Clinical deep dive 

Disease state overview 
Pancreatic cancer is a type of cancer that starts as a growth of cells in the pancreas. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and accounts for about 90% of all cases. PDAC begins in the cells lining the ducts carrying digestive enzymes out of the pancreas. The cause of pancreatic cancer is unknown however there may be some factors that increase risk. Risk factors for developing pancreatic cancer include being elderly, smoking, Type 2 diabetes, pancreatitis, a family history, excessive alcohol drinking, and obesity.  

Lung cancer is a type of cancer that begins when cells in the lung develop changes in their DNA and begin to grow out of control. These cancer cells can form a tumor that invade and destroy healthy body tissue. Symptoms from lung cancer usually present in more advanced disease. Risk factors for developing lung cancer include smoking, second-hand smoke, and radiation therapy. Lung and bronchus cancer is fairly common. It is more common in men, especially African American men, compared to women. There are two major types of lung cancer (non-small cell lung cancer [NSCLC] and small cell lung cancer [SCLC]) with majority of cases being NSCLC (85%) followed by SCLC (15%). NSCLC is usually diagnosed in the elderly and the median age is 71 years. 

Neuregulin-1 (NRG1) gene fusions are genetic alterations that occur when the NRG1 gene merges with another gene, resulting in a hybrid protein that can promote cells to grow and become distinct. Tumors that are NRG1+ are associated with aggressive tumor growth, poor prognosis, and have limited therapeutic options. NRG1+ tumors are rare, occurring in < 1% of solid tumors, including 0.5% to 1.8% of pancreatic cancers and 0.3% to 1.7% of lung cancers. 
 

Epidemiology 
Pancreatic cancer is the tenth most common cancer type. About 66,440 new cases of pancreatic cancer and about 51,750 deaths are expected in 2024. The risk of developing pancreatic cancer increases with age and the median age at diagnosis is 70 years. Pancreatic cancer is slightly more common in men compared to women. In 2021, there were an estimated 100,669 people living with pancreatic cancer in the US. Majority of cases (51%) are diagnosed after the cancer has metastasized and these persons have a very small chance of survival, 5-year relative survival is 3.1%. 

Lung cancer is the third most common cancer type. It is estimated that 234,580 new cases of NSCLC will be diagnosed in 2024, and 125,070 deaths are expected to occur. In 2021, there were about 610,816 people living with lung and bronchus cancer in the US. NSCLC accounts for 80% to 85% of all lung cancer cases and SCLC accounts for 10% to 15% of cases. Lung cancer occurs mostly in the elderly with most people diagnosed over 65 years of age. Majority of cases (53%) are diagnosed after the cancer has metastasized and these patients have a 5-year relative survival rate of 8.9%. 
 

Treatment 
Treatment for pancreatic cancer depends on the stage (extent) and location of the cancer. Treatments may include surgery, ablation or embolization, radiation therapy, chemotherapy, targeted therapy, immunotherapy or a combination of these. The National Comprehensive Cancer Network (NCCN) guidelines version 3.2024 for the treatment of pancreatic adenocarcinoma currently recommend, in patients who progress with metastatic disease and are not candidates for radiation therapy (unless palliative care), FOLFIRINOX (fluorouracil (5-FU)/leucovorin plus oxaliplatin and irinotecan), NALIRIFOX (liposomal irinotecan plus 5-FU plus leucovorin plus oxaliplatin) or gemcitabine plus albumin-bound paclitaxel (all category 1 recommendations) as preferred first-line therapy with good PS (0 to 1). Other recommended regimens include gemcitabine with or without erlotinib (cat 1), or capecitabine, or albumin-bound paclitaxel plus cisplatin (cat 2A). Additionally, there are kinase inhibitors useful in certain circumstances. When PS is 2, the preferred category 1 regimen is gemcitabine plus albumin-bound paclitaxel. 

Treatment for NSCLC is based mainly on the stage of the cancer. Other factors include a person’s overall health and lung function, as well as certain traits of the cancer itself. Treatment options can include surgery, radiation therapy, and systemic therapy which includes chemotherapy (e.g., platinum-based regimen), immunotherapy, targeted therapy or a combination of these. NCCN guidelines version 11.2024 for the treatment of NSCLC, currently recommend, in advanced or metastatic adenocarcinoma, large cell, NSCLC, (with no contraindications to programmed cell-death [PD-1] or programmed cell-death ligand [PD-L1] inhibitors), pembrolizumab or cemiplimab-rwlc plus carboplatin or cisplatin plus pemetrexed (all category 1 recommendations) as a preferred regimen with PS 0 to 1. Other recommended regimens include (e.g., atezolizumab plus carboplatin plus paclitaxel plus bevacizumab, cat 1). When PS is 2, the preferred regimen is carboplatin plus pemetrexed (cat 2A). 
 

Drug and clinical trial overview 

Zenocutuzumab was studied in eNRGy, an open-label, multicenter, phase 1/2 trial, evaluating the safety and antitumor activity of zenocutuzumab in 189 adults with NRG1+ pancreatic cancer, NSCLC or other tumors. Patients included in the study were at least 18 years old and had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Patients had locally-advanced, unresectable or metastatic solid tumor malignancy with documented NRG1 gene fusion, identified through molecular assays. Patients received zenocutuzumab 750 mg IV every two weeks over an every four-week cycle until disease progression and were followed for up to two years. 

The primary outcome was overall response rate (ORR, percentage of patients whose tumors decrease in size by ≥30% using Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]) per investigator’s assessment. Patients achieved an ORR of 37.2% in NSCLC arm and 42.4% in PDAC arm. The median duration of response (DOR) was 14.9 months in NSCLC arm and  9.1 months in PDAC arm. The median time to response was 1.8 months in both cancer types and the clinical benefit rate (best overall response of complete response, partial response or stable disease lasting  ≥24 weeks) at 24 weeks was 61.5% in the NSCLC arm and 72.7% in the PDAC arm. Most patients (88%) experienced at least one adverse event and most were at least grade 1 or grade 2. The most common adverse events were diarrhea, asthenia/fatigue, nausea, anemia, infusion-related reaction, dyspnea, vomiting, abdominal pain, constipation, and decreased appetite. The most common grade 3 or grade 4 events (experienced in 6% of patients) were anemia, dyspnea, alanine aminotransferase (ALT) increase, and aspartate aminotransferase (AST) increase.