Clinical Updates on the Treatment of Advanced Cholangiocarcinoma - Episode 13

Advanced Cholangiocarcinoma: Transition to Precision Medicine 

April 5, 2021
John L. Marshall, MD, Georgetown University

,
R. Kate Kelley, MD, UCSF Helen Diller Family Comprehensive Cancer Center

,
Sameek Roychowdhury, MD, PhD, James Cancer Hospital & Solove Research Institute

,
Milind Javle, MD, MD Anderson Cancer Center

A panel of GI oncologists comment on the transition to targeted therapy and immunotherapy as treatments for advanced cholangiocarcinoma, as well as highlight predictive and prognostic markers that can help guide treatment decisions with novel therapies.

John L. Marshall, MD: Welcome back to our OncLive® discussion focusing on cholangiocarcinoma. We’re going to focus on new therapies in this segment.

This transition to targeted therapies and precision medicine is having an impact on GI [gastrointestinal] cancers. This year at ASCO [American Society of Clinical Oncology Gastrointestinal Cancers Symposium], they gave us a prize for molecular profiling and target identification in GI cancers. A lot of that is being driven by MSI [microsatellite instability], but other targets are also important across the spectrum of GI cancers, and biliary tree cholangiocarcinoma cancers are no exception; in many ways, they have been at the forefront of this discussion. In your patient with breast cancer, you would never treat a patient without knowing ER/PR [estrogen receptor/progesterone receptor], HER2, triple negative, etc, and for colon cancer, we would never treat a patient without now knowing RASBRAF, MSI, etc. Lung cancer is the classic example; you would never treat without knowing the targets. We are getting that way in biliary tree cancers because we now have targets that are frequent enough and are reliable predictors of benefit for different treatments. We need to incorporate them in our decision-making around treatment for these cancers.
 

We just reviewed all the different chemotherapy options available for our patients, and as we saw, we quickly run out of options after a few lines of therapy. Our median survivals are not anywhere where they need to be. Our patients want us to do better for them, and one of the strategies is through precision medicine, which might take us down immunotherapy or targeted therapy approaches. We’re also seeing clinical trial designs that are in support of this. If you have the right drug and the right target, then your studies can be smaller, faster, have higher readouts, and faster approvals and access for our patients. However, these drugs do have adverse effects. Unlike the good old days where we might have 1000 patients exposed to a drug, we now have hundreds of patients exposed to a drug, and knowing how to manage those toxicities that are emerging and are drug-specific is important.
 

I feel precision medicine frustration and fatigue. I send these tests off for patients with the hope that what’s going to come back is a remarkable, Willy Wonka golden ticket-type therapy. Most of the time, I open that report, and I don’t see anything that changes what I have in front of me. When you talk about tests that aren’t that frequent, we get frustrated. A 25% return rate on a disease that you might only see 5 or 6 times a year may not feel worth it, but I think part of what we want to emphasize during our discussion today is the importance of doing this testing correctly using today’s standards, so if that golden ticket is actually sitting across from you in the exam room, you don’t miss it. You do the right test and find that patient who might benefit from these remarkable new therapies.
 

Katie, what are the markers? What are we looking for in this disease, and what’s the high list that you would want to roll out for a patient with bile duct cancer?
 

R. Kate Kelley, MD: I liked the golden ticket analogy. You mentioned 25%. I would say maybe up to 40% of cholangiocarcinoma, particularly intrahepatic, may have an actionable or targetable therapy option. That’s based on data from a greater-than-10,000-patient impact cohort at Memorial Sloan Kettering Cancer Center that’s been published. The definition of actionability can be flexible, but if we look at intrahepatic cholangiocarcinomas, for example, around 15% to 18% will have an FGFR2 fusion, a driver-activating fusion, or other rearrangement in the fibroblast growth factor receptor 2 gene. We’ll talk more about the therapies for that, but pemigatinib is the first that is FDA approved and has shown durable responses in patients with that fusion.
 

The next most prevalent in intrahepatic cholangiocarcinoma is an IDH1 mutation at about 13% to 18%, so looking at both, about 15% in intrahepatics are targetable by the drug ivosidenib. Again, we’ll talk more about the drugs in the next section. At a lower frequency but also prevalent in all biliary tract cancers, from hilar and distal in intrahepatic—we don’t know whether there’s a proclivity for anatomic site yet—are BRAF mutations in around 5% to 7%, which have shown themselves to be very active when targeted. Then we get into the real golden tickets that are quite rare. We don’t know exactly where they live in terms of intrahepatic or extrahepatic, but those are things like NTRK fusions, ROS1 fusions, and MSI-high. I think NTRK and ROS are rare, in the probably 1% range, but have been reported, including in the registrational packets for the drugs, specifically mentioning larotrectinib and entrectinib. With MSI-high, the data are pretty variable, and we do not have much, but somewhere in the 2% to 7% range will have either somatic or germline. Those are the golden tickets we don’t want to miss.
 

John L. Marshall, MD: That’s up in the tree, right? Those are primarily intrahepatic. Does it get drier as we go more distally?
 

R. Kate Kelley, MD: The first 2 that I mentioned are almost exclusive to intrahepatic, and those are FGFR2 and IDH1. For the BRAF, MSI-high, and NTRK, we don’t know exactly where they live. The one I neglected to mention that is higher in extrahepatic and gallbladder is HER2, or ERBB2, either amplification or overexpression. All of those are important to know about.
 

John L. Marshall, MD: I agree with you. I don’t want to underestimate the return on these tests because the list you just gave, we would all put as highly actionable. Some companies will put TP53 in actionable mutations, and we all nod our heads to that, but what am I going to do about that clinically?

Transcript Edited for Clarity

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