FDA approves zanidatamab for biliary tract cancers with high HER2 levels 

On November 20, 2024, the U.S. Food and Drug Administration granted accelerated approval to the drug zanidatamab (Ziihera^®) to treat advanced and metastatic bile duct cancer (cholangiocarcinoma) and other biliary tract cancers that have high levels of a protein called HER2 and do not respond to chemotherapy. The clinical trial that resulted in the drug’s approval was co-led by gastrointestinal medical oncologist and early drug development specialist James J. Harding, MD, of Memorial Sloan Kettering Cancer Center (MSK). 

Biliary tract cancers are uncommon and aggressive tumors that affect the ducts and organs that make and store bile and release it into the small intestine to aid in digestion. This category of cancers includes cholangiocarcinomas, tumors that can form inside or outside the liver, and tumors of the gallbladder. 

“These cancers are rare, making up just 3% of all gastrointestinal cancers,” Dr. Harding says. “But MSK is a major center for biliary tract cancer research and treatment. We are evaluating multiple novel treatment approaches, and a key focus of our work is on molecular testing of these tumors and finding ways to target them with precision medicine.” 

Bispecific Antibody Zanidatamab Works in Multiple Ways  

Zanidatamab targets a protein called HER2, which is found at abnormally high levels not only in a subset of biliary tract cancers but also in some breast cancers, lung cancers, and stomach cancers, among other types. Other medications have already been approved to target this protein, but zanidatamab is in a relatively new class of drugs called bispecific antibodies. 

The way zanidatamab works is different from other HER2-targeted therapies. After it seeks out HER2 on the surface of cancer cells, it attaches itself to the protein in two different places rather than in one, as is the case with earlier drugs.  

By blocking the protein in two places, the drug not only prevents the protein from sending out signals that allow tumor cells to grow and thrive, it also causes the protein to degrade. There’s another benefit. All this unusual activity alerts the immune system that something isn’t right, resulting in yet another hit on the cancer cells as immune cells move in to attack. 

Zanidatamab for Bile Duct Cancers Clinical Trial Results 

In a phase 2b clinical trial published in The Lancet Oncology, in June 2023, the investigators reported that: 

• 41.3% of participants had confirmed objective responses, meaning that their tumors shrank by a measurable amount. 
• 18% had treatment-related significant side effects, including diarrhea and weakened ability of the heart to pump. No patients, however, had severe side effects and there were no treatment-related deaths. 

That global trial, called HERIZON-BTC-01, was co-led by Dr. Harding. It enrolled 87 patients from the United States, Europe, and Asia. Because this population of patients is uncommon, MSK reached out to hospitals in the MSK Cancer Alliance as well as partners in NYC Health + Hospitals to identify those who might benefit. 

How Zanidatamab Treated Rob’s Gallbladder Cancer 

One person who benefitted from the trial is Rob, now 42, a husband, father, and attorney who lives in a suburb of Philadelphia. 

Rob learned he had cancer in October 2020 after going to the emergency room with terrible abdominal pain. After exams and testing, doctors there recommended he have his gallbladder removed. 

After Rob woke up from surgery, he was shocked to learn that the surgeons had found a lesion the size of a walnut on his gallbladder. Not only that, but they had incidentally found a lesion in his liver as well, which they also removed. Analysis of the lesions confirmed the worst: Rob had stage 4 gallbladder cancer. 

Going to an Expert at MSK for the Latest Gallbladder Cancer Treatments 

 Rob knew right away he wanted to consult with the experts at MSK. Both of his parents had been MSK patients, and he had a college friend who practices at MSK: gastrointestinal medical oncologist Steven Maron, MD, MSc. When Dr. Maron learned about Rob’s diagnosis, he suggested that Rob meet with Dr. Harding. 

 Dr. Harding recommended that Rob first receive six months of chemotherapy. He was able to receive that treatment in Philadelphia, closer to his home. But when scans showed that his disease had progressed, he had the opportunity to enroll in a clinical trial at MSK in New York. 

 Participating in a Clinical Trial at MSK Was Convenient 

Dr. Harding told Rob that because his gallbladder cancer had high levels of HER2, he had the opportunity to join a clinical trial testing zanidatamab, which he would get as an infusion at MSK every two weeks. Scans about a month after his first dose showed that his cancer was already shrinking. 

Rob found the zanidatamab treatment to be significantly easier on his body than chemotherapy and only experienced a few minor side effects. “I was able to keep working throughout my treatment, even in waiting rooms and while I was receiving my infusions,” he says. Additionally, the study sponsor paid for his hotel when he had to stay in New York overnight. 

A Change in Treatment After Rob’s Cancer Came Back 

After about a year on the study, Rob’s cancer started to grow again. However, tests confirmed it still had had high levels of HER2. So Dr. Harding switched him to another HER2-targeting drug, called trastuzumab deruxtecan (Enhertu^®). At the time, it was considered investigational for biliary tract cancers, but Dr. Harding worked to get Rob access to the drug, given the unique molecular profile of his cancer and the hope he would benefit.  

His tumors began shrinking again. Because trastuzumab deruxtecan is a widely available drug, Rob was able to receive this treatment through his care team closer to home while continuing to have regular telemedicine visits with Dr. Harding. 

Now Showing No Signs of Cancer, Rob Is Enjoying Life 

 Rob’s most recent scans show no evidence of disease. Currently taking a break from treatment, he’s enjoyed several trips with his family, including to France and Japan. 

Rob says he feels fortunate.  

“This is a dismal disease, but I was treated at a world-class institution that was able to give me access to an experimental drug that was not otherwise available,” he says. “MSK is an amazing institution. Everyone there is brilliant, but also extremely caring. I’m also thankful that they continue to collaborate with my care team closer to home, making sure I get the best care in the appropriate places. I am thankful to my family, friends, and providers who continue to support me through this journey.”