The current landscape for metastatic cholangiocarcinoma is somewhat limited. At this time, for patients in the first-line setting, the standard-of-care regimen is still the ABC-02 regimen of gemcitabine and cisplatin that has been in practice for some time. The ABC-02 trial demonstrated an overall survival benefit for the combination—11.2 months. For patients who have progressed following first-line therapy, unfortunately we don’t have a true standard of care.

The closest we have to that is the recently presented ABC06 trial that looked at the combination of FOLFOX [5-fluororacil, leucovorin calcium, oxaliplatin] plus supportive care compared with supportive care alone. The trial did show a benefit in overall survival in the second-line setting—6.2 months—when compared with placebo. Because it was a phase 3 trial, it’s considered by many to be the standard of care in the second-line setting. Beyond this, other chemotherapy combination regimens have been studied. We don’t have high-level evidence for other regimens, and there’s certainly a need for additional therapeutics for this disease.

In the past few years, there’s been a great deal of research and work done identifying various mutations that occur in cholangiocarcinoma. These mutations and changes are potentially actionable, and this has really led to the development of novel therapeutics that can be beneficial in a subset of patients.

With a better understanding of the molecular pathways that are involved in cholangiocarcinoma, we have the ability to design drugs that are highly selective for specific pathways. This is beneficial because by doing this, you can potentially limit the toxicities of compounds and avoid additional toxicities that may occur because of off-target effects from the therapies.

Advanced Cholangiocarcinoma: Current Treatment Landscape

Next-generation sequencing has identified a variety of mutations and genetic changes that occur in cholangiocarcinoma. Of the very common ones is the fibroblast growth factor receptor 2 [

] aberrations and rearrangements, as well as mutations that tend to occur in about 10% to 16% of intrahepatic cholangiocarcinomas. Additional mutations include 

 rearrangements occur in about 8% to 9% of patients. 

 amplification has been reported in 16% of cases. 

 [human epidermal growth factor receptor 2] amplification has been reported in 11% to 20% of cases. Finally, a very small subset of patients has the 

 V600E mutation, and that tends to occur in about 5% of patients.

The targets that have been identified may be predictive of response if you have the appropriate therapeutic available. There is not a lot of information about the prognostic benefit of the various subtypes of cholangiocarcinoma, perhaps with the exception of the 

 aberrations and rearrangements. Recently presented data at ASCO [the American Society of Clinical Oncology Annual Meeting] retrospectively looked at a group of patients who had the 

 rearrangement. That study identified this in younger women. These patients tend to have a normal CA [cancer antigen] 19-9 level. They have a higher propensity for bone metastases. Interestingly enough, their response to first-line chemotherapy with cisplatin and gemcitabine is usually short—about 6 months. However, taken as a whole, these patients tend to do a lot better, with a median survival around 36 months.

As we have come to the realization that there are actionable mutations that occur in this disease, it’s more important to do next-generation sequencing in all patients who have metastatic cholangiocarcinoma. I am in favor of testing patients who have locally advanced disease as well. It’s important to identify these mutations early, because then there is an opportunity to enroll these patients in clinical trials or, perhaps, give them a targeted therapy for their specific aberration.

Testing for next-generation sequencing should be done at diagnosis in patients who have metastatic or locally advanced disease. In select cases, it is reasonable to actually consider repeat testing at time of progression, based on emerging data that show that by identifying new mutations in patients, you can selectively tailor their future therapies to allow them to have a better response.

Driver Mutations in Advanced Cholangiocarcinoma

FGFR2 disease is quite an interesting area. There’s been quite a bit of excitement for this specific subset of patients. As recent as April of this year, there was an FDA approval of a pan-FGFR1, FGFR2, and FGFR3 inhibitor, pemigatinib. The drug’s approval was based on a trial known as the FIGHT-202 trial, which was a trial of 146 patients. These patients included a group of patients who had 

 fusions or rearrangements. In fact, those patients accounted for about 107 of the patients in the trial. What the trial demonstrated was that pemigatinib resulted in an overall response rate of 35.5%. Among those patients, 3 had actually achieved a complete response. The duration of response was 7.5 months, and the progression-free survival was 6.9 months.

The drug did have some toxicity. As a class of medications, these drugs can cause hyperphosphatemia, which is manageable. There was also a minority of patients who did develop detachment of the retinal epithelial membrane, indicating the need for these patients to undergo ocular examinations while they’re on the drug. Other toxicities were included, including diarrhea in 47% of the patients. But overall, it was a highly tolerable regimen, and this drug was approved based on this data.

The other compound that also is in the same class is the drug infigratinib. This is also an inhibitor of FGFR1, FGFR2, and FGFR3. This drug has been given fast-track designation by the FDA, mainly based on the data that have been presented most recently at ESMO [the European Society for Medical Oncology Congress]. This was a single-arm trial looking at infigratinib given daily for 21 days with a 1-week rest period following that. The primary objective of the trial was to look at overall response rate, then duration of response and progression-free survival. This trial also included 3 cohorts of patients. The first cohort of patients are patients who have an 

 fusion or rearrangement, the second group is patients who have other FGF abnormalities, and a third group is patients who have actually progressed on an FGFR2 inhibitor and are being considered for the infigratinib trial.

One of the interesting things I pointed out to you is that it appears that patients who are exposed to infigratinib earlier may have a better response rate. And so the thought was to design a phase 3 trial to look at infigratinib in the first-line setting. The PROOF trial is open and is accruing patients. The trial includes patients who have unresectable recurrent or metastatic cholangiocarcinoma who have not had any prior systemic therapy in the metastatic setting. These patients all need to have had an 

 fusion. This can be either tested centrally or locally, and they need to have a very good performance status.

These patients have been randomized in a 2:1 fashion to receive either the oral infigratinib compound or receive standard-of-care chemotherapy with gemcitabine and cisplatin. The patients are actually followed until radiographic progression of disease. At that time, patients who are on the chemotherapy arm have an opportunity to cross over to infigratinib. This trial has started to accrue patients. There are patients on the study for whom we do not have any information regarding efficacy or safety results.

FGFR2 Inhibitors in Advanced Cholangiocarcinoma

The majority of the FGFR2 inhibitors, including pemigatinib and infigratinib, are highly selective for the 

 receptors. There is some variability in terms of their off-target activity against the 

 seems to be mitigating the diarrhea that is associated with these compounds and also may be mitigating, for example, the dry eyes that are seen. As a result, a drug that has less selectivity for 

 can potentially have fewer instances of diarrhea and dry eyes.

If you look at the data that are available for second-line chemotherapy, the results are quite dismal. The progression-free survival [PFS] ranges from about 2 to maybe 4 months. Overall survival ranges from 6 to 8 months. The response rate is in the single digits—6%. When you compare that with pemigatinib data and infigratinib data, we see a stark difference. Both of these agents have response rates in the 30% range, and they certainly have a PFS that is longer than what we see with second-line chemotherapy—around 6.8 months.

Advanced Cholangiocarcinoma: FGFR2 Inhibitors vs Chemo

It’s quite an exciting time in metastatic cholangiocarcinoma, with identification of various multiple pathways that are potentially actionable. There’s been a lot of excitement, rightfully so, around management of the subset of patients who have 

 fusions and rearrangements. We have 1 approved drug, pemigatinib, and another drug that has a fast-track designation, infigratinib. In the future, we hope to have a better understanding of the resistant patterns and identify other FGFR inhibitors that can be utilized in these patients upon progression. Perhaps we will also be looking at combination therapies to overcome mechanisms of resistance.

Understanding the mechanisms of resistance is an area of active research, and we do have some understanding. We know that 

 does cross-talk with other receptors. For example, some of the mechanisms of resistance that have been identified have been amplifications of the EGFR pathway, MET pathway, as well as upregulation of the PI3 kinase pathway and the RAS/MAP kinase pathway. In addition to that, you could actually get mutations in these other pathways, including EGFR and MEK. We are also finding that patients who progress on the FGFR2 inhibitors can actually develop mutations in the ATP binding site of these drugs that render them ineffective to the drug they’re on. With the better understanding of the resistance patterns, we have the potential to consider future therapies that would allow us to combine them. There is potentially a rationale for combining FGFR inhibitors with drugs that are targeting EGFR or the PI3 kinase pathway.

Recently, there were data presented looking specifically at 1 patient—for example, with infigratinib—who had progressed on the drug. When the patient’s tumor was sequenced, it was identified that they had developed a mutation in the ATP binding site. In addition, they had an upregulation of the PI3 kinase pathway. This suggests that combining an mTOR inhibitor along with FGFR can perhaps allow us to mitigate that resistance and allow patients to respond again.

Finally, there are differences between the FGFR inhibitors. There is a potential for using another FGFR inhibitor in the case of resistance, and this is really the reason why I pointed out the possibility and need for doing next-generation sequencing at progression to be able to identify these changes in a patient’s tumor.

In the realm of FGFR inhibitors, there’s a lot of theoretical information out there on combining it with EGFR-directed therapies—mTOR inhibitors, for example. But to my knowledge, there are no active trials looking at those combination therapies. There is certainly a role to better understand this. In terms of chemotherapy, we are seeing that combining chemotherapy with immunotherapy may give us higher results. Recently, there have been a couple of abstracts presented as recently as ASCO [the American Society of Clinical Oncology Annual Meeting] 2020 that have shown, for example, the combination of gemcitabine-cisplatin with targeted immunotherapy with durvalumab is associated with much higher response rates and progression-free survival. The data are intriguing because they suggest that the combination of chemotherapy-immunotherapy or even combination immunotherapy may have a role in future treatment of this disease.

Role of Targeted Therapies in Advanced Cholangiocarcinoma

Advanced Cholangiocarcinoma: Current Treatment Landscape

Driver Mutations in Advanced Cholangiocarcinoma

FGFR2 Inhibitors in Advanced Cholangiocarcinoma

Advanced Cholangiocarcinoma: FGFR2 Inhibitors vs Chemo

Optimizing Therapy for Advanced Cholangiocarcinoma