Immunotherapy and Targeted Therapy Approaches Drive Advances in Biliary Tract Cancer

Flavio G. Rocha, MD, FACS, FSSO

The varied landscape of biliary tract cancer has long stalled therapeutic developments, but disease subdivisions may provide insight into the best avenues for effective treatments and individualized care, according to Flavio G. Rocha, MD, FACS, FSSO. In particular, Rocha highlighted that treatment with durvalumab (Imfinzi) plus gemcitabine and cisplatin has the potential for further study beyond the findings from the phase 3 TOPAZ-1 trial (NCT03875235).

“It has been an exciting time in cholangiocarcinoma with all the new molecular information and all the new drug development,” said Rocha, who is an associate professor of surgery in the Division of Surgical Oncology and the Hedinger Chair and division head of surgery in the Division of Surgical Oncology in the School of Medicine at Oregon Health & Science University, in an interview with OncLive^®.

In the interview, Rocha discussed the types of biliary tract cancer and what has been learned about them, explained the effects of systemic therapy on surgery, and relayed remaining questions pertaining to the efficacy of immunotherapy.

OncLive^®: Please provide some insight on the epidemiology and pathogenesis of biliary tract cancer.

Rocha: [To clarify,] biliary tract cancer is a conglomerate of several disease entities. What they have in common is that they grow along the biliary tract epithelium that starts in the liver and goes from the microscopic ducts [flowing] down into the larger channels, [such as] the hepatic ducts and the common bile ducts. There is an offshoot of that to the gallbladder, which is usually lumped into biliary tract cancers. [The tract also] moves down into the head of the pancreas and out to the small bowel. [Biliary tract cancer] is a collection of different diseases.

When thinking about how to [differentiate] biliary tract cancer, cholangiocarcinoma and gallbladder cancer are the 2 main divisions. Then, within cholangiocarcinoma, there is also a subdivision into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. We put them all together because [cholangiocarcinoma] is a relatively rare disease here, in the United States, with around 4000 to 8000 cases. However, [this disease] is much more prevalent in other countries—especially Asia, where we think epidemiology may [be a contributing factor]. In Asia, we know there is an association with parasitic infections. [For example], liver flukes cause inflammation in the bile [ducts] in patients with cholangiocarcinoma.

Gallbladder cancer is interesting because some areas are known to be endemic with it. We see a much higher incidence in countries like Chile and India. In the United States, we see certain populations that have a higher incidence of gallbladder cancer, for example, in our Native American community. Some genetic and environmental factors contribute to the development [of this disease].

What we’re seeing as a trend in the United States, however, is that in general, the onset of liver disease, whether from hepatitis or from metabolic syndrome, is predisposing patients to develop more intrahepatic cholangiocarcinoma than extrahepatic cholangiocarcinoma. The incidence used to be higher for the extrahepatic component than for intrahepatic disease. We [continue to learn] a bit more about the disease process and how it may develop.

How have the many subdivisions of this disease have influenced drug development?

The patterns of biology are different. For example, gallbladder cancer tends to present either asymptomatically or very late with symptoms, but it tends to spread early, so we see a higher proportion of patients present with metastatic stage IV disease. We also see in some ways, but to a lesser degree [than extrahepatic disease], the intrahepatic component, because those patients present with a liver mass that may or may not be symptomatic. They may present with a solitary mass or multiple masses at 1 time. Extrahepatic cholangiocarcinoma may present a bit earlier, because when the bile ducts get obstructed, people can develop jaundice, and it’s hard to ignore jaundice or cholangitis, which is an infection of the bile ducts.

The way the patterns of the disease grow is the way they present. This certainly presents challenges for drug development and treatment. As a surgeon, it also presents a challenge with what operation should be done, whether it is a liver resection [alone], a pancreas resection [alone, or] some combination.

We’ve also learned that these differences in biology are probably due to the genetic components [of these diseases]. We’re learning that cholangiocarcinoma has a rich mutational landscape. The profiles are different between these tumors. For example, [although we see] a higher proportion of KRAS-[mutated] cancers in gallbladder and extrahepatic disease, we don’t often see KRAS being the driver of intrahepatic cholangiocarcinoma. We do see an increased incidence of actionable mutations in intrahepatic cholangiocarcinoma, with certain mutations like IDH1 and FGF2 fusions. That’s where much of the drug development has been focused.

How have you seen systemic therapy affecting surgery, and how may this therapeutic approach continue to make an impact in the future?

A trend in general in most gastrointestinal cancers is that many new treatments and novel therapies are typically targeted at the advanced disease population where there are no other treatments available. As a surgeon, I would love to see that treatment paradigm moved up to convert patients who were not initially thought to be surgical candidates because they have locally advanced disease, and that can be potentially down staged.

This is what we’re seeing, for example, with the new triplet regimen, gemcitabine, cisplatin, and nab-paclitaxel [Abraxane], which was being investigated in the stage IV setting. We recently took that to a neoadjuvant approach to see if we could convert patients from what we termed to have oncological high-risk disease and [instead] get them to surgery.

[We want to achieve the] same with the molecular markers. We were operating on patients when they had a liver mass without a diagnosis, [but now] we are increasingly asking for that piece of tissue to do the [molecular] profiling to see whether we can recognize some actionable mutations. The [mutations] that come to mind are those like microsatellite instability [MSI], because that’s an entity that we can now treat with immunotherapy [and see] fantastic results. [It makes me think] back to some of the cases I’ve had recently where we’ve treated large liver masses in patients with MSI-high disease or Lynch syndrome, [and they] have had almost a complete response [CR] to just the drug therapy alone. [A CR without surgery] would be the home run.

What is known so far about the durability of benefit with immunotherapy?

The most recent data we have is from the TOPAZ-1 trial, which looked at an unselected patient population with advanced biliary tract cancer that was treated with gemcitabine, cisplatin, and durvalumab. TOPAZ-1 was a positive trial [for the triplet] compared with chemotherapy alone.

However, we don’t have good information on the subsets [of patients]. One subset analysis might be favoring patients in Asia, one may be favoring locally advanced disease, and one may be favoring intrahepatic cholangiocarcinoma. However, we don’t know the details yet.

The important part of this is [to determine] the durability [of these benefits]. In TOPAZ-1, durvalumab was given as a combination therapy, but also as a maintenance regimen, whereas the control arm only had the chemotherapy alone and was stopped at 6 months. The next important questions to ask are: What should the duration of therapy be? Should we give it preoperatively or postoperatively? What subsets of patients are likely to benefit the most? The MSI-high population certainly benefits, but in these unselected patients, who are most likely to benefit from this treatment?

What ongoing or planned research are you excited to see explored at Oregon Health & Science University?

Here, at Oregon Health & Science University, we certainly have a keen interest in biliary tract cancer. We take a multidisciplinary approach and have ongoing protocols for neoadjuvant chemotherapy.

As a follow-up to the TOPAZ-1 study, which was presented at [the 2022 ASCO Annual Meeting,] we are going to be part of the [phase 2] OPTIC trial [NCT05514912], which is in development, and is looking at a similar population of patients with resectable intrahepatic cholangiocarcinoma. Those patients will be profiled, and those who have a FGF2 fusion will be treated with an FGF2-targeted agent, followed by a resection. Those who do not have an actionable FGF2 mutation will then be treated with what will hopefully be the new standard, which is gemcitabine, cisplatin, and nab-paclitaxel.

In addition to that, we also offer hepatic arterial infusion therapy, which is a device that is implanted and delivers chemotherapy straight to the liver. We have seen some success with that approach in intrahepatic cholangiocarcinoma with bulky or multifocal tumors because the chemotherapy is directed straight to the liver, which is the area of the tumor and typically the area of recurrence following resection.

What facets of multidisciplinary biliary tract cancer treatment would you like to emphasize to fellow surgeons or medical oncologists?

Let’s work together. Let’s try to bring some of these treatments perhaps earlier in the treatment sequencing. [We should also work] with our interventional radiology colleagues. We give many therapies locoregionally.

The ultimate goal is [determining whether] we [can] provide the optimal treatment sequencing as all these treatment modalities come into play. We’re learning that perhaps the molecular landscape may also be different between early-stage and late-stage disease. We may need to tailor our approaches based on patient factors, liver factors, and tumor factors.