New FGFR Inhibition Therapies Show Promise in Intrahepatic Cholangiocarcinoma


Biliary tract cancers have become the model for precision oncology because of its complex molecular landscape.

In the solid tumor space, FGFR inhibition has been an incredibly promising area for drug development because there are a number of different tumor types that demonstrate alterations in the FGFR pathway, explained Rachna T. Shroff, MD, FASCO, during a presentation at the American Society of Clinical Oncology 2023 Annual Meeting. Alterations in the FGFR pathway can range from occurring in head and neck cancers and breast cancers to non–small cell and small cell lung cancer and rhabdomyosarcoma.

Chalk drawing of human liver with medical term. Concept of learning medicine

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“Additionally, urothelial cancer really led the way in terms of drug development,” Shroff noted. “These alterations can also cross a huge spectrum that include mutations, amplifications, as well as fusions. Therapeutically, in terms of drug development, it’s been a really complex space to understand how FGFR inhibitors can specifically target tumor type as well as understanding if they work in varying alterations.”

Intrahepatic cholangiocarcinoma is where the FGFR fusions are most relevant, according to Shroff. FGFR fusions have historically been thought of as being 10%-15% of intrahepatic cholangiocarcinoma, although Schroff noted that the range may more likely be in the 10% range due to a greater understanding of the disease today.

“Biliary tract cancers have become the model for precision oncology, and it’s become that model because of its complex molecular landscape,” Shroff said. “We’ve historically thought of biliary tract malignancies as 1 tumor type, but we now know that not only are they anatomically distinct, but they are also molecularly complex and are absolutely an area in which we need to understand the biomarkers so that we can understand our therapeutic options.”

The first drug approved by the FDA for cholangiocarcinoma was pemigatinib (Pemazyre; Incyte), which was approved in August 2022. Pemigatinib, an oral reversible FGFR inhibitor, has been evaluated for several different tumor types, but the FIGHT-202 trial (NCT02924376) provided the initial data published in Lancet Oncology.

“These patients were very refractory, with the efficacy of therapy in the second-line and beyond setting quite low,” Shroff said. “The overall response rate initially was 35.5%, and a lot of the patients received this therapy in the second-line setting, even though the scope of the study was second, third, and beyond.”

In these patients with FGFR fusions, there’s a median progression-free survival (PFS) of 6-9 months (95% Cl 6.2-9.6). For refractory cholangiocarcinoma, the median PFS for chemotherapy options are usually in the 2-3 month range, according to Shroff.

“So this was really exciting, and that’s what led to the FDA approval of pemigatinib for patients with FGFR2 fusion positive advanced cholangiocarcinoma in April of 2020,” Shroff said. “This was our first FDA approval in that space.”

More recently, futibatinib (Lytgobi; Taiho Oncology) has been under investigation for FGFR2 fusions or other rearrangements in a multicenter, open-label phase 2 trial (NCT02052778). This study is being conducted across 11 countries, with patients enrolled with unresectable or metastatic intrahepatic cholangiocarcinoma, measurable disease per Response Evaluation Criteria in Solid Tumors v1.1, prior gemcitabine (Gemzar; LillyMedical) plus platinum-based chemotherapy, progression after 1 or more systemic therapy, Eastern Cooperative Oncology Group Performance Status 0 or 1, and no prior treatment with FGFR inhibitor.

“Futibatinib is an oral FGFR inhibitor that is covalently bound, so it’s slightly different from pemigatinib,” Shroff said. “This study was a single phase 2 study with a primary endpoint of objective response rate.”

Patients were treated with futibatinib 20 mg orally once-daily, continuously in 21-day cycles. Additionally, patient responses were confirmed by a second tumor assessment 4-6 weeks after the initial response, according to Shroff.

“These data just came out earlier this year in the New England Journal of Medicine,” Shroff said. “[The results show] this is an impressive drug. This is 103 patients with an objective response rate of 42%, and a disease control rate of 83% in refractory cholangiocarcinoma. I think it’s also exciting to see a median duration of response of 9.7 months. When we’re talking about these patients, we usually do not see that sort of durability with chemotherapy, or even in the targeted therapy space.”

The investigators in this trial also did a lot of great work to really understand FGFR infusion cholangiocarcinoma for the patients who were enrolled, according to Shroff. Additionally, they looked to further understand what some of the co-occurring alterations could be for these patients as well.

The results of the trial showed a PFS of 9.0 months (95% Cl, 6.9-13.1) and an overall survival (OS) of 21.7 months (95% Cl, 14.5–NE). Gemcitabine and cisplatin (GemCis), which was historically used for this patient population, had a median OS in advanced biliary tract cancer of 11.7 months, according to Shroff.

“We had [previously] slightly upped the bar with GemCis durvalumab [Imfinzi; AstraZeneca] and GemCis pembrolizumab [Keytruda; Merck & Co],” Shroff said. “So to see an OS of 21.7 months is truly exciting and clinically meaningful for our patients.”


Shroff RT. FGFR Inhibition: Crossing the Heme/Solid Tumor Divide. Presented at: 2023 ASCO Annual Meeting in Chicago, IL; June 3, 2023. Accessed June 4, 2023.

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