT02912949) is a phase 2 component of a phase 1 / 2 clinical trial of zenocutuzumab in patients with NRG1 fusion positive cancer who do not have other driver mutations. ⁴˒⁷ The major outcomes evaluated were confirmed overall response rate (ORR) and duration of response (DOR). For pancreatic adenocarcinoma (n= 30), ORR was 40% (95% CI: 23%, 59%) and DOR range was 3.7- months to16.6 months with one complete response reported. 

Zenocutuzumab-zbco is administered as 750mg intravenous every 2 weeks until progression or intolerance. The most frequent side effects observed were diarrhea (18%), fatigue (12%) and nausea (11%).⁴˒⁷ The annual WAC is $617,500 which is $406,286 greater than the next highest cost therapy, oral  olaparib ($211,214 annual WAC).¹⁵ Cost effectiveness analysis of zenocutuzumab-zbco is needed to assess the value of this novel agent.   

The approval of a new agent to manage rare and hard-to-treat pancreatic cancer subtypes is a positive step forward. Zenocutuzumab-zbco’s high price along with low complete response rates and unknown overall survival may limit therapy uptake. Continued research and discovery of medications with positive clinical outcomes in the larger pancreatic cancer population is needed to improve current survival rates.  

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