Milind Javle, MD

 A key takeaway point for my colleagues in community oncology is, cholangiocarcinoma is a diagnosis of exclusion; it requires careful pathology, and it requires multidisciplinary care. It does not necessarily need a lot of aggressive investigations to narrow down the diagnosis. Molecular profiling has been transformative in this disease, and it’s important to consider molecular profiling as early as possible during the disease course. The access to targeted therapies, such as with infigratinib with 

 fusions, has truly changed the course of this disease. I would encourage my colleagues in the community to consider these types of treatments that I’ve described, targeting 

, and others. However, the key would be to get a good biopsy specimen for molecular profiling or perhaps with ctDNA [circulating tumor DNA] so we can help our patients beyond the standard systemic chemotherapy.

One of the reasons that I’ve advocated early molecular diagnosis was from our own experience with the infigratinib study. Patients who received infigratinib in the second line had a higher response rate than those who received infigratinib in subsequent lines of therapy. We are expecting now that when these targeted drugs are used in the first line during the investigational trial, perhaps we’ll see an even stronger signal. I hope the time will come when we don’t have to use chemotherapy anymore for these patients and spare these unnecessary toxicities. That time is not here yet, but I think we will get there with appropriate and early use of molecular profiling.

Case: A 61-Year-Old Woman with Metastatic Cholangiocarcinoma

A 61-year-old woman presents with jaundice and changes in stool and urine color.

Enlarged liver is palpable on physical examination

Blood work reveals serum levels of CA 19-9 (1400 U/ml), bilirubin 2 mg/dL, ALT 550 U/L, AST 120U/L

Patient undergoes CT imaging and is found to have multiple liver masses, consistent with metastatic disease or intrahepatic cholangiocarcinoma (iCCA)

Histopathological examination identifies adenocarcinoma, CK7+, CK20-, HepPAR-, TTF- consistent with cholangiocarcinoma or upper GI Primary

Patient is diabetic and somewhat non-compliant with her diabetes medication

Patient is treated with chemotherapy (gemcitabine + cisplatin) for 24 weeks.

Patient is monitored for disease progression every 2-3 months by CT imaging.

Patient does well for 1 year after initiation of treatment but now has elevated CA 19-9 levels.

MRI scans show several liver and bone lesions but no signs of brain metastases.

Lab results are normal (absolute neutrophil count 4,000/mm3, platelets 150,000/ml, hemoglobin 12.1 g/dL

Patient undergoes NGS testing (Foundation Medicine, Inc.) and is found to have FGFR2-BICC1 gene fusion

Patient meets eligibility criteria for infigratinib phase 2 study and is enrolled in the trial and being treated with infigratinib

Patient does not show any signs of disease progression on MRI scans for six months, suggestive of stable disease and CA19-9 levels stay within normal limits.

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Concluding his reflection on novel therapies in patients with cholangiocarcinoma, Milind Javle, MD, provides closing thoughts and practical advice for his community colleagues.

Key Takeaways for the Treatment of Cholangiocarcinoma

The past year-and-a-half has been truly remarkable for cholangiocarcinoma for the patients and for the providers. We have now 3 drugs that are approved. In the 

 field, we have infigratinib, like I described, as well pemigatinib. For those with 

 mutation R132, ivosidenib is an approved drug in that situation. Clearly patients have options with targeted therapy, which I feel are much more tolerable and superior to systemic chemotherapy, and these options didn’t exist just over a year ago. It’s an exciting time for us.

Pemigatinib was the first drug to be FDA approved for the treatment of 

 fusion cholangiocarcinoma, and the results are very remarkable. The response rate in the pivotal study called FIGHT with pemigatinib for 

 fusion cholangiocarcinoma, indicated a response rate of about 35%, duration of response about 8 months, progression-free survival about 6 months, and overall survival of about 21 months. These are very encouraging results. Most of the people treated with pemigatinib had received this drug in the second line of therapy, so they were less treated. Regardless, there were several patients treated in the third and subsequent line, and they also seemed to do very well. Toxicities with pemigatinib are similar to that of infigratinib and include hypophosphatemia, some of the mucositis, and also patients can develop diarrhea, ocular toxicities. Several of these effects are class effects related to FGFR inhibition because these drugs are very specific inhibitors, therefore they have this class effect of toxicities.

There have been several other exciting developments that have not yet necessarily met the FDA bar for approval, but have become a part of the NCCN [National Comprehensive Cancer Network] guidelines now, such as the treatment of cholangiocarcinoma with 

 V600E mutation. This mutation occurs commonly in melanoma and in about 5% of cholangiocarcinoma. Dabrafenib and trametinib, which is a combination of BRAF plus MEK inhibition, appears to be very effective with almost a 40% response rate, and is now in the NCCN guidelines. Our group performed a study with trastuzumab and pertuzumab, a combination that’s widely used in breast cancer. We investigated 

-amplified biliary tract cancer, again a very promising signal, that was published recently in 

 and we hope will meet the bar for NCCN guidelines.

Immunotherapy has been an amazing development over the past decade, and there have certainly been immunotherapy trials in cholangiocarcinoma as well. MSI [microsatellite instability]-high status in cholangiocarcinoma occurs in only about 1% of patients; for them, checkpoint inhibitors like pembrolizumab and nivolumab are very promising. In terms of patients with cholangiocarcinoma who are not MSI high, immunotherapy shows a signal that is quite modest. There was a KEYNOTE trial with pembrolizumab that enrolled over 100 patients, and the response rate seen was about 5.6%. There may be a tendency toward a somewhat higher response with PD-L1, but this is not proven. Nivolumab shows a similar response rate in a smaller study, about 10%.

There are now studies being conducted with immunotherapy in combination with targeted therapies, and we hope that with those types of combinations we will get a better signal. In the first-line setting, there are 2 important phase 3 trials. One is with gemcitabine and cisplatin plus or minus pembrolizumab. This trial has completed its accrual, and we hope that it will advance the cause of immunotherapy in the first-line setting. Similarly, there’s another trial called TOPAZ being conducted with durvalumab in combination with gemcitabine and cisplatin in Asia as well as in the Western world. The results of that trial are eagerly awaited.

Dr Milind Javle discusses novel therapies recently approved or under investigation across multiple lines of therapy in patients with cholangiocarcinoma. 

Recent Changes in the Cholangiocarcinoma Treatment Landscape

 In this pivotal trial of infigratinib, enrolled patients were extensively treated. In fact, only about one-third had received 1 prior line of therapy, and the rest had received 2 or more lines of therapy. This was a heavily pretreated population. They were treated with infigratinib, 125 mg daily on a 3 weeks on, 1 week off schedule. The overall response rate in the trial was 23%. Interestingly, we noted that patients who had received fewer lines of therapy had a better response rate compared with those who had received 2 or more lines of therapy. The progression-free survival in this trial was 7 months, the duration of response was 5 months, and overall survival extended to beyond 12 months; this was a pivotal and positive trial. I’ve just described the results of FOLFOX [folinic acid, fluorouracil, oxaliplatin] standard chemotherapy, which are relatively poor in comparison. Therefore, this drug got an accelerated approval from the FDA. The accelerated approval mechanism is a conditional approval that requires a subsequent phase 3 trial, which is being conducted at this time. This is called the PROOF trial. The patients who have not received any prior chemotherapy, treatment-naïve patients, are treated with infigratinib vs gemcitabine and cisplatin in the first-line setting. We are still waiting on the results of this trial, but it’s very exciting that patients like the one described now have an FDA-approved option for the treatment of cholangiocarcinoma with infigratinib. This is now known as Truseltiq, which was only the second drug to be approved by the FDA for cholangiocarcinoma. It is certainly a historic event for treating this disease.

At our institute, we were one of the leading sites for the CBGJ398X2204 trial that included infigratinib. We have treated several patients with this therapy. Most of these patients have done quite well with progressive disease or partial responses. There are some toxicities that are encountered with this drug, but in general these are manageable. The most common toxicities include hyperphosphatemia, or elevation of levels of phosphate, which must be carefully followed and sometimes treated with dietary restriction of phosphate, and chelating agents. Other toxicities include anorexia, alteration in taste, mucositis. There is a very low incidence of diarrhea, alopecia. The 2 important toxicities to watch out for are ocular. The most common ocular toxicity is dry eyes, however there are serious ocular toxicities, including retinal pigment epithelial detachment and central serous retinopathy. These are again rare and mostly grade 1 or 2, but must be carefully followed and watched for.

Milind Javle, MD, shares his personal experience and insights on the approval and use of infigratinib, an FGFR2 fusion–targeted therapy, in patients with previously treated advanced cholangiocarcinoma. 

Metastatic Cholangiocarcinoma: Phase 2 Infigratinib Study and Personal Experience With Infigratinib

For patients who do not have actionable mutations, the first-line chemotherapy is still based on the ABC-02 trial, which is gemcitabine and cisplatin. While this is the standard of care, it’s relatively suboptimal. The response rate is in the 20% to 30% range, progression-free survival of 6 to 8 months, and overall survival of 11 months. Therefore, although it is a standard, this is a standard that we hope we can change with therapy. There have been many promising trials, including one recently conducted in the United States with gemcitabine, cisplatin, and Abraxane [paclitaxel] that we hope will change this paradigm.

In the second-line setting, the ABC-06 trial investigated the use of FOLFOX [folinic acid, fluorouracil, oxaliplatin], which is the standard chemotherapy used in colon cancer, and also used in cholangiocarcinoma. Again, it is very modest in terms of how effective it is, with a 5% response rate, progression-free survival of 4 months, and overall survival of only 6 months. Clearly, this is an area that needs further investigation, and cholangiocarcinoma represents an area of great unmet need.

Going back to our patient, she received appropriate first-line treatment, gemcitabine and cisplatin. She had a good ECOG [The Eastern Cooperative Oncology Group] performance status of 1. She handled the treatment, however not surprisingly, she experienced disease progression and the tumor stopped responding after a few months of therapy.

Oncologist Dr. Milind Javel provides an overview of first- and subsequent-line treatments for patients with cholangiocarcinoma. 

Treatment Options for Metastatic Cholangiocarcinoma

 Because this cancer is relatively infrequent, unfortunately there’s no routine screening for it. However, there should be a high index of suspicion when patients have asymptomatic elevation of liver function tests that seem to persist, unexpected loss of weight, and discomfort in the upper abdomen that cannot be explained. These are some of the common symptoms that persist occasionally for months or even years before patients are diagnosed. The challenges that occur in practice are that most patients are diagnosed at an advanced and an unresectable stage and surgery is not possible, and in fact cure is not possible.

Another confirming factor in diagnosis is that the pathologist will not clearly describe that this is cholangiocarcinoma. They will describe that this is an adenocarcinoma and rule out stomach, rule out upper GI [gastrointestinal], rule out pancreas, rule out cholangiocarcinoma, etc. Therefore, in this situation it’s important that we perform immunohistochemical investigations and really talk to the patient and obtain a history, which may point to a particular primary tumor site. In this case, there was no history. There was very good immunohistochemical analysis that pointed to the site of primary. In my practice I see patients who are referred to me who have undergone a series of tests and sometimes unfortunately unnecessary tests to find the site of primary. Cholangiocarcinoma is essentially established by clinically excluding other sites of primary and by a proper pathology analysis, so really the clues in pathology and biopsy can reveal a diagnosis. It does not need any more fancy complicated investigations.

Molecular profiling has been transformative in the management of cholangiocarcinoma. In fact, if you look at all the GI cancers put together, cholangiocarcinoma has more actionable mutations than any other GI cancer. It’s important that we perform molecular profiling or next-generation sequencing in all patients with cholangiocarcinoma, in my opinion, as early as possible. Going back to some of the studies our group did over 7 or 8 years ago, we found that almost 50% of patients with cholangiocarcinoma, especially intrahepatic cholangiocarcinoma, have actionable mutations in 

 V600E, MSI [microsatellite instability], and many other such low-hanging fruit that we can target effectively with approved medications today.

While I say molecular profiling should be done universally in all patients with cholangiocarcinoma and relatively early, clearly there are challenges. Extrahepatic cholangiocarcinoma or hilar cholangiocarcinoma has very little tissue, so we don’t biopsy specimens. Often these are cytology, so you don’t have enough DNA to perform the sequencing. In fact, even in intrahepatic cholangiocarcinoma, which presents as a mass-forming lesion, we should be able to get enough tissue and enough DNA for analysis. However, it depends on the quality of the biopsy. If there’s an FNA [fine needle aspiration] or there’s an ERCP [endoscopic retrograde cholangiopancreatography] brushing, or biopsy through endoscopy, then tissue is not going to be enough. In those situations, perhaps you do need a repeat biopsy. In extrahepatic cholangiocarcinoma, it’s almost uncommon to get a core biopsy with tissue if the tumor is restricted to the hilar.

If there is adequate tissue, we need to do next-generation sequencing. There are several approved commercial panels that test 300 to 400 genes that are of interest for targeted therapy. You must remember that even in patients who don’t have enough tissue, we now have an alternative with circulating tumor DNA. There are very promising platforms where you obtain a vial of blood, it gets spun, and we get information regarding actionable mutations in the blood. The problem with that is the specificity is high, but the sensitivity is low. In other words, not all tumors shed enough DNA to be detected in the blood. Then for some more esoteric tests, for instance, 

 fusions, they’re not always detectable on circulating tumor DNA testing. It is an evolving field, but clearly it is available, and we should consider it for patients who don’t have enough tissue for molecular testing based on tumor-based biopsy.

Dr Milind Javle discusses challenges that exist in the early identification of cholangiocarcinoma, as well as the benefits of comprehensive molecular profiling.

Diagnosing Cholangiocarcinoma: Challenges and Molecular Profiling

 The patient being described here is a 61-year-old woman who was previously healthy other than a mild case of diabetes that is somewhat poorly controlled. She also has metabolic syndrome; she is overweight, and she’s working on that, as we all do. She presents with painless jaundice or alteration in liver function tests; she goes to her primary physician, has blood work, and it was noted there that the bilirubin and liver enzymes were elevated, suggesting that there is some degree of blockage of the biliary tree. This then led to further investigations, including a sonogram. It was thought to be gallstones, but then it turned out that she actually had a mass in the liver. There was a follow-up CT scan, which revealed a large central mass in the liver, along with some satellite...within the liver, as well as regional lymph nodes.

After all the results of these tests, she was diagnosed with cancer, although we were not quite sure what type of cancer. This was followed by a core needle biopsy of the liver, which revealed adenocarcinoma. It was clearly not liver cancer, or hepatocellular cancer [HCC], but it was adenocarcinoma. The possibilities here are a primary liver cancer, such as cholangiocarcinoma, not HCC, or it could be metastatic disease coming from other sources.

Since the diagnosis or site of the primary tumor was uncertain, there were further investigations that were initiated, including immunohistochemical analysis of the biopsy tissue. This revealed that the tumor was CK7-positive, CK20-negative, so clearly it was an adenocarcinoma. It was coming from perhaps an upper GI [gastrointestinal] source, or pancreatic, or a biliary source. There were further investigations, including: HepPAR [immunohistochemical stain] for HCC, which was negative, CDX2, which was negative. Other investigations included 

 for lung cancer and ER/PR [estrogen receptor/progesterone receptor] for breast cancer, all of which were negative. This was then a diagnosis of exclusion. The diagnosis that the pathologist suggested and that the clinician readily agreed to was intrahepatic cholangiocarcinoma, or a primary cancer involving the bile ducts within the liver.

The patient was started on systemic chemotherapy because clearly this mass was multifocal; it was involving vasculatures. It was not resectable, so she was started on systemic chemotherapy with gemcitabine and cisplatin given weekly on a 2 weeks on, 1 week off schedule per the ABC-02 trial. The patient tolerated this treatment well, and she received follow-up imaging every 2 months. She did relatively well for the first 4 months, and then a subsequent restaging scan showed that there was progressive disease in the liver as well as in the bones. This suggested that the tumor had become refractory to systemic chemotherapy.At this time, the patient had molecular profiling through next-generation sequencing using a core biopsy that was obtained from the tumor.

This patient was treated a couple of years ago when there was no approved therapy for this cancer in terms of targeted therapy. Molecular profiling in this case revealed a 

 gene fusion, which is one of the most common 

fusions seen in cholangiocarcinoma. She was enrolled in a clinical trial with infigratinib. This was a phase 2 trial that enrolled about 120 patients. This trial included patients with cholangiocarcinoma who had received prior systemic chemotherapy, either first line or subsequent line, and had to have adequate laboratories, renal, and hepatic function for enrollment. Patients were required to have measurable disease, and then received infigratinib in a dose of 125 mg daily on a 3 weeks on, 1 week off schedule. The duration of this therapy was until progression, and each cycle was defined as 4 weeks in duration. This patient was enrolled on this trial, and she tolerated the therapy. She received this therapy well; at the first restaging scan we noted that there was no more progression, there was stable disease. Many of the patient’s symptoms appeared to have improved as well; she continued on this therapy for a total of 6 months, experiencing stable disease as her best response.

Cholangiocarcinoma is thought to be a rare cancer, however, in fact, there are about 10,000 to 15,000 patients being diagnosed in the United States every year. This disease is more common in other parts of the world, such as in Asia. Unfortunately, the disease is rising in incidence, perhaps because of the epidemic of obesity, metabolic syndrome, and diabetes. In addition, there are other substance abuse causes, such as alcohol hepatitis. In this situation, because this was thought to be a cancer of unknown primary, it led to further investigations, such as immunohistochemical analysis. It’s quite typical that cholangiocarcinoma is in fact a diagnosis of exclusion. That is, you rule out other possibilities based on clinical grounds and sometimes with the need of endoscopy. In this case, an endoscopy was not performed because she really didn’t have any upper GI symptoms.

However, because she had jaundice, we did perform an ERCP [endoscopic retrograde cholangiopancreatography] and a stent placement in bile duct, in the common hepatic duct where the obstruction was. During that process, there was an endoscopy that showed no primary in the stomach. This is quite typical in this case to make this diagnosis by excluding other cancers. Also quite typical now, and it should be more so, is molecular profiling, that is obtain a tissue biopsy and send it for next-generation sequencing.

Expert oncologist Milind Javle, MD, reviews the diagnosis and treatment of intrahepatic cholangiocarcinoma in a 61-year-old who presents with jaundice and changes in stool and urine color. 

Milind Javle, MD | Authors

Articles

Key Takeaways for the Treatment of Cholangiocarcinoma

Recent Changes in the Cholangiocarcinoma Treatment Landscape

Metastatic Cholangiocarcinoma: Phase 2 Infigratinib Study and Personal Experience With Infigratinib

Treatment Options for Metastatic Cholangiocarcinoma

Diagnosing Cholangiocarcinoma: Challenges and Molecular Profiling

Case Review: A 61-Year-Old Woman With Metastatic Cholangiocarcinoma