Anthony El-Khoueiry, MD

 In summary, the treatment of cholangiocarcinoma has evolved significantly. It’s important to remember the heterogeneity of this disease based on site of origin but also molecular alterations. This is a disease that’s broken down into molecular subtypes. Testing early is important. We have the option of sequencing therapies. Frequently, we start with chemotherapy in the first line. Down the road, we may be doing chemotherapy plus PD-L1 with durvalumab, based on the TOPAZ-1 study. We have second-line options, both chemotherapy, such as FOLFOX [5-fluorouracil, leucovorin, oxaliplatin]. But we also have all the targeted therapies that could be used in the second or third line. If we’re going to use a targeted therapy, my bias is to use it earlier in the second line and leave the chemotherapy options, such as FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], for the third line if possible, because the targeted agents can be quite effective. The earlier they’re used, the more benefit the patient is likely to thrive. In general, this is a disease where we’re actively learning whenever the opportunity arises, with significant recent developments. Please refer patients for clinical trials because these are critical for advancing the treatment of this disease, which is still quite rare. Thank you for your attention.

Videos

Anthony El-Khoueiry, MD, provides a brief review of sequencing therapy for patients with cholangiocarcinoma in the modern treatment landscape. 

Sequencing Therapy in the Current Treatment Landscape of Cholangiocarcinoma

 What about the tolerability of these targeted agents in cholangiocarcinoma? Let’s talk about the FGFRinhibitors as a class. The most common toxicity—and it’s a class effect, which makes sense mechanistically—is hyperphosphatemia. This is seen commonly with these agents, and it’s frequently mild. Sometimes if the elevations of phosphorus are significant, 1 may have to recommend a low phosphorus diet and use some of the phosphorus-binding agents, such as sevelamer hydrochloride, to manage that. Stomatitis would be another relatively common adverse effect. Other things to watch for would be GI [gastrointestinal] toxicity, including nausea, vomiting, diarrhea, and rashes.

A less common adverse effect would be ocular toxicity with subretinal fluid accumulation, such as central serous retinopathy. These patients should have an eye exam at baseline. If they have a history of retinal diseases, they should be evaluated. Frequently this subretinal fluid is self-limited and low grade, and it tends to improve on its own. But it’s something to be conscious about and monitor. With IDH inhibitors, there similar toxicities of fatigue, GI toxicity, nausea, vomiting, diarrhea, rashes, and mucositis at times. These are the types of toxicities to keep in mind.

Focused discussion on the adverse events that may occur when managing cholangiocarcinoma with targeted therapies.

Cholangiocarcinoma: Adverse-Event Management

 I’d like to walk you through the therapeutic approach to advanced cholangiocarcinoma. If we think about first-line therapy, the combination of gemcitabine and cisplatin has been the standard of care for several years. In the last few weeks, we saw a press release reporting that the TOPAZ-1 clinical trial—which examined gemcitabine-cisplatin plus durvalumab, the anti–PD-L1 antibody vs gemcitabine-cisplatin alone—met its primary end point. We haven’t seen the data, but this trial seems to have been closed by the data-safety monitoring committee because of a survival benefit. It was felt to be unethical to continue with the trial. We’re excited and looking forward to the results of this trial, which may lead to the approval of durvalumab with chemotherapy as the new first-line standard. But today the standard continues to be gemcitabine and cisplatin.

In the second line, there are multiple options, and the second-line choice may be influenced by the molecular makeup of the tumor. Hopefully, the patient has had molecular profiling of their tumor before or during first-line treatment. If the patient has no targetable alterations—we’ll come back to this in a minute—the current standard of care, based on the ABC-06 trial, is the combination of 5-FU [5-fluorouracil] and oxaliplatin: FOLFOX [5-fluorouracil, leucovorin, oxaliplatin]. This was compared with active symptom control and showed a modest benefit in PFS [progression-free survival] and OS [overall survival]. Unfortunately, the responses are very rare, and the duration of benefits seems to be rare. We’re still talking about an immediate PFS of less than 4 months in general with this option. But if there are no targetable alterations, FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] is an option. Of course, clinical trials are a great option for second-line cholangiocarcinoma.

Let’s talk about the specific molecular subgroups. If the patient has an FGFRalteration—the most common is theFGFR2 fusion—we have accelerated approval of 2 agents, infigratinib and pemigatinib. Both target FGFR2 alterations, and both are approved oral agents that could be used in the second or third line. The response rates with these agents are from mid 20% to low 30%, and the median PFS is close to 7 months, which is significantly better if you compare it side by side with giving chemotherapy in the second line, where the median PFS is 2 to 4 months. It’s certainly an effective and promising option.

The challenge is that many patients develop resistance. There are established resistance mechanisms that occur, both in FGFRitself and in other parallel pathways. Second-generation agents are being tested in that space. If the patient has an IDH1 mutation, abrocitinib is approved in this space based on the ClarIDHy trial, which was the first molecularly targeted phase 3 study in biliary cancers. This randomized patients in a 2:1 fashion with abrocitinib vs placebo. It allowed crossover. The primary end point was PFS, and it met its primary end point. The PFS with abrocitinib was about 2.7 months vs 1.4 with placebo. The disease control rate was above 50% with abrocitinib compared with mid-20% with placebo.

Later, with longer follow-up, there was a trend in favor of abrocitinib for overall survival, about 10.5 months vs 7 with placebo. An adjusted analysis was done to account for the crossover—because the trial allowed crossover from placebo to abrocitinib—and 70% of the patients did cross over. When accounting for that crossover, and the analysis is adjusted for that, the difference in OS becomes more striking, with a hazard ratio of 0.49 and a median OS of 10.5 months with abrocitinib vs about 5 months with placebo. This is a novel, established option. I spent more time on this because this is a phase 3 trial, and these are final results. With infigratinib and pemigatinib, these are accelerated approvals based on phase 2 data, but they’re consistent data with targeting FGFR.

Lastly, I’ll mention that there are emerging therapies. These are not approved, but there are data for agents that target HER2 [human epidermal growth factor receptor 2], such as the compound known as CW25, as well as the combination of trastuzumab and pertuzumab, which have shown promise in HER2-amplified or 

-mutated cholangiocarcinoma. This is something to keep in mind and refer to. The same with BRAF. There is a study known as ROAR that looked at the combination of BRAF and neck and showed promising activity in that space. A very small subset of patients may make it to the third line. Clinical trials are a priority in that space. If clinical trials aren’t an option, and if the patient had gemcitabine-cisplatin and then FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], then some of the targeted agents that target FGFR orIDH could be used in third line, along with the other agents that we mentioned targeting HER2 and BRAF.

A comprehensive review of chemotherapy and targeted agents available to treat cholangiocarcinoma throughout various lines of therapy.

An Overview of Treatment Advances in Metastatic Cholangiocarcinoma

 In cholangiocarcinoma over time, these various sites can be broken down by site of origin—intrahepatic, extrahepatic, gall bladder, Klatskin, hilar cholangiocarcinoma—and they can harbor different molecular alterations. We’re making significant progress in targeting some of these alterations. We have some drugs approved for these specific alterations. This disease is being broken down into specific molecular subtypes. The alterations vary by site of origin. Intrahepatic cholangiocarcinoma tends to have FGFR2 alterations and 

 mutations vs gallbladder and extrahepatic cholangiocarcinoma, which tend to have HER2[human epidermal growth factor receptor 2] alterations,EGFR alterations, and some RAS and RAF alterations. These aren’t exclusive, but they’re more frequent in extrahepatic and gall bladder compared with intrahepatic. Other alterations can be picked up in cholangiocarcinoma, including BRCA and other DNA-repair alterations, as well as ARC, ROS

 and MET, but I’d like to focus on FGFR,IDH,HER2, andRAF. For all these there are emerging therapies, and we may come back to this later today. ForIDH and FGFR, we have approved agents.

Because cholangiocarcinoma is broken down into molecular subtypes, and because we have therapies approved for specific molecular subtypes—and many others in clinical trials—it’s become critical that we do molecular profiling on these tumors. The preferred test is a next-generation sequencing test that would be quite comprehensive, to pick up FGFR, IDH, HER2, RAF, RAS, and DNA-repair alterations. I would highlight these specifically. I would favor these patients being tested with first-line treatment if possible, before or along with starting first-line therapy, because a large proportion of these patients may make it into the second and third lines. Currently, we have FGFR-targeted therapies andIDH

targeted therapies approved for second and third lines. We have data on emerging HER2-targeted therapies that have some activity. Knowing that these alterations up front could help develop a treatment strategy for these patients.

This is a disease that remains quite rare, and there are clinical trials that are testing some of these targeted therapies in first line. If we have this information before the patient starts first-line therapy, they may end up being referred for a specific clinical trial to examine whether targeting FGFRor IDH along with chemotherapy may be superior to chemotherapy alone, for example. I wouldn’t want to miss those opportunities. At times, tissue may be insufficient or inadequate, and doing liquid biopsies with circulating tumor DNA is certainly reasonable. It’s happening in other tumor types. There’s a reasonable level of concordance between what we see in liquid biopsies and what we see in the tumor. Keeping that option in mind is also important.

Expert insight on the current role of biomarker testing and targeted therapy in cholangiocarcinoma management.

Cholangiocarcinoma Management: Role of Biomarkers and Molecular Testing

 Cholangiocarcinoma continues to be a relatively rare tumor. But a subset of it, what it’s known as intrahepatic cholangiocarcinoma, seems to be on the rise over the past couple of decades. It continues to increase in incidence for reasons that are not completely specified. In general, when we talk about biliary cancers, we’re talking about a few sites of disease. We might be talking about intrahepatic cholangiocarcinoma. We might be talking about hilar cholangiocarcinoma, previously known as Klatskin tumors. We might be talking about extrahepatic cholangiocarcinoma, which usually involves the common bile duct, but not ampullary cancer. We might be talking about gall bladder carcinoma. There are different subsets within the umbrella of biliary cancers that’s important to keep in mind.

As far as diagnosis, there are 2 issues to keep in mind. One is that extrahepatic and Klatskin tumors can be difficult to diagnose because of the difficulty in obtaining tissue verification. Often times, if this is a localized tumor, it requires an ERCP [endoscopic retrograde cholangiopancreatography] with brushings. The yield can be low and may have to be repeated, and sometimes the assistance of an endoscopic ultrasound may increase the yield. That’s 1 diagnostic challenge that can be an issue. If the disease is resectable—and if it definitely looks like cancer, even without being able to verify the diagnosis of cancer on tissue—sometimes the surgeons may proceed to operate.

As far as intrahepatic cholangiocarcinoma, these tumors historically were frequently reported as cancers of unknown origin, or unknown primary cancers, but we’ve learned over time how to diagnose intrahepatic cholangiocarcinoma. Part of it is a diagnosis of exclusion. Typically these patients present with liver tumors—it could be 1 or multiple—and end up having a biopsy, and the way to diagnose intrahepatic cholangiocarcinoma 1 is the histology has to be consistent. It has to be an adenocarcinoma. It has to have the right histologic appearance. Usually, these are CK7-positive, CK20-negative tumors. They may be CA19 [cancer antigen 19]–positive as well. And there’s a diagnosis of exclusion. We make sure that there’s no mass in the stomach, in the esophagus, and that there’s no other upper–GI [gastrointestinal] primary and there’s no other primary elsewhere. Doing an endoscopy or colonoscopy isn’t mandated. If the clinical presentation and the histology are consistent with intrahepatic cholangiocarcinoma, it would be sufficient to call it that.

The other thing I would add is that these patients can have delayed diagnoses, especially the intrahepatic cholangiocarcinoma, because the liver is a large organ, the tumors can grow silently, and patients can present with malnutrition, pain, and significant failure to thrive. Paying attention to nutritional status and performance status, doing interventions to improve nutrition, and the activity level of the patient with physical therapy are important because performance status is a definite prognostic indicator for the outcome of patients with these types of cancers.

Anthony El-Khoueiry, MD, reviews cholangiocarcinoma subtypes and outlines strategies in identification and diagnosis.

Identification and Diagnosis of Cholangiocarcinoma

 In closing, it is certainly exciting to see that we have many more treatment options available for patients with advanced HCC [hepatocellular carcinoma] at this time. It’s important to note, however, that because of the availability of multiple options, we have some challenges ahead of us—I have already alluded to 1 of them—as to what would be the optimal sequence of these agents. There are going to be more studies needed in that regard. I believe that many of us face the challenge of seeing patients with more advanced liver cirrhosis, such as Child-Pugh stage B cirrhosis, and a lot of these agents have been studied in Child-Pugh stage A setting only. This is an area that requires more studies going forward.

We have some limited data that are emerging. We have some safety data for sorafenib in Child-Pugh stage B based on registry data. We also have a small cohort of 40 patients with nivolumab that was part of the CheckMate040 trial where nivolumab was studied as a single agent for patients with Child-Pugh stage B, with a score of 7 and 8. The response rate was comparable to Child-Pugh stage A, about 12% in that cohort, and the toxicity profile was comparable, with a slightly higher risk of AST [aspartate aminotransferase]/ALT [alanine aminotransferase] elevation. But the therapy was relatively well tolerated. For the patients with Child-Pugh stage B who responded to the therapy, many of them converted from Child-Pugh stage B to stage A. But this will be a continuing area of investigation.

I will note that there are many other combinations under consideration, especially in the first-line setting. These include combinations of PD-1 with TKIs [tyrosine kinase inhibitors], such as pembrolizumab with lenvatinib and pembrolizumab with regorafenib. The pembrolizumab-lenvatinib combination is currently in a phase 3 setting being compared with lenvatinib alone. The phase 1 data with this combination looks quite promising as well, with a response rate in the mid-30% range and a median PFS [progression-free survival] that’s at 9 months.

There is the combination of durvalumab and tremelimumab, the HIMALAYA trial, which is comparing DURVA-TREME [durvalumab-tremelimumab] with durvalumab alone and with sorafenib alone. We are awaiting the readout for this. For the nivolumab-ipilimumab combination, I mentioned the accelerated approval in the second line already, but there’s actually a first-line study comparing this combination with sorafenib or lenvatinib, investigator choice.

Lastly, I’d like to comment on the fact that these active systemic therapies are being evaluated in earlier stages of disease. There are adjuvant trials ongoing, looking at nivolumab in the adjuvant setting, pembrolizumab post resection as well in the adjuvant setting, and atezolizumab and bevacizumab post resection. Combination studies with local regional therapy, with liver-directed therapy, are ongoing as well.

Critically important is to start thinking about the time to transition from liver-directed therapy to systemic therapy. Because we have more systemic therapy options available, it is important that we do not overtreat patients with TACE [transarterial chemoembolization] or with Y90 radioembolization, which could become futile at some point. Liver function may deteriorate, and then we may miss the opportunity to sequence the systemic therapies.

This is an area of continuing evaluation. The criteria for shifting from liver-directed to systemic therapy are not all standardized, but there are some widely accepted ones. If the patient develops worsening liver function on liver-directed therapy, they should be switched to systemic therapy if they’re still candidates. If they develop extrahepatic disease, if they develop portal vein invasion, they should be switched to systemic therapy. But there are also more data that after 2 TACEs to the same lesion, if we do not achieve a complete response, the likelihood of additional TACE being helpful is very low. Therefore, this may be an indication again to switch to systemic therapy if the patient still has active disease. Similarly, if patients present with liver-limited disease that’s quite bulky or multifocal, the likelihood of local regional therapy achieving long-term control is low. A subset of these patients with BCLC [Barcelona Clinic Liver Cancer] stage B, with multifocal high-burden disease, may qualify to start systemic therapy up front.

In summary, this is an exciting time for the disease, with more treatment options for our patients. But certainly there is a continuing need for more enrollment in clinical trials and more learning in this space. Thank you very much.

Case: A 69-Year-Old Man with Stage 4 Hepatocellular Carcinoma

A 69-year-old man presented with vague right upper quadrant abdominal discomfort, decreased appetite and occasional nausea and vomiting

PMH: diabetes, medially controlled; hepatitis B virus diagnosed and treated 8 years ago

SH: moderate amount of alcohol use (2-3 drinks a day)

Labs: AFP 425 ng/mL, bilirubin 1.2 mg/dL, AST 102 U/L, ALT 116 U/L, ALP 380 U/L, INR 1.6, albumin 3.6 g/dL, BUN 15 mg/dL, creatinine 1.5 mg/dL, plt 205,000

Abdominal ultrasound revealed 2 hepatic lesions

Chest/abdominal/pelvic CT scan confirmed 2 lesions in the right hepatic lobe measuring 3.2 cm and 5.5 cm, a suspicious lesion in the left lung lobe, and wide-spread lymphadenopathy noted

Biopsy findings showed grade 3 HCC with marked fibrosis

Surgical consult: unresectable due to tumor size and location

Treatment with atezolizumab + bevacizumab was initiated

First imaging shows stable disease at 2 months; imaging at 4-month follow-up showed 2 new lung lesions

Treatment was subsequently changed to cabozantinib 60 mg PO qDay

Anthony El-Khoueiry, MD | Authors

Articles

Sequencing Therapy in the Current Treatment Landscape of Cholangiocarcinoma

Cholangiocarcinoma: Adverse-Event Management

An Overview of Treatment Advances in Metastatic Cholangiocarcinoma

Cholangiocarcinoma Management: Role of Biomarkers and Molecular Testing

Identification and Diagnosis of Cholangiocarcinoma

Future Treatment Landscape of Advanced HCC