Cholangiocarcinoma Emerges as Key Target of FGFR Inhibitor Research

Sameek Roychowdhury, MD, PhD

Recent data have shown that fusions in FGFR1/2/3 can be targetable in many cancers, particularly in cholangiocarcinoma. FGFR inhibitors are now being tested in clinical trials of patients with these fusions.

“I would say that as far as the landscape of FGFR across cancers, we are really only looking at the tip of the iceberg. We really don't know who else is going to have it,” said Sameek Roychowdhury, MD, PhD. “Everyone should be tested for it.”

Findings from 2 studies presented at the 2018 ESMO Congress showed the potential for the FGFR inhibitors infigratinib and pemigatinib in patients with cholangiocarcinoma. Both agents demonstrated favorable safety profiles in their respective studies, as well as signals of antitumor activity. It is still early, however, and the management of adverse events (AEs) is something that needs to be stressed, Roychowdhury said.

OncLive: What is the importance of FGFR inhibitors in cholangiocarcinoma?

In an interview with OncLive®, Roychowdhury, an associate professor at The Ohio State University Comprehensive Cancer Center, discussed the potential for FGFR inhibitors in the treatment of patients with cholangiocarcinoma who harbor FGFR fusions.Roychowdhury: FGFR gene fusions, sometimes called translocations or rearrangements, have emerged as a significant target for therapy, not only in cholangiocarcinoma, but also in other cancer types. The most common gene fusion in cholangiocarcinoma that is intrahepatic is FGFR2, but we have also seen FGFR1 and FGFR3 in other cancer types, such as urothelial carcinoma, pancreatic cancer, and breast cancer. For each of these cancer types, especially cholangiocarcinoma, early trials involving inhibitors of the FGFR gene, which is a receptor tyrosine kinase, [have] emerged.

There are about 10 FGFR inhibitors in this clinical space being tested in this population who have FGFR fusions. For the most part, we are seeing some promising results. Patients are either having partial responses or rare complete responses. More commonly, we are seeing patients develop stable disease that goes on for quite a long time. We are seeing an improvement in progression-free and probably overall survival. The studies are ongoing.

Should FGFR inhibitors be tested in a tumor-agnostic fashion?

The most common tumor types where we see [FGFR fusions] are cholangiocarcinoma and urothelial cancer. However, we are seeing this in any solid tumor as a fusion. The frequency of this is low, but it is high enough that it is worthwhile for us to find these patients and offer them therapy, because they have a good chance of benefitting. Over the last couple of years, we have seen patients beyond cholangiocarcinoma and urothelial cancer—including prostate cancer, neuroendocrine tumors, head and neck cancer, breast cancer, and pancreatic cancer—with FGFR-driving genetic alterations. Finding these fusions has allowed patients to qualify for an FGFR inhibitor of some kind and benefit [from it]. As we [do genetic testing on] more and more patients, we are going to find more candidates for testing.As a principle, companies developing and driving FGFR inhibitors are interested in getting these drugs to patients who will benefit. My understanding is that they are interested in patients who have marker-positive cancer, regardless of cancer type. There are definitely disease-specific studies; however, these markers are not limited to patients who have a certain cancer type. We are seeing them in multiple tumor types, and patients are benefitting. The landscape of FGFR drug development isn't limited to 1 or 2 cancer types; any cancer type with a driving alteration in FGFR could be a candidate.

We saw some early findings for pemigatinib and infigratinib presented at the 2018 ESMO meeting. Could you share your thoughts on those?

I can see the possibility of a marker-driven approach to therapy as opposed to a disease-driven approach. Two examples in the past 2 years are microsatellite instability—high cancers and immunotherapy, as well as the most recent approval of an NTRK inhibitor for patients who have NTRK fusion–positive tumors. As long as patients are going to benefit, that could be the course that these companies take. Certainly, physicians want to see that as well. We want to see the right patients benefit from the right drug.These drugs have been in phase I/II expansion studies for solid tumors including cholangiocarcinoma, as well as urothelial cancer. Both are inhibitors of the FGFR kinase and are selective for FGFR1/2/3. They are both oral drugs and appear to have some efficacy in patients with FGFR-positive cancers. As a class of drugs, these 2 have a similar profile of AEs, which includes fatigue, hyperphosphatemia, mucositis, gastrointestinal complaints, and arthralgia. Overall, they are similar, but certainly, as we see more data for efficacy and toxicity, we will learn more. It is still very early, but we are seeing some promising findings.

As a class, [FGFR inhibitors] have had similar AE profiles. Over time, these start to add up. In patients who are benefitting from these therapies, often for months, there is some cumulative fatigue that starts to add up. Is it relative to the benefit? It has been worth it. People's lives are being extended. Down the road, I can see allowing for some more holidays, or breaks, for the therapies to allow them to be more tolerable.

Moving forward, what are the next steps for FGFR inhibitors?

Mucositis is one of the things we have seen, and I borrowed some tricks that we use in other cancer types. I use a steroid mouthwash in patients to quell some of that oral mucositis, and I have started to use that preventatively to either reduce the severity or duration of any mucositis or small mouth sores that we see. That is not a randomized, controlled trial; that is just me trying to do the best I can for supportive care. If they have fewer days of mucositis, that is worth it.These agents are the first-generation FGFR inhibitors, so I am excited to see both the continued study of their efficacy in patients who have FGFR alterations, and I am excited to see new diagnostics to help us identify patients with FGFR alterations. I am excited to see that the next generation of drugs [will likely have] more efficacy and potentially reduced AE profiles.

We are benefitting patients now, but we have to be cognizant of what happens when the disease becomes resistant to the therapy. We are very interested in studying drug resistance to these FGFR inhibitors. So much so that about 2 years ago, we started a study of body donations, where we have partnered with patients and their families. Thus far, none of these patients have been cured, but a lot of them have benefitted.

Many of them go on to succumb to their disease, so we previously asked them to donate their bodies for cancer research after death. Over the last 2 years, we have completed 9 autopsies for research with our patient partners to collect the sites of disease. We can look at how the tumor evolved over time to become resistant. We are looking at concepts, including clonal evolution and tumor heterogeneity. Therefore, understanding drug resistance to these novel inhibitors are going to help us strategize the next steps.