Optimizing Therapy for Advanced Cholangiocarcinoma

Saeed Sadeghi, MD: 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 FGFR2 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 FGFR 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.

Transcript edited for clarity.