Afsaneh Barzi, MD, PhD

There are good chemotherapy combinations in this patient population. We talked about FOLFOX [folinic acid, fluorouracil, oxaliplatin] based on the ABC-06 trial, and we talked about 5-FU [fluorouracil] and Onivyde [liposomal irinotecan] based on the NIFTY trial. There are targeted therapies for patients we are identifying, and in those who are MSI [microsatellite instability]-high, pembrolizumab remains a recommended second-line therapy in this patient population. Outside of that, although there are some smaller studies and a recommendation by NCCN [National Comprehensive Cancer Network] to consider immunotherapy in subsequent lines of therapy, I would say I don’t have any high-quality data to strongly recommend immunotherapy. I think we have very good chemotherapy options that have shown efficacy in trials and very good targeted therapy options, if you’re thinking about immunotherapy, we should really see trials that are evaluating immunotherapy in second and subsequent lines of therapy. Additionally, if immunotherapy makes its way to the frontline setting, and if patients are all potentially exposed to immunotherapy in the frontline setting, the role of this treatment in subsequent lines of therapy is going to go away. Immunotherapy in the second and subsequent lines of therapy for cholangiocarcinoma is not high on my list for most patients.

I would say cholangiocarcinoma is a mysterious disease. It is important to make sure our patients have cholangiocarcinoma. Patients present with liver metastatic disease, but a patient with colon cancer would present liver metastatic disease, so appropriate work-up to make sure this is truly cholangiocarcinoma is important. If a patient hasn’t had a colonoscopy, considering colonoscopy and EGD [esophagogastroduodenoscopy] is important. There are some data that cholangiocarcinoma, and especially intrahepatic cholangiocarcinoma incidence, is rising, but it is believed that the rise is actually based on a better classification of tumors of unknown primary to cholangiocarcinoma. My general advice is if you see somebody with liver lesions, and you do a biopsy and it comes back adenocarcinoma, hepatobiliary primary, that is not necessarily a pancreatic cancer if you don’t see anything in the pancreas. That’s an important consideration because for the pancreas, FOLFIRINOX [folinic acid, fluorouracil, irinotecan, oxaliplatin] is a standard therapy. However, in a recently published study, FOLFIRINOX is actually not a good therapy for cholangiocarcinoma. We must be careful to label these patient cases appropriately and make sure we rule out common diseases such as colon cancer. And again, for a biopsy of the liver that reads as hepatobiliary malignancy, if you don’t really see any pancreatic cancer or pancreatic lesions, think about cholangiocarcinoma. The treatment paradigms are very different, and it’s important to think about that.

Next, I would say don’t forget the molecular testing in this disease. This disease now has targeted therapies that are FDA approved. There are also many trials that are ongoing, targeted therapies that have good data behind them although they don’t have FDA approval, and those treatments are listed in the NCCN guidelines. I think as oncologists, our most important job is to label these cases appropriately, do not mislabel a patient with cholangiocarcinoma as having pancreatic cancer, and do not label them as cancer of unknown primary. It is our responsibility to label them appropriately, and it is on us to do appropriate and timely testing for identification of biomarkers. It’s on us to appropriately transition them from one line of therapy to another, and to not miss the opportunity for the patient to get exposed to an effective therapy that can control their disease for a long time.

Case: A 75-Year-Old Man with Metastatic Cholangiocarcinoma

A 75-year-old man presents with abdominal pain and weight loss.

History of hepatitis B infection more than 10 years ago and hypertension which is controlled with medication

Blood work reveals serum levels of CA 19-9 (1200 U/ml), bilirubin 1.5 mg/dL, ALT 250 U/L, AST 95 U/L

Histopathological examination identifies adenocarcinoma with primarily mucin-producing glands

Patient is identified to have intrahepatic cholangiocarcinoma (iCCA).

CBC is unremarkable (absolute neutrophil count 3,500/mm3, platelets 300,000/ml, hemoglobin 10.1 g/dL)

ECOG PS is 1 and the patient is in good health.

Patient is referred to oncologists for next steps and is started on treatment with gemcitabine and cisplatin in June 2021.

Patient is experiencing grade 2-3 neutropenia and fatigue and the oncologist has adjusted the dose to reduce toxicities with chemotherapy.

Videos

Clinical pearls regarding molecular testing and treatment selection in metastatic cholangiocarcinoma.

Sequencing Therapy With Novel Agents in Metastatic Cholangiocarcinoma 

Ivosidenib was also FDA approved this year for patients with cholangiocarcinoma and an 

 mutation. There was a randomized study looking at ivosidenib versus placebo, allowing the patients on placebo to be switched over to ivosidenib. It showed an improvement in the PFS [progression-free survival], which was the basis for FDA approval. In the control arm, the PFS was 1.4 months, and in the ivosidenib arm the PFS was 2.7 months with a hazard ratio of 0.37, and a significant 

value. Although numerically it’s a small improvement, it is a very respectable hazard ratio of 0.37, so I think it is an active drug. It is an oral agent.

The one thing about the drug that’s very interesting is one of the most common toxicities is ascites. However, when you look at the trial, the placebo arm experienced almost as much ascites as the treatment arm. One question remains, is this molecular change, which is an 

 mutation, potentially resulting in more peritoneal involvement in ascites than other tumor types? We do not know the answer. But the important thing is careful attention to management of ascites in this patient population. The drug is also associated with nausea, vomiting, diarrhea, and loss of taste and appetite. Those are toxicities that as oncologists we are feel more familiar with and more comfortable managing them. However, one cannot argue with the fact that we now have a targeted drug for patients with 

mutations. Testing is the only way you’re going to find these patients with these molecular alterations.

Implications for treating select patients with metastatic cholangiocarcinoma with ivosidenib as second-line therapy. 

IDH Inhibition in Metastatic Cholangiocarcinoma 

 Pemigatinib and infigratinib have FDA approval for second and subsequent lines of therapy in patients with cholangiocarcinoma with 

 fusions or alterations. For both drugs, the approval is based on a single-arm study. Pemigatinib was looked at in a study with 146 patients, 108 of them having an 

 fusion. Pemigatinib had a response rate of 36% and a very prolonged duration of response of more than 6 months in this patient population; that’s a very respectable response rate. Similarly, infigratinib had a response rate of 23%, a disease control rate of 84%, and duration of response of 5 months with a big range going up to 19 months. These are both single-agent studies. They’re smaller studies, so we can’t really say which one is better, but both of them showed a respectable response rate and a good duration of response. It is also important that both of these trials showed a more than 80% disease control rate. Now, I know we are looking at response and we all like the tumor shrinkage or response, but disease control rate is an important goal to achieve. Remember, before these patients go on these treatments, they must have had disease progression, and that’s why they transitioned to this therapy. If we reverse the disease progression to stable disease, that is a good goal to be recognized.

I also would add that these treatments are associated with significant and unique toxicities, some of which are fairly new to the oncology community. Therefore, awareness about those toxicities is important in the care of these patients. The one thing that’s important is for both drugs, time to response is about 2 to 3 months. In other words, these patients don’t respond very quickly to these treatments; that’s an even bigger reason to be careful about the toxicities and not fail the patients because of experience of an early toxicity in this population. I would go back to the response rate of these agents: both these agents have, as I said, a very respectable response rate. In fact, what makes it very interesting is when we look at the first-line therapy, which is gemcitabine and cisplatin, the response rate is 28%. Then we look at the response rate in the second-line setting, and we see a rate in the same range as the first-line setting. That to me in the oncology community is impressive. What we know across the tumor types, as we go through the lines of therapy, is the response rate goes down and the duration of response goes down. The fact that we see these impressive responses in the second-line setting in this population speaks to the importance of this target for this tumor type. Therefore, it falls on us as oncologists to not miss any patient who would have a chance to be treated appropriately with these agents.

Both infigratinib and pemigatinib are FDA approved, and have class-related toxicities. Those include hyperphosphatemia, skin-related toxicities, and ocular toxicities. There are several ocular toxicities, including dry eye, which is the most common ocular toxicity. However, they’re also associated with pigmentation in the retina, which is very similar to the MEK inhibitors; many oncologists are familiar with MEK inhibitor from other diseases or other settings. The one important thing for these patients is to do an ophthalmological examination before initiating the therapy, and then at 1 month. If there are no issues at 3 months, then continue every 3 months with an ophthalmological examination. The dry eye can be bothersome to these patients, and consideration of supportive measures, such as artificial tears and things like that, are justified. If the dry eye is very severe, working with an ophthalmologist to offer other prescriptions to help manage these toxicities is critical. We want to make sure that we manage the toxicities well and allow the patient to see the benefit of these drugs.

The other class-effect toxicity is hyperphosphatemia. Again, as oncologists, we are not really used to hyperphosphatemia; it is something that’s bread and butter for nephrologists dealing with patients with end-stage renal disease, but it’s not common for us in our field. This class of drugs basically does result in significant hyperphosphatemia. The development of hyperphosphatemia is early, usually within the first 2 to 3 weeks. It’s important to check these patients, check the laboratory results at roughly 2 weeks after the start of treatment. It is important to look at the panel for the electrolytes that we are checking. A lot of us do a CMP [comprehensive metabolic panel], but a CMP does not contain phosphorus normally, so we may have to order that. That’s important to keep in mind. If and when hyperphosphatemia happens, it’s important to use phosphate binders. We can advise the patients on dietary modifications that would reduce the ingestion of phosphorous-containing foods that would help with the control of hyperphosphatemia.

As I mentioned, the other toxicities are skin and nail toxicities. A lot of these patients experience changes in the nail, like brittle nails, paronychia; the bed of the nail can get raised and can get very painful. It’s both something that looks different and is not pleasant, so patients need to be counseled about them, and it should be appropriately managed. There are published papers with regard to the management of these things. I think as an oncologist, it’s important to be aware of them, pay attention to these adverse effects, and find a way to manage them.

Insight pertaining to the use of infigratinib and pemigatinib, FGFR inhibitors, as second-line therapy for metastatic cholangiocarcinoma.

FGFR Inhibitors for Metastatic Cholangiocarcinoma 

For advanced metastatic cholangiocarcinoma, the standard of care is gemcitabine and cisplatin based on the ABC-02 trial, which was published almost 12 or 13 years ago. There are 2 trials that are worth mentioning. One is the SWOG-S1815 trial and the PI [principal investigator] is [Rachna] Shroff, [MD] . This looked at triplet chemotherapies, where they added Abraxane [nab-paclitaxel] to gemcitabine-cisplatin. Everybody’s eagerly waiting for the results of the trial. On October 25th [2021] there was a press release from AstraZeneca reporting that the TOPAZ trial, which looked at gemcitabine-cisplatin versus gemcitabine-cisplatin in combination with durvalumab, had met its primary end point for improvement in overall survival. It was a positive trial. Although I haven’t seen any of the results, I think it is very encouraging that maybe immunotherapy is going to be a therapeutic option for the frontline setting of patients with cholangiocarcinoma. One thing that we must keep in mind is that in many of these frontline therapies, whether we look at ABC-02 or TOPAZ, or many other trials, there is a mix of cholangiocarcinoma and gall bladder cancer. In other words, these are trials for biliary tract cancer, and therefore, gall bladder cancer is also included in the trial population. It’s important to know those caveats and minor differences between these trials. There’s another trial that I am guessing we should see the results for some time very soon. That’s KEYNOTE-966, which looked at the combination of pembrolizumab with gemcitabine and cisplatin. I am guessing if the…trial was positive, that this one hopefully will be positive too, so the results of that one are eagerly awaited.

The gentleman in this case received an excellent therapy. I think gemcitabine-cisplatin is the upfront therapy in this patient population. This patient had a bilirubin level under 2 [mg/dL]; I know we are cautious about using gemcitabine in patients with high bilirubin. He did have a performance status of 1, all of which are meeting the requirement for offering this therapy. It’s not the easiest therapy; it does have adverse effects like any other chemotherapy that we offer. I think the oncologist is doing a fabulous job monitoring the patient and adjusting based on the toxicities that were reported, which included fatigue and neutropenia. I think the treatment was very appropriate. The data I shared for gemcitabine-cisplatin and durvalumab are very new. It wasn’t available at the time this patient was diagnosed, and it’s not a standard of care as we are speaking. We’re just seeing a glimpse into the data, however, yes, this gentleman got very appropriate therapy.

I think clinical trials are important in every oncological disease we look at. For cholangiocarcinoma, the importance of clinical trials is magnified…because it is a rare disease. We should think about how we all have to come together, from the oncology community to the patients, to actually find the best treatment for these patients. We do not have a lot of specimens to test, with a limited number of patients in a rare disease, and therefore for those we have, we have to make sure we are channeling them to the appropriate clinical trials. As I mentioned earlier, about 15% to 20% of cholangiocarcinoma cases have targets. Therefore, there are many ongoing trials exploring these targets in this patient population. An example is that infigratinib, which now has an FDA approval in subsequent lines of therapy in patients with an 

 alteration, has an ongoing trial in the frontline setting with the control arm of gemcitabine-cisplatin. It is looking to see if this would be an opportunity to look at the chemotherapy-free or targeted therapy-only option in these patients with 

 alterations. It’s important to identify these patients and refer them for trials. Similarly, futibatinib, which is another drug targeting 

 alterations, is looking in the frontline setting for patients with 

 alterations. Again, it’s looking for a chemotherapy-free option, at least for a select patient population.

There are numerous ongoing trials in the second and subsequent lines of therapy; we must truly think about these trials and channel our patients appropriately. Going back to what I mentioned earlier, timely molecular testing is our key for identification of patients with targetable alterations, and referral of these patients to the appropriate trials.

An overview of the standard of care for patients with metastatic cholangiocarcinoma, and the significance of conducting clinical trials that increase the number and types of therapies available to patients with fewer adverse events and better results.

Treating Metastatic Cholangiocarcinoma 

I gave a few examples of targeted therapies finding their way into the landscape of cholangiocarcinoma. Therefore molecular testing has become a paradigm for evaluation of patients with cholangiocarcinoma. A variety of targeted therapies have FDA approval in the setting as mentioned: ivosidenib, pemigatinib and infigratinib are examples of that. Other targeted therapies, although not FDA approved, they do have basically data to support them, such as 

 mutations. There are also tumor agnostic therapies such MSI [microsatellite instability] and 

fusions that, considered together, provide the rationale for looking for these changes in this patient population. The questions are: when to test, what to test, what to look for in a test, and what platform of testing is the most appropriate? I do believe that in patients who are fit, upfront testing is the best strategy. Part of the reason for that is No. 1, there are clinical trials in the upfront setting that we may be able to get these patients on. However, the more important thing is that this can be a rapidly progressive disease with a rapid decline in the patient condition. If they’re discovered to have disease progression, the time that is spent to identify any marker in that window can potentially be detrimental to the patient condition and the opportunity for use of a targeted therapy. Therefore, earlier testing for better identification of the potential biomarkers for therapy is recommended in this patient population.

The other problem with this patient population is sometimes the biopsy specimen that we have on these patients is very small. I may submit tissue that I have that’s obtained through the diagnostic process, then the result I get is that the tissue is inadequate for NGS [next-generation sequencing] or any other molecular testing that we are interested in. If the patients are in good shape, that provides the opportunity for repeat biopsy, better testing, and gives us a window of opportunity to identify the right patient for the right treatment. The other question is, what kind of testing should we do? I know many of us in the oncology community have been users of next-generation sequencing, which in my opinion is an appropriate platform to use in this patient population given the multitude of the targets. The fact that tissue may not be adequate to do test by test by test, the thing that we must to be careful about is we have to look at the results of the molecular or NGS testing very carefully. Usually when we get the results, on the front page is a summary of the findings.

The real question is not what was found on the tissue, but also what wasn’t found. Usually in the back of the report there is a table that says whether the tissue was inadequate, or the amount and the quantity of DNA, or the technology was inadequate for testing specific targets. That’s important to know. An example is that if you’re looking for 

 fusions, which are the biomarker for infigratinib and pemigatinib, and you look back and it says they could not verify the presence of 

 fusions, then not seeing that result on the front page doesn’t mean the patient doesn’t have it. It only means we need to dig deeper to identify these patients and be certain that a negative result is a true negative result. Another thing is the use of liquid biopsies and whether there’s a justification for using liquid biopsy in this setting. Although liquid biopsies are good and well validated for mutations, their ability to detect other genomic alterations, such as fusions or rearrangements, is very limited. Relevant to the 

 fusions, there was an abstract that was presented at ASCO [American Society of Clinical Oncology annual meeting] 2019 that looked at the Guardant360 test for detection of an 

 alteration in the urethral cancer population. The Guardant360 test was correlated with the tissue testing. Only 25% of the patients who on the tissue had 

Although these tests are evolving and are getting better, purely relying on liquid biopsies for this unique genomic alteration should be avoided. The other caveat with the liquid biopsies is the timing of the test. Testing the patient at the time of their best response to therapy isn’t optimum for identifying the cell-free DNA. You can imagine that if a patient had responded to therapy, the shedding of the tumor or the volume of the DNA in the circulating blood is less, and therefore the likelihood of finding something that would be guiding the treatment goes down. To summarize, I think NGS is the standard testing. Testing should be done on the tissue, and liquid biopsies should be avoided for the most part. If for any reason there is a patient for whom it’s difficult to obtain a repeat biopsy and we’re relying on liquid biopsy, we should do the testing at a time when the patient is progressing or has maximum quantity of the tumor to reduce the chance of not detecting adequate DNA, and as a result, the changes we’re looking for to guide our therapy.

Recommendations for conducting molecular testing and biopsies to learn more about patients who present with metastatic cholangiocarcinoma.

Biomarkers in Metastatic Cholangiocarcinoma

There is no standard or recommended screening strategy for cholangiocarcinoma. These patients are diagnosed based on their symptoms, even in the population with high risk for development of cholangiocarcinoma, such as primary biliary cirrhosis. Given the challenges and difficulties in identifying the cancer, it’s not generally recommended to screen these patients. There is no imaging modality or laboratory tests that would identify these patients. I think the one thing that’s very important is for patients, such as this gentleman, who present with persistent symptoms like abdominal pain going on for month after month, it’s important to not just assume that the abdominal pain is related to GERD [gastroesophageal reflux disease], or for a young female to assume it’s related to IBS [irritable bowel syndrome. We need to look radiographically to see if there are any tumors identified by imaging. I would say the best screening modality is paying attention to the symptoms that these patients present with. Look for early identification of the disease with the appropriate use of imaging in patients with persistent symptoms.

I cannot say I have a recommendation that’s ready for prime time and for implementation in practice [for earlier detection of cholangiocarcinoma]. I would state that there is newer pan-cancer screening technology based on cell-free DNA and methylation patterns that are discovered in the cell-free DNA, such as a test from GRAIL, that is providing a window of opportunity for early detection of these cancers. I would caution that these technologies are not ready for wide adoption and use, but I am hopeful that work on these technologies and better development would provide a tool for early detection of these patients in the near future.

Dr Afsaneh Barzi explains why screening measures for cholangiocarcinoma are so important to patient outcomes. 

Afsaneh Barzi, MD, PhD | Authors

Articles

Sequencing Therapy With Novel Agents in Metastatic Cholangiocarcinoma

IDH Inhibition in Metastatic Cholangiocarcinoma

FGFR Inhibitors for Metastatic Cholangiocarcinoma

Treating Metastatic Cholangiocarcinoma

Biomarkers in Metastatic Cholangiocarcinoma

Improved Screening Measures for Cholangiocarcinoma