Clinical, Scientific Updates at CCF 2022 Highlight Advances in Cholangiocarcinoma

The co-chairs of the Cholangiocarcinoma Foundation 2022 meeting, Lipika Goyal, MD, MPhil, of Harvard and Massachusetts General Hospital, and Jesper B, Andersen, PhD, of the University of Copenhagen, Denmark, reviewed clinical and scientific developments.

As recently as 2006, cholangiocarcinoma—or biliary duct cancer—did not have a standard of care, much less advanced treatments. But the rise of precision medicine and research to create models of how this rare disease works have improved options for the 8000 patients diagnosed each year in the United States, according to the co-chairs for the 2022 Cholangiocarcinoma Foundation (CCF) annual conference, held February 23-25 in Salt Lake City, Utah, and online.

Lipika Goyal, MD, MPhil, assistant professor of Medicine at Harvard Medical School and a faculty member in gastrointestinal medical oncology at Massachusetts General Hospital, offered an overview of the clinical developments in cholangiocarcinoma (CCA), while Jesper B, Andersen, PhD, associate professor and group leader at the Biotech Research and Innovation Centre at the University of Copenhagen, Denmark, reviewed progress in basic science—especially the development of biomarkers—that is advancing treatment in the disease.

Andersen likened his early years of researching CCA at the National Institutes of Health (NIH) to Sisyphus pushing a boulder up the hill. Fifteen years ago, he said, the landscape was bereft not only of treatments but even cell lines for research. “There was nothing,” Andersen said.

Fast forward to 2022, Goyal said, and there have been great strides. She highlighted a tripling in the number of clinical trials and Andersen pointed to the soaring number of papers published in the field—including 2000 last year—as signs of progress.

Goyal is best known for her work on how FGFR resistance develops and how patients can benefit for longer stretches from FGFR inhibitors, a new class of targeted therapy (the first, pemigatinib, sold as Pemazyre, was approved for previously treated patients in 2020).

Her talk reviewed recent progress in chemotherapy, targeted therapy, and immunotherapy. One reason for progress, she said, is that the field has moved beyond characterizing CCA purely by where it is in the body and instead looking at each tumor’s mutations. “Now, we’re learning to segregate this disease into different molecular buckets,” she said, with the hope that partnering with scientists can yield the same progress seen in melanoma, lung, or colon cancer.

Acquisition of tissue through biopsies and donations has allowed researchers to build models of the disease, which Goyal said are now used to develop “more rational clinical trials that have a better chance of helping patients.”

Chemotherapy. Goyal said that the chemotherapy standard of gemcitabine and cisplatin would now be joined by the immunotherapy durvalumab, based on recent results from the TOPAZ-1 trial; these data were presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI). She also highlighted other new data presented at ASCO GI, which found that adjuvant treatment with S-1, an oral fluoropyrimidine derivative, improved overall survival when given after surgery.

Also, Goyal reviewed a study led by the CCF that seeks to pinpoint which patients need adjuvant therapy after resection. One method being pursued is to collect patients’ blood after surgery for a liquid biopsy; analysis for circulating tumor DNA may reveal whether cancer is likely to recur.

Targeted therapy. Reviewing patients’ tissue after biopsy can reveal whether patients have a mutation driving the cancer—and in cholangiocarcinoma, Goyal said, there is no shortage of targets. The 2020 breakthrough of achieving FDA approval for therapies that targeted FGFR2 alterations is just a start, she said. And it’s what has caused experts in the field to think about cholangiocarcinoma differently.

“Over time, we think of the different anatomic subtypes by mutation as well,” Goyal said. A campaign to reach patients and urge them to ask about biomarker testing is just part of the solution. “The onus is on us as oncologists to offer [testing] to all patients, especially because now there are FDA approved therapies.”


Basket trials, which study mutations across multiple tumor types, have been a boon for CCA research, since it’s still a rare disease despite rising numbers. In some cases, there wouldn’t be enough patients to merit an entire study, but the disease could be studied in an arm or even a few patients in a larger study. Today, patients with CCA can be included in clinical trials involving well-known therapies that have been used to treat other cancers, so more is known about adverse events. Goyal offered the example of research with pertuzumab and trastuzumab, HER2 inhibitors used for years in breast cancer, which have now demonstrated tumor shrinkage in CCA.

A first-in-human trial involving an agent called RLY-4008 produced incredible results in a 35-year-old patient whose tumor was unresectable. He received the FGFR2-specific inhibitor, which caused his tumor to shrink 83%, to the point where he could have surgery. Studies like this are less risky than in the past, Goyal said. “A lot of oncologists don't do phase 1 trials; sometimes they feel like, ‘oh, the response rate is 5%.’ But we now have these models—we now have this way of interrogating tumors to figure out what's the mutation,” she said. “So clinical trials in phase 1 are having much more efficacy than they used to.”

Immunotherapy. Goyal offered additional details on TOPAZ-1, noting that the patients who received durvalumab along with the standard chemotherapy combination had much better survival at 24 months—25% vs 10%.She highlighted the tail on the curve in the results, saying, “There's a population of patients who are getting significant benefit at 2 years, even though the actual difference in median survival was not too different.”

Biomarker advances. In his talk, Andersen described how researchers in cholangiocarcinoma have emerged from “the Dark Ages,” and are catching up in precision oncology, including next-generation sequencing (NGS). Ten years ago, Andersen’s work at NIH led to the first genomic classification prognostic classifier in CCA, which is still used. At that time, Andersen identified that patients with poor prognosis had inflammation and higher levels EGFR or HER2 expression, and KRAS mutations. Those who lived longer, he said, had changes in genes involving immune responses. In time, the work led to the identification of IDH1, KRAS, TP53 and other cancer drivers. Identification of the IDH1 mutation led to the 2021 approval of ivosidenib (Tibvoso).

A separate study classified existing drugs by the pathway of their response, with the hope of using “off the shelf” treatments—drugs already used to treat other cancers—to help specific groups of patients with cholangiocarcinoma. The number of patients in the study being treated this way grew from 500 to 1500 in just a few years.

A half dozen important studies in the past 18 months have focused on single-cell genomics, which examines the individuality of cells, made possible by NGS. Andersen said this work helps answer important questions. “For example, with immunotherapy, we can start to understand why some will respond and some will not respond, because it gives an intensified view of the stromal and immune cell niche.” This work also gets into the role of proteins and how cells interact with one another, he said.

Biomarkers matter, he said, “because if we really are to make a difference in cholangiocarcinoma, we need to diagnose the disease much earlier than today.” Andersen explained how there are many types of biomarkers, including prognostic biomarkers that can monitor both the development of the disease but also the response to therapy. This can answer whether it makes sense to continue therapy, or whether it should be stopped.

Notably, Andersen said, bile duct cancers are being studied alongside more common cancers in major biomarker studies, such as the DELFI study at Johns Hopkins that is examining circulating tumor DNA.


Biomarker research may allow for greater matching of patients to drugs and even prompt investigators to take a second look at therapies that fared poorly in clinical trials. “If we now find the right patients, maybe we can also reuse some of those drugs that are already out there,” he said.