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Antibody Treatment Could Fight Rare But Deadly Bile Duct Cancers
  • Posted June 12, 2023

Antibody Treatment Could Fight Rare But Deadly Bile Duct Cancers

Patients with bile duct cancer might soon have an additional treatment available to them, thanks to a newly discovered tumor target.

Some bile duct cancers are driven by a mutated HER2 gene, which has also been implicated in cancers of the breast, esophagus and prostate, researchers report in a new study.

An experimental drug targeting HER2 mutations, zanidatamab, produced powerful results in a small group of patients with advanced bile duct cancers. About two out of five patients (41%) responded to the drug, with their tumor shrinking by more than one-third, said lead researcher Dr. James Harding, a gastrointestinal oncologist with Memorial Sloan Kettering Cancer Center in New York City.

By comparison, only 5% to 15% of bile duct cancer patients respond to chemotherapy, said senior researcher Dr. Shubham Pant, a gastrointestinal oncologist with the University of Texas MD Anderson Cancer Center, in Houston.

“And in these patients [in the study], responses happened quickly,” Harding said, noting that half of patients showed some benefit from zanidatamab within 1.8 months.

“It also appeared to be quite durable, with a median duration of response of 12.9 months,” Harding added. “This really does show clear anti-cancer activity in this patient subset, and warrants further exploration.”

Pant presented findings from this clinical trial at the recent annual meeting in Chicago of the American Society of Clinical Oncology and the results were published online simultaneously in The Lancet Oncology.

Bile duct cancer is a relatively rare cancer, with an estimated 8,000 new cases diagnosed in the United States each year, according to the American Cancer Society.

The bile ducts are a series of thin tubes that run from the liver to the small intestine. They deliver bile from the liver and gallbladder, which is used to help digest fats as they pass through the intestines.

Unfortunately, diagnosis usually occurs late, after the cancer has spread, said Dr. Arif Kamal, chief patient officer for the American Cancer Society.

The overall five-year survival rate for bile duct cancers is just 9% for those starting within the liver and 11% for those starting outside the liver, the ACS says.

“The challenge of bile duct cancer is trying to treat it, because most of the time you find it very far advanced,” Kamal said.

Mutated HER2 genes have been implicated in other cancers, and small studies had potentially linked these mutations to bile duct cancer as well, Harding said.

The HER2 gene creates proteins that control the growth and repair of different cells in the body.

“This protein, when it's not working correctly, makes cancer grow,” Harding explained.

Zanidatamab is an antibody treatment that works by binding to and blocking the errant HER2 proteins, preventing them from fueling bile duct cancer, Harding said.

For this phase 2b clinical trial, the research team recruited 87 bile duct cancer patients to receive zanidatamab, which is administered via IV every two weeks.

All of the patients' cancers were advanced, fueled by HER2 mutations, and had stopped responding to chemotherapy, the study authors said.

The most common side effects of zanidatamab were diarrhea, with 37% experiencing gastrointestinal symptoms. Other side effects included infusion-related reactions like allergic responses, pain at the injection site, nausea or flu-like symptoms.

The study did not assess overall survival among patients, but it's expected that this drug will help extend a patient's life rather than cure their cancer, Harding and Pant said.

“It's not a curative option for our patients, but it definitely does give them long-term disease control, which is also very important,” Pant said

Zanidatamab will still require a full-fledged phase 3 trial before it can be approved for treatment. Given that bile duct cancer is so rare, this confirmatory trial could take some time to conduct, the researchers warned.

Future studies will also need to figure out when zanidatamab or some other HER2-blocking drug would need to be given to provide maximum benefit to a patient, said Dr. Dierdre Cohen, director of gastrointestinal oncology for the Mount Sinai Health System in New York City.

“We look forward to really understanding where within the treatment paradigm HER2 targeting lies, and with which agent,” Cohen said. “Where each of these are going to lie within the continuum of a patient's journey, and also ultimately understanding those who are resistant to HER2 targeting and why. And for those who respond, what are the mechanisms of resistance and can we overcome them with different strategies?”

Not all bile duct cancers are driven by HER2 mutations. But the realization that HER2 is involved in some bile duct cancers is part of a larger effort to find new targeted therapies for this cancer, the researchers said.

Drugs already have been developed to block other genetic factors in bile duct cancer like FGFR2 and IDH1, Harding said.

Along with advances in surgery and immunotherapy, these drugs are providing fresh hope for bile duct cancer patients, Kamal said.

Until now, bile duct cancer has been so deadly that patients quickly progress through chemotherapy to hospice care, with little to no study done of their individual tumor, Kamal said.

“What this highlights is that workup is extraordinarily important because you might have a targeted therapy available now,” Kamal said. “There may be patients who would otherwise not be treated at all, or be treated with regimens that we're not sure are going to work, who now have a new option potentially.”

And, he added, “It also highlights the need for bile duct cancer patients to seek clinical trials because of the increased appreciation that there are activating markers that can be targeted. I would encourage any person who has bile duct cancer to make sure that there's a biopsy, make sure that it is evaluated for any type of activating marker and make sure that they think about clinical trials.”

Kamal pointed out that “it used to be that cancer clinical trials were the place of last resort, meaning you ran out of other options, you went to pursue a clinical trial. Today, clinical trials are how to get to the front of the line for the newest and greatest things in oncology. It is now less about experimentation and more about access to innovation.”

More information

The American Cancer Society has more about bile duct cancers.

SOURCES: James Harding, MD, gastrointestinal oncologist, Memorial Sloan Kettering Cancer Center, New York City; Shubham Pant, MD, gastrointestinal oncologist, University of Texas MD Anderson Cancer Center, Houston; Arif Kamal, MD, chief patient officer, American Cancer Society; Dierdre Cohen, MD, director, gastrointestinal oncology, Mount Sinai Health System, New York City; The Lancet Oncology, June 2, 2023, online

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