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The FDA recently approved a new targeted therapy for certain lung and pancreatic cancers, based on a global trial involving our academic health system partner Georgetown Lombardi Comprehensive Cancer Center and MedStar Health patients. The trial showed that the treatment safely slows the growth of tumors, which led to its approval by the FDA for use in certain lung and pancreatic cancers.
On the surface of cells that make up some cancers, a complex process occurs that causes them to grow and divide out of control. An altered protein known as an Neureglin 1 (NRG1) fusion can sometimes bind to receptors on a cell, boosting normal growth patterns and leading to a tumor.
The trial results, published in The New England Journal of Medicine, identified a bispecific monoclonal antibody targeted therapy called zenocutuzumab (Bizengri) that can disrupt the signaling pathway responsible for the growth of these cancers despite standard treatment.
NRG1 is a gene crucial for the growth and development of the heart and nerves, as well as other physiological processes. Sometimes, it can break and fuse with another gene. This genetic alteration changes how NRG1 behaves.
NRG1 fusions occur in less than 1% of cancers. When NRG1 fusions bind with HER3 receptors, it can lead to constant signaling that makes the cells grow and divide uncontrolled. NRG1 fusions are rare but happen in some cancers more than others.
About 87% of lung cancers are the non-small cell type. Research shows NRG1 fusions are found in less than 1% of Asian, Caucasian, and non-reported ethnicities. In one type, called invasive mucinous adenocarcinoma, 10%-30% of tumors have NRG1 fusions. For patients with these tumor types, standard treatments don’t work well.
Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer. The KRAS gene is not mutated in about 10% of tumors (called KRAS wild-type). About 0.5% of all pancreatic cancers can have NRG1 fusions, but they’re found in 1.3% of KRAS wild-type pancreatic cancers. NRG1 fusions are found in other types of cancer in even smaller numbers.
Tumors with NRG1 fusions don’t usually respond well to traditional cancer treatments such as chemotherapy and radiation therapy. Our research led to an accelerated approval of zenocutuzumab-zbco (Bizengri) by the Food and Drug Administration (FDA). This is the first targeted therapy for these difficult-to-treat cancers of the lung and pancreas.
A safe and effective therapy.
Working with researchers around the globe, we participated in a Phase 2 clinical study to evaluate the effectiveness and safety of zenocutuzumab.
Across all the study sites, 204 patients with 12 different types of NRG1 fusion-positive tumors enrolled in the study. They all received an injection of zenocutuzumab every two weeks until their cancer showed signs of progression.
Of the 158 whose cancer was measurable and who enrolled at least 24 weeks before we stopped collecting data, 30% responded to the treatment. Many different types of tumors responded to the drug. These included 29% of lung cancer patients with NRG1 fusions and 42% of patients with pancreatic cancer with NRG1 fusions.
Zenocutuzumab didn’t cure these cancers, but it did stop them from growing, most often for about 11 months, with only mild side effects such as diarrhea and fatigue. Our study shows that this drug could help patients with NRG1 fusion tumors live longer, higher-quality lives.
Related reading: What You Need to Know About Alcohol and Cancer Risk.
Disrupting cell growth signals.
Zenocutuzumab is a bispecific monoclonal antibody drug, which means it can bind to two molecular targets simultaneously. The drug is designed to block NRG1 fusions from activating the HER2 and HER3 proteins. It binds with HER2, which stops HER3 from interacting with the NRG1 gene. This disrupts signaling to the cancer cells with NRG1 fusions to grow and divide constantly.
Zenocutuzumab can also help the immune system respond by making cancer cells more obvious to the body’s immune cells so they can be eliminated. Now that we know this targeted treatment is safe and effective, we are working to identify more types of tumors with NRG1 fusions to benefit more patients.
Genetic sequencing can find NRG1 fusions.
Next-generation sequencing can help us learn whether a patient’s tumor has NRG1 fusions. In the lab, a sample of the tumor’s DNA is examined for many biomarkers simultaneously. Yet research has shown that these tests don’t always identify NRG1 fusions in all patients.
For the greatest accuracy, more sensitive sequencing of RNA (a molecule similar to DNA that carries genetic information and is involved in making proteins) can be effective at spotting NRG1 fusions. Patients whose cancers aren’t responding well to traditional treatments, especially those with non-small-cell lung cancer and KRAS-negative pancreatic cancers, may benefit from this additional sequencing.
Related reading: Pharmacogenetics Research: More Precise Cancer Treatment, One Genetic Variant at a Time.
At the forefront of molecular testing.
Zenocutuzumab isn’t a cure, but it can help patients with rare cancers live longer, higher-quality lives. For now, this treatment is only approved for non-small-cell lung cancer or KRAS wild-type pancreatic cancer. We expect it would work for others, but they’re so rare that it’s hard to enroll enough patients for a study.
Georgetown’s Lombardi Comprehensive Cancer Center is at the forefront of molecular testing. MedStar Health Research Institute is proud to partner with our colleagues to help more people learn about this important work. We’re always working to identify molecular targets like NRG1 fusions so new drugs can help more people live longer, healthier lives.
