Progress in precision therapies for advanced cholangiocarcinoma: inhibitors of FGFR1–3

Cholangiocarcinomas are malignant tumours arising from the bile ducts. The majority present at an advanced stage when surgical resection, the only curative treatment, is not possible. Indeed, when surgery is possible, a high proportion recur. For patients with advanced disease, conventional cytotoxic chemotherapy can lead to modest improvements in survival (1). More recently, the addition of immunotherapy has been shown to provide further marginal benefits with an improvement in median overall survival of less than 2 months when compared with chemotherapy alone (2).

With increasing access to molecular profiling of cancers, we are developing a greater understanding of the genetic alterations responsible for cholangiocarcinoma. Potentially targetable alterations appear to be particularly prevalent in intrahepatic cholangiocarcinoma, with studies reporting more than two thirds of cases having potentially actionable alterations including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%) (3). This has led to the investigation of specific targeted therapies for patients with identified alterations (4), with most progress having been made in the use of FGFR inhibitors. In intrahepatic cholangiocarcinoma, of all forms of DNA alteration (mutation, fusion or amplification), FGFR2 fusions appear to be the most sensitive to FGFR inhibitors (5) The agents pemigatinib and infigratinib have received US Food and Drug Administration (FDA) approval for treatment of cholangiocarcinoma with FGFR2 fusion or rearrangement and futabitinib and derazantinib have been granted orphan drug designation by the FDA for treatment of the same population.

Pemigatinib, a selective inhibitor of FGFR1, FGFR2 and FGFR3, was the first of these agents to be approved, with accelerated FDA approval being granted in April 2020 based on the findings of the FIGHT-202 study (6,7) demonstrating clinical efficacy in cholangiocarcinomas with FGFR2 fusions or rearrangements, and establishing the drug’s safety profile in this population. Since the initial publication considerable further data have emerged. Rasool et al. (8) have undertaken a helpful systematic review of this evidence with the goal of consolidating data from all reported clinical trials and securing a better understanding of the efficacy and safety of this drug in cholangiocarcinoma patients with FGFR2 alterations.

Following a predefined process of study selection, five studies were identified that met the inclusion criteria. The studies included two phase 2 trials, a prospective study that was part of an expanded access programme and two observational retrospective cohort studies. These studies included a total of 459 patients, but treatment response data were only available for four of the studies, accounting for 370 patients. The vast majority (86%) of patients included had received at least one prior therapy, usually chemotherapy.

The authors found that across the studies that collected response data, 3% of patients achieved complete response (CR), 40% a partial response (PR) and 36.7% achieved stable disease (SD). Fourteen-point-nine percent patients experienced progressive disease (PD).

The studies reported variable progression-free survival (PFS) rates with median PFS ranging from 6.3 to 8.7 months, likely reflecting differences in the patient populations included in each study such as the number of prior therapies received.

Significant adverse events reported across the studies included hyperphosphataemia (in 48%), diarrhoea (in 28.6%), alopecia (in 32.7%) and fatigue (in 33%). Ocular toxicity was also reported, including dry eyes, keratitis, retinal detachment, corneal abrasion, trichiasis, blurred vision and conjunctivitis, highlighting the need for careful monitoring and early ophthalmology assessment in case of symptoms.

The authors reasonably conclude that the data demonstrate that pemigatinib offers modest therapeutic efficacy in this setting. Whilst this is welcome progress for patients with this disease, clearly a number of questions and challenges remain.

The role of pemigatinib as a first-line therapy for cholangiocarcinoma patients with FGFR2 alterations needs to be established, in comparison with current first-line standard of care therapies. The FIGHT-302 study NCT03656536 (9) is seeking to address this, comparing the efficacy and safety of pemigatinib with gemcitabine and cisplatin in the first-line treatment of patients with advanced cholangiocarcinoma with FGFR2 alterations. Results of this study are awaited with interest.

However, undertaking large phase 3 randomised trials in this setting has proved challenging due to the rarity of the condition (only 10–15% of intrahepatic cholangiocarcinomas having the required FGFR2 alteration). Given limited infrastructure for molecular testing another challenge is to identify patients with FGFR2 alterations in a suitably timely manner ahead of starting first-line therapy, especially given that patients can deteriorate rapidly and commencing first-line therapy cannot be delayed. The SAFIR-ABC10 NCT05615818 is attempting to address this by introducing molecular targeted therapies, including an FGFR inhibitor, after four cycles of first-line standard of care systemic therapy, thus allowing time to undertake molecular testing whilst not delaying the start of first-line therapy.

There remain significant problems with toxicity, some of which, such as hyperphosphataemia, are on-target effects of FGFR inhibition. A more selective FGFR2 inhibitor, lirafugratinib, has been developed. By avoiding FGFR1 and FGFR4 inhibition the risk of hyperphosphataemia and diarrhoea appears to be lower with this agent (10).

Duration of PFS remains disappointing and it is clear that resistance to FGFR2 inhibition develops rapidly. A number of resistance mechanisms have been identified. Secondary mutations in the FGFR2 kinase domain may develop (10). Monitoring for changes in circulating tumour DNA (ctDNA) may allow earlier detection of genetic changes leading to resistance, allowing earlier switching of treatment and potentially reducing the risk of polyclonal resistant subclones (11). It is hypothesized that using an irreversible kinase inhibitor such as futibatinib, rather than a reversible inhibitor like pemigatinib, may overcome such acquired gatekeeper mutations (12).

It has also been proposed that EGFR-dependent pathways may act as a bypass mechanism to FGFR inhibition (13), raising the possibility of combination therapies to improve efficacy. Tinengotinib is a new multikinase inhibitor with EGFR inhibitory effects and is being tested in a trial for patients with cholangiocarcinoma who have received one prior chemotherapy and one prior FGFR inhibitor (14).

In summary, progress is being made in the precision therapy of advanced cholangiocarcinoma. Rasool et al.’s systematic review helpfully summarises the data that supports the use of pemigatinib in cholangiocarcinomas with FGFR2 alterations, whilst highlighting the limitations of this treatment and the need for further research to improve patient outcome

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-274/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-274/coif). J.W. reports that his institution has received honoraria from Incyte in return for speaking at educational events. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
2. Oh DY, He AR, Bouattour M, et al. Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study. Lancet Gastroenterol Hepatol 2024;9:694-704. [Crossref] [PubMed]
3. Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 2014;19:235-42. [Crossref] [PubMed]
4. Li Y, Yu J, Zhang Y, et al. Advances in targeted therapy of cholangiocarcinoma. Ann Med 2024;56:2310196. [Crossref] [PubMed]
5. Ellinghaus P, Neureiter D, Nogai H, et al. Patient Selection Approaches in FGFR Inhibitor Trials-Many Paths to the Same End? Cells 2022;11:3180. [Crossref] [PubMed]
6. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol 2020;21:671-84. [Crossref] [PubMed]
7. Vogel A, Sahai V, Hollebecque A, et al. An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202. ESMO Open 2024;9:103488. [Crossref] [PubMed]
8. Rasool W, Alami Idrissi Y, Ahmad O, et al. Safety and efficacy of pemigatinib in patients with cholangiocarcinoma: a systematic review. J Gastrointest Oncol 2025;16:699-710. [Crossref] [PubMed]
9. Bekaii-Saab TS, Valle JW, Van Cutsem E, et al. FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol 2020;16:2385-99. [Crossref] [PubMed]
10. Hollebecque A, Borad M, Goyal L, et al. Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. Ann Oncol 2022;33:S1381. [Crossref]
11. González-Medina A, Vila-Casadesús M, Gomez-Rey M, et al. Clinical Value of Liquid Biopsy in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma During Targeted Therapy. Clin Cancer Res 2024;30:4491-504. [Crossref] [PubMed]
12. Wu Q, Ellis H, Siravegna G, et al. Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma. Clin Cancer Res 2024;30:198-208. [Crossref] [PubMed]
13. Wu Q, Zhen Y, Shi L, et al. EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma. Cancer Discov 2022;12:1378-95. [Crossref] [PubMed]
14. Piha-Paul SA, Goel S, Liao CY, et al. Preliminary safety and efficacy of tinengotinib tablets as monotherapy and combination therapy in advanced solid tumors: a phase Ib/II clinical trial. J Clin Oncol 2023;41:abstr 3019.