Building PROOF In Advanced Cholangiocarcinoma

CUREWinter 2020
Volume 19
Issue 1

Researchers hope the new PROOF trial will show that infigratinib, a targeted drug, will expand options in treating advanced cholangiocarcinoma. Patients are enrolling now.

Dr. Tara Seery would like cholangiocarcinoma to follow in lung cancer’s footsteps.

An oncologist and researcher who is investigating a medication to treat the rare type of cancer that affects the bile ducts, which carry digestive fluid from the liver to the intestines, Seery wants to see patients with cholangiocarcinoma benefit from a growing array of targeted drugs that move from clinical trials to approval by the Food and Drug Administration (FDA), just as lung cancer has.

She imagines a time when, instead of having few therapeutic options, patients with advanced cholangiocarcinoma will choose from a broad selection of targeted agents and be able to switch to another if one stops working.

Seery, who specializes in gastrointestinal cancers at the Chan Soon-Shiong Institute for Medicine in California, is furthering that vision as an investigator in the phase 3 PROOF trial. The study is testing the experimental drug infigratinib as a first-line treatment in patients with inoperable or metastatic cholangiocarcinoma that carries an alteration in the fibroblast growth factor receptor 2 (FGFR2) gene. The drug inhibits the activity of the cancer-driving protein FGFR2, which is produced when that gene and another one fuse or switch places.

Infigratinib recently received fast-track designation from the FDA, which means its development and review will be expedited because it could potentially fill an unmet need for people with a serious condition.

“We had little progress in cholangiocarcinoma for quite some time, and every patient was treated with (the chemotherapies) gemcitabine and cisplatin for the past 10 years,” Seery says. “Finally, it’s coming to light that there are (targeted) treatments that are a possibility for these patients. A trial demonstrated that up to 40% of patients have a genetic mutation that could make them eligible for targeted therapy clinical trials.

“Cholangiocarcinoma is starting to experience the same kinds of advances that lung cancer underwent 10 years ago, when the first of many effective targeted therapies began to emerge as the genetic aberrations that drive lung cancer became better understood. By treating patients according to their specific mutations, our goal is to help them live longer and maintain a good quality of life.”


FGFR alterations occur across a spectrum of cancer types, including cholangiocarcinoma, bladder, breast, endometrial, lung, colorectal and pancreatic. About 7% of cancer cases express FGFR mutations, and 19% of those are specifically FGFR2 alterations, Seery says.

In cholangiocarcinoma, FGFR2 alterations are more common, occurring in 15%-20% of cases. “It’s the most frequent mutation that we see in intrahepatic cholangiocarcinoma,” Seery says. That category of the disease occurs in the small bile ducts inside the liver.

Patients with the alteration make up a unique subtype of those with cholangiocarcinoma, according to Seery. “Typically, we do see the alteration in an earlier stage of the disease, and usually a higher proportion of the patients are younger. It is seen in Caucasians more than in Asians,” she says.

Studies are being conducted to determine if infigratinib will slow the proliferation of, or even kill, tumor cells in this population of patients.

Specifically, in those who have cholangiocarcinoma with FGFR2 alterations, the PROOF trial (NCT03773302) is comparing the effectiveness of infigratinib versus the standard treatment (a pairing of gemcitabine and cisplatin). Twice as many patients will be assigned to infigratinib compared with chemo- therapy. Already enrolling and treating patients, the trial includes 36 sites throughout the United States.

The main goal of the study is to determine progression- free survival, meaning how long patients stay free of disease progression, and to determine whether that period of time lasts longer with infigratinib or chemotherapy. The trial will also test whether patients live longer while taking infigratinib versus chemotherapy.

Participants will be monitored every eight weeks with CT scans or MRIs to check whether their cancer has grown, spread, shrunk or stayed static. If the cancer progresses, patients who were being treated with chemotherapy can switch to receive infigratinib instead and remain in the study, Seery says.

Known side effects of the experimental drug include elevated phosphorous levels in the blood; fatigue; inflammation of the lips and mouth; hair loss and constipation.

liver cancer PROOF infigratinib FGfr2 trial QED

To participate, patients should be in fairly good health with the exception of their cancer and have had no previous systemic or targeted treatment for cholangiocarcinoma. Those interested can get more information by visiting


Because there is currently no curative treatment for this population, Seery says, stable disease and improving or maintaining quality of life are the most important goals in caring for patients with cholangiocarcinoma.

In a previous research study, infigratinib generated a 6.8-month progression-free survival (even after patients had been on multiple other therapies for their cholangiocarcinoma). Just over 84% of participants experienced either a partial response or stable disease.

These results encouraged researchers to start the PROOF study to see if using infigratinib before any other treatments could extend progression-free survival beyond the eight months demonstrated with chemotherapy.

Giving the two treatments back-to-back could keep patients’ disease stable longer, Seery says.

Infigratinib is one of about five FGFR inhibitors in development, and Seery expects it to fit into the field well, perhaps functioning as a first treatment for advanced disease while other agents will treat cholangiocarcinoma that has developed resistance to the drug.

Cholangiocarcinoma can also be driven by IDH, BRAF or MET mutations or ERBB2 amplifications, all of which may be treatable with other targeted drugs, Seery says. That is why patients should insist that their tumors undergo molecular testing, she says: Without it, they will not know if they might benefit from infigratinib or any other targeted drug.

“It’s the most important thing that a patient can do,” she says of the testing. “Right now, we’re trying to get word out so that everyone is aware there are treatments based on these mutations. Not every physician is aware of the mutations. If a patient knows and says something, maybe it will spark the clinicians to order the test.”

This content is sponsored by QED Therapeutics.

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