Futibatinib Receives FDA Approval for Intrahepatic Cholangiocarcinoma With FGFR2 Fusions and Rearrangements

Lipika Goyal, MD, Director of GI Oncology, Stanford Cancer Center, Palo Alto, California, discusses the Food and Drug Administration (FDA) approval of futibatinib for patients with intrahepatic cholangiocarcinoma and FGFR2 fusions or rearrangements. Dr Goyal is the lead investigator of the FOENIX-CCA2 study, the results of which led to this accelerated approval.

In the phase 2 FOENIX-CCA2 study, the objective response rate (ORR) of patients treated with futibatinib was 42%, and the duration of response (DoR) was 9.5 months. Dr Goyal explains that it was the combination of this high ORR and long DoR which helped to achieve the FDA approval.

On September 30, 2022, the FDA granted accelerated approval to futibatinib, 20 mg orally once a day, for patients with locally advanced or metastatic inraheptatic cholangiocarcinoma with FGFR2 gene fusions or rearrangements who have been previously treated.  

Transcript:

Hi, my name is Lipika Goyal and I'm the director of GI Oncology at Stanford Cancer Center.

What is futibatinib?
Futibatinib is a targeted therapy that we have for cholangiocarcinoma. It specifically targets FGFR, the fibroblast growth factor receptor. There are 4 different FGFRs, 1 through 4, and futibatinib targets all 4 of them. It's distinct from the other 2 FGFR inhibitors that have gained FDA approval for FGFR fusion- and rearrangement-positive cholangiocarcinoma in that it binds covalently to FGFR. The other 2 drugs, infigratinib and pemigatinib, bind reversibly to FGFR.

What data led this this accelerated approval?
There was a phase 2 trial, the FOENIX-CCA2 study, and that was 103 patients with FGFR2 fusion- or rearrangement-positive intrahepatic cholangiocarcinoma that have been previously treated. And all of them received futibatinib 20 mg once a day. The primary end point in this study was objective response rate, and the ORR was 42%, exceeding what it needed to be a positive trial. The duration of response was 9.5 months. It was really the combination of having this high overall response rate and this long duration of response that helped it achieve accelerated approval by the FDA.

What is the existing treatment landscape for this patient population?
Right now, for the treatment landscape of cholangiocarcinoma in the frontline, we have chemotherapy, gemcitabine-cisplatin, and we also have chemo-immunotherapy, gemcitabine-cisplatin and durvalumab. Then, in the next line, we have different kinds of chemotherapy agents, but we also have targeted therapies and futibatinib fits in here in the next line therapy, after first line, for patients with FGFR2 fusion- and rearrangement-positive cholangiocarcinoma.

There are 3 different FGFR inhibitors that have gained FDA approval. Futibatinib is the latest one to gain approval. But 2 prior drugs that gained approval were pemigatinib and also infigratinib. These 2 drugs are slightly different than futibatinib, in that pemigatinib and infigratinib are reversible inhibitors and futibatinib is a covalently binding irreversible inhibitor. But overall, these are different options for patients with this disease.

Recently, the team that makes infigratinib decided to cease commercial availability of this drug so now there'll be 2 options for FGFR2 fusion-positive cholangiocarcinoma, which are futibatinib and pemigatinib.

What is the safety profile of futibatinib?
Overall, futibatinib is a well-tolerated medication. It has side effects that are similar to other drugs in-class, so other FGFR inhibitors. The most common side effect is hyperphosphatemia. What we see is that we're trying to hit FGFR2, because the patients with cholangiocarcinoma have FGFR2 fusions or rearrangements, but futibatinib, like the other FGFR inhibitors, is a pan-FGFR inhibitor so it also hits FGFR1. When you hit FGFR1, it impacts the interaction between FGFR2 and FGFR1 in your kidneys, for example, so you cannot waste phosphorus and also you can't waste phosphorus from your gut and so you end up with high serum phosphorus levels. For a majority of patients who get these FGFR inhibitors, including futibatinib, that’s just a lab value and it doesn't have any clinical implications. In some cases, people can develop crystallization of calcium and phosphorus and they can develop, for example, kidney stones or they can develop calciphylaxis, which are little crystals below people's skin. The other side effects that we see with futibatinib, people can have hair loss, they can have some diarrhea, hand-foot syndrome, and some nail changes. Overall, it's very similar to what we see with other FGFR inhibitors.

What advice do you have for oncologists who are interested in using futibatinib?
What I would say for any oncologists who are taking care of patients with intrahepatic cholangiocarcinoma, the number one thing is to make sure to get tumor molecular profiling. Just as we have FGFR2 fusions in about 10% to 15% of intrahepatic cholangiocarcinomas, we also have a series of other targets that are actionable: IDH1 mutations, HER2 amplifications, NTRK fusions, RET fusions, MSI-high, BRAF-V600E mutations. And for all of these, we have drugs that are either FDA-approved or that are in the NCCN guidelines. Profiling tumors is really important, so we can give people effective drugs, like futibatinib and other FGFR inhibitors and other targeted therapies.

It’s also important to monitor when people are on futibatinib for the phosphorus and also get a baseline eye exam. In rare instances, people can also have some retinal detachment and so following patients with serial eye exams is important. But overall, we are really excited that we have this new drug for patients with cholangiocarcinoma.

Will this approval have an immediate impact on real-world practice?
Yes, it's definitely an immediate impact with the approval of futibatinib, because we have a really effective drug for patients with FGFR2 fusions. For anyone who is found to have this alteration, it's a very good option for patients