History and presentation
A 69-year-old female diagnosed with localized stage T1b cholangiocarcinoma underwent an extended left hepatectomy with focally involved resection margins in April 2020. Adjuvant therapy was omitted due to prolonged postoperative intra-abdominal sepsis. She remained disease-free until December 2021, when a follow-up CT scan revealed a suspicious 6 mm lesion in liver segments 7/8. A subsequent CT scan in August 2022 showed interval enlargement of the lesion, confirming liver metastasis.
After a multidisciplinary meeting, the patient was referred to our unit in September 2022 to initiate systemic treatment. At the time of referral, she remained asymptomatic, with good Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, in spite of history of cerebrovascular accident, with ongoing aspirin. The patient also had hyperlipidaemia and had been on simvastatin since 2017.
Treatment and response
In November 2022, the patient was started on palliative chemotherapy with gemcitabine and cisplatin. Due to suboptimal neutrophil counts, the dose had to be reduced to 80 percent. After three cycles, follow-up CT scan in February 2023 revealed an overall increase in size of liver metastases, with similar or increased metabolic activity suggestive of disease progression, and a new lytic lesion in the right sacrum, suggesting osseous metastasis. (Figure 1A)
Second-line capecitabine and oxaliplatin was initiated in March 2023, with the dose reduced to 85 percent to enhance tolerability. Treatment was discontinued after two cycles once the results of next-generation sequencing (NGS) became available in April 2023 and showed a fibroblast growth factor receptor 2 (FGFR2) fusion (FGFR2 exon 17/TACC1–7). Additional co-mutations included MCL1 amplification, POLB, and a TSC2 splice acceptor.
Pemigatinib (13.5 mg QD), an FGFR2 inhibitor, was initiated in May 2023, on a 2-weeks-on, 1-week-off schedule. A CT scan in August 2023, 3 months after initiating pemigatinib, showed interval lesion reduction in size in hepatic segment 8 compared with the previous report. Another lesion along the resection margin remained grossly similar and one other smaller previously noted segment 7/8 lesion had resolved completely, indicating partial response. (Figure 1B) The right sacral lesion remained stable. While the patient responded well to treatment, she developed grade 1–2 paronychia, initially managed conservatively but later requiring pemigatinib dose reductions in October 2023 and February 2024 to a final dose of 4.5 mg QD. The treatment schedule remained unchanged.
The patient’s paronychia became mild following dose reduction and referral to a podiatrist for toenail treatment. Other adverse events (AEs) observed early in treatment included grade 1 oral mucositis, occasional diarrhoea, and mild hyperphosphataemia (6.63 mg/dL), which were effectively managed with a medicated mouthwash, loperamide, and a low-phosphate diet, respectively. The patient also developed lower limb cramps at month 2 of pemigatinib treatment, which were likely related to concurrent use of rosuvastatin for management of hyperlipidaemia, as they resolved after statin discontinuation. The cramps resumed after rosuvastatin rechallenge. Thus, the statin was discontinued permanently. Ophthalmologic assessments performed regularly found no retinal detachment.
Of note, pemigatinib’s dose reduction did not affect treatment response, as quarterly follow-up imaging from November 2023 through June 2025 confirmed stable disease. As per June 2025 CT scan, the patient’s disease remained stable, with mild shrinkage at the surgical margin. (Figure 1C) To date, the patient has received 39 cycles of pemigatinib and has achieved 26 months of progression-free survival (PFS), which was ongoing at the time of writing.
Discussion
Cholangiocarcinoma presents significant treatment challenges, with only around 35 percent of patients eligible for curative resection. For patients with advanced disease, second-line treatment options after frontline gemcitabine plus cisplatin remain limited, and the efficacy of second-line chemotherapy is modest, as seen in our patient. NGS molecular profiling helps identify targetable mutations, such as FGFR alterations, which are found in 10–16 percent of cholangiocarcinoma patients.1
Pemigatinib is the first targeted therapy approved for adults with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 fusions or rearrangements who have progressed after ≥1 prior line of systemic therapy.2,3 In the single-arm, multicohort, phase II FIGHT-202 study, pemigatinib demonstrated durable responses and survival benefits in patients with FGFR2 fusions, with an objective response rate (ORR) of 37.0 percent, a median duration of response (DoR) of 9.1 months, a median overall survival of 17.5 months, and a median PFS of 7.0 months.4
Beyond clinical trials, a recent US study demonstrated pemigatinib’s efficacy in the real-world setting, reporting a real-world PFS of 7.4 months and a real-world ORR of 59.2 percent in cholangiocarcinoma patients – exceeding values reported in FIGHT-202.2 These findings contradict conventional expectations, as real-world effectiveness is typically lower than in clinical trials, where patient selection is more stringent.5 Our patient’s remarkable 26 months of PFS further illustrates the robust efficacy of pemigatinib in the real-world setting, highlighting the potential for selected patients with FGFR2 fusions to achieve prolonged disease control.2,4
To optimize treatment efficacy in cholangiocarcinoma, early and proactive molecular profiling is essential. Performing NGS testing at an earlier stage enables timely initiation of targeted therapy, potentially sparing patients from poorly tolerated chemotherapy, which is also of limited efficacy.1,4 Assessing co-mutations may also be of prognostic value, as results from the phase II basket trial FIGHT-207 indicated poorer responses to pemigatinib in patients with TP53 co-mutations and higher response rates among those with BAP1 alterations. The data, however, are observational and further research is needed for wider implementation in the clinic.4,6
Various strategies can help manage common AEs associated with pemigatinib. For patients who develop paronychia and onycholysis, early referral to podiatry teams can effectively minimize nail-related complications. To prevent prolonged hyperphosphataemia, which can lead to muscle cramps due to calcium-phosphate crystal deposition, a low-phosphate diet should be adopted when serum phosphate levels exceed 5.5 mg/dL, and dose reduction may be required if serum phosphate is at ≥7 mg/dL. Regular ophthalmological check-ups are important to prevent rare cases of retinal detachment and other visual symptoms. When necessary, dose reductions can help manage toxicities and improve tolerance, which in our patient’s case did not impact efficacy.3
Conclusion
This case underscores the importance of timely NGS testing to identify FGFR2 fusions for initiation of targeted therapy. Pemigatinib offers meaningful survival benefits with a manageable safety profile, demonstrating the potential of precision medicine to considerably improve outcomes of patients with advanced cholangiocarcinoma.