Cholangiocarcinoma: New Targeted Therapies on the Horizon

Targeted Therapies in Oncology, July 2016, Volume 5, Issue 5

An increasing number of investigators are focused on developing therapies specifically for cholangiocarcinoma as rates for the disease are rising. 

Rachna Shroff, MD

If it seems like cholangiocarcinoma rates are increasing, that’s no coincidence. According to Rachna Shroff, MD, assistant professor of Gastrointestinal (GI) Medical Oncology at the University of Texas MD Anderson Cancer Center, part of the increase is that better diagnostics have allowed for the reclassification of some tumors from carcinoma of unknown primary to cholangiocarcinoma. “More concerning is that the lifestyle factors we’re all seeing in increased numbers— cirrhosis, obesity, fatty liver disease–all probably play a part in causing this disease,” she says.

The good news is that investigators and pharmaceutical companies are showing an unprecedented interest in cholangiocarcinoma. Since 2010, the standard of care in advanced biliary tract cancers has been cisplatin plus gemcitabine, as shown by Valle et al in their phase III randomized, controlled trial known as the ABC-02 study, which was published in theNew England Journal of Medicine.

Now, an increasing number of investigators are focused on developing therapies specifically for cholangiocarcinoma. “Since it has historically been thought of as an orphan disease, companies have been reluctant to put resources into a trial that might not be completed due to patient accrual difficulties,” says Shroff. “But we’ve proven that it’s actually quite feasible to accrue to cholangiocarcinoma trials.”

Shroff points to two current multicenter phase II trials in which she is involved. One is examining Novartis’s oral drug BGJ398, which blocks the activity of fibroblast growth factor receptors (FGFRs) in patients with FGFR fusions or alterations. Investigators accrued all 47 cholangiocarcinoma patients in about 18 months, half the expected time.

She is also the principal investigator of a trial examining the effects of adding nab-paclitaxel (Abraxane) to the standard gemcitabine and cisplatin regimen in advanced biliary cancers. In just over a year, the trial has accrued 37 out of 50 planned biliary cancer patients: “We’ve had to put a temporary hold on accrual because our research staff couldn’t keep up with the demand.” She expects accrual to be completed by the end of 2016, twice as quickly as expected.

Additionally, several companies gaveTargeted Therapies in Oncologyan inside look at their cholangiocarcinoma pipelines.


Ignyta, Inc.’sentrectinib(RXDX-101) is an investigational agent that targets NTRK 1/2/3,ROS1, and ALK gene fusions. The company presented combined data from its two phase I trials (ALKA and STARTRK-1) at the European Society of Medical Oncology (ESMO) and American Association for Clinical Research (AACR) annual meetings showing that the drug appears to be safe and well tolerated.

In those trials, which had 119 patients total, investigators observed confirmed responses in 19 of 24 patients (79%) with extracranial solid tumors that had the gene targets, were naïve to inhibitors of those targets, and had received an efficacious dose. Responses were seen across 6 distinct histologies; in NTRK-rearranged tumors, the drug achieved responses in four different histologies. Brisk responses (within 4 weeks) and durable responses of up to 2+ years were achieved.

Ignyta is currently accruing patients for STARTRK-2, an open-label multicenter phase II basket study across multiple solid tumors. The study will operate in 15 countries at approximately 150 sites, including 40 to 50 in the United States.

“We also have the ability to open sites quickly if a patient can’t get to an already-open site,” says Pratik Multani, MD, Ignyta’s chief medical officer. “We can enroll patients based on their results from previous testing and are also making the companion diagnostic free as part of the trial.”

That’s because Ignyta needs mutation data from as many tumor samples as possible to bolster its unusual strategy of working toward a scientific and regulatory innovation based on a molecular label.

“Think of entrectinib as a drug for NTRK-mutated tumors rather than a specific tumor type, such as cholangiocarcinoma,” suggests Multani. “No drug has that kind of label, but that is the underlying premise of our STARTRK-2 basket trial. Only through broad profiling of various tumor types to identify potential targets can we generate the necessary clinical data.”

He notes that Ignyta’s own testing has identified molecular targets that are not currently recorded in the literature: “This strengthens the message that we can find these tumor types only by widespread testing.”

For more information on the phase II trial for entrectinib in patients with NTRK, ROS1, and ALK gene fusions, please visit


Agios Pharmaceuticals is targeting the mutant metabolic enzyme IDH1, whose mutations are believed to affect cell differentiation throughout the tumor life cycle in a variety of solid tumors, like cholangiocarcinoma, that are difficult to treat or have no standard therapy.

“IDH1m inhibitors may be the first targeted medicine available for cholangiocarcinoma, chondrosarcoma and glioma,” says Samuel Agresta, MD, vice president and head of clinical development at Agios. “We believe these drugs could potentially change the treatment paradigm for patients with IDHm-positive solid tumors the way Herceptin did for HER2+ breast cancer.”

AG-120 acts differently from standard chemotherapy. “It doesn’t necessarily kill the mutant cell, but prompts it to go through the appropriate maturation into a more mature cell that can perform as a nonmutated cell,” Agresta says.

Agios has completed a single-arm dose escalation trial with 62 patients, which identified a recommended phase II dose of 500 mg given once daily in 28-day cycles. Of these, 25 patients (40%) were cholangiocarcinoma patients. Of the 55 patients still on the trial at data cutoff, 20 were cholangiocarcinoma patients. Of these, 1 patient achieved a partial response and 11 patients had stable disease. Agresta notes that patients with stable disease were living 30 to 50+ weeks, which he believes foretells measurable clinical benefit in the expansion phase and future studies. The expansion phase is currently enrolling 4 cohorts each of 25 patients; one cohort will consist of a homogeneous subset of cholangiocarcinoma patients. A randomized study of AG-120 in IDH1m-positive cholangiocarcinoma is planned to begin later this year.


Finally, Halozyme Therapeutics, Inc. is taking yet another investigational approach by examining whether PEGylated human recombinant PH20 (PEGPH20) can deplete hyaluronan (HA) in the tumor microenvironment.

“Our hypothesis has been that high levels of HA in tumors leads to difficult-to-treat disease, so reduction in the HA levels with PEGPH20 could improve the effectiveness of other cancer therapies,” says Michael LaBarre, PhD, Halozyme’s chief scientific officer. “Previously published literature reports that high levels of HA can correlate with decreased median survival in several solid tumor types, including pancreas, non-small cell lung, gastric and metastatic breast cancers.”

LaBarre, a chemist, explains that HA is a large polysaccharide that absorbs water and forms a gel-like mass in the tumor. “In animal models with high amounts of HA, PEGPH20 has been shown to reduce HA levels, which can lead to reduced intratumoral pressure, decompressed vasculature and increased perfusion, which in turn can lead to increased access for therapeutics and immune cells,” he says.

The company recently opened HALO-301, a randomized double- blind phase III trial to compare PEGPH20 with paclitaxel plus gemcitabine with paclitaxel plus gemcitabine and placebo in 420 patients with advanced pancreatic cancer. “We also see cholangiocarcinoma as a potential target disease for investigation,” LaBarre says. “In general, it has high levels of HA and nonclinical data shows that PEGPH20 can be combined with many classes of therapies, including checkpoint inhibitors.”

These potential therapies all differ significantly, but one constant in clinical practice should be acquiring tumor profiling data. MD Anderson’s Shroff urges oncologists to send off diagnostic tissue for next-generation sequencing on all cholangiocarcinoma patients even before referring them to a tertiary medical center.

“That message is starting to get out to our colleagues because we do see a fair number of patients come in with testing already performed. This profiling data may identify actionable mutations in up to 30% of cholangiocarcinoma patients and can help guide us about what clinical trials to offer in the future,” says Shroff.


Valle J, Wasan H, Palmer D, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.N Engl J Med.2010;362:1273-1281.