Cholangiocarcinoma is an aggressive cancer of the bile ducts that includes intrahepatic and extrahepatic disease. This malignancy is often diagnosed at an advanced stage, which is associated with a poor prognosis. For patients with advanced unresectable or metastatic tumors not amenable to locoregional therapy or surgery, standard first-line chemotherapy (typically gemcitabine plus cisplatin) results in a median progression-free survival of approximately 8 months and a median overall survival of no more than 1 year.¹ Historically, few effective treatment options have been available following disease progression on chemotherapy, highlighting the need for more effective therapeutic options.^2,3

Approximately half of all patients with cholangiocarcinoma have genetic alterations with oncogenic potential including mutations, gene fusions, amplification, and overexpression, which include those affecting the fibroblast growth factor receptor (FGFR) gene.^4,5 FGFR alterations can cause constitutive activation of this receptor, triggering unregulated tumor growth. FGFR genomic alterations are common in intrahepatic cholangiocarcinoma, particularly FGFR2 mutations and gene fusions (~15%).⁶ These data provided the rationale for therapeutic targeting of this receptor and led to clinical development of multiple FGFR kinase inhibitors. Several such agents have demonstrated efficacy as second-line or greater therapy for FGFR-altered advanced cholangiocarcinoma including infigratinib, pemigatinib, futibatinib, erdafitinib, and derazantinib, although currently only infigratinib and pemigatinib have been approved by the U.S. Food and Drug Administration (FDA) for this indication. (Erdafitinib is approved for locally advanced or metastatic urothelial carcinoma with susceptible FGFR2/3 alterations and progression with at least one line of prior platinum-based chemotherapy).

FGFR-Targeted Inhibitors

Infigratinib was evaluated in a phase II trial in patients with locally advanced or metastatic cholangiocarcinoma bearing FGFR2 fusions/rearrangements and progression on at least one gemcitabine-containing regimen. Of the 108 patients in the full analysis set, 88 (81%) had FGFR2 gene fusions and 20 (19%) had other FGFR2 rearrangements. Most (94%) had extrahepatic metastases, and more than half had received two or more (between three and eight) prior lines of therapy. At a median follow-up of 10.6 months, the objective response rate was 23.1% and was similar across patient subgroups.⁷ The overall median progression-free survival was 7.3 months, with a median overall survival of 12.2 months. When analyzed by prior lines of therapy, the objective response rate was 34.0% in the second-line setting, and the median overall survival for second-line infigratinib was 14.5 months compared with 8.7 to 14.4 months for third-line therapy and beyond. On the basis of these data, infigratinib was approved in May 2021 for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

Pemigatinib was evaluated in a phase II trial (FIGHT-202) in patients with advanced/metastatic or surgically unresectable cholangiocarcinoma bearing FGFR2 gene fusions or rearrangements. Patients had received between one and five lines of prior therapy. Of the 146 patients enrolled, 107 had FGFR2 gene fusions/rearrangements (20 had other FGFR2 alterations, 18 had no FGFR2 alterations, and 1 had an undetermined FGFR2 alteration). At a median follow-up of 17.8 months, the objective response rate was 35.5% for those with FGFR2 gene fusions/rearrangements (no responses were seen in other patient subgroups) and median progression-free survival was 6.9 months.⁸ These results led to the FDA approval of pemigatinib for previously treated patients with advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or other rearrangement as detected by an FDA-approved test.

Other FGFR inhibitors have demonstrated efficacy in advanced cholangiocarcinoma as well. Futibatinib received FDA Breakthrough Therapy designation in April 2021 for patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements, including gene fusions, based on results of a phase II trial.⁹ Responses were also observed with erdafitinib in Asian patients with advanced cholangiocarcinoma and FGFR alterations who had progressed after at least one prior treatment.¹⁰ Preliminary results from a phase II trial of derazantinib in patients with HER2-negative intrahepatic cholangiocarcinoma harboring FGFR2 alterations indicated an objective response rate of 21.4%^11,12; this study is also evaluating derazantinib in combination with paclitaxel, ramucirumab, or atezolizumab.

FGFR Genomic Profiling

Use of infigratinib or pemigatinib for advanced cholangiocarcinoma requires confirmation of an FGFR2 fusion or other rearrangement as detected by an FDA-approved test.^13,14 Genomic analysis should be conducted (preferably using next-generation sequencing) to identify these or other driver aberrations that may inform selection of targeted therapy.¹⁵ “It's imperative to also perform RNA-based sequencing,” noted Sameek Roychowdhury, MD, PhD, of The Ohio State University Comprehensive Cancer Center, “since you could be missing 10% to 20% of your patients who may have an FGFR2 alteration that could go undetected by DNA sequencing, which is imperfect.”

It's imperative to also perform RNA-based sequencing, since you could be missing 10% to 20% of your patients who may have an FGFR2 alteration that could go undetected by DNA sequencing, which is imperfect.Sameek Roychowdhury, MD, PhD

Ideally, such testing should be performed on all cholangiocarcinoma patients at diagnosis rather than at disease progression to avoid undue delays in obtaining results, a point emphasized by Rachna Shroff, MD, of the University of Arizona Cancer Center in Tucson. “The one thing that we, as a cholangiocarcinoma community, cannot underscore enough is that every single patient needs to have biomarker testing done right at the time of diagnosis, so we know what we have available to us in terms of therapy,” she said. Earlier rather than later initiation of such therapy may improve outcomes and can reduce the use of other potentially less effective and more toxic agents. Sequencing can also indicate the precise breakpoint and type of FGFR2 fusion, which may affect sensitivity to FGFR inhibitors.¹⁶

The one thing that we, as a cholangiocarcinoma community, cannot underscore enough is that every single patient needs to have biomarker testing done right at the time of diagnosis, so we know what we have available to us in terms of therapy. Rachna Shroff, MD

Emerging data suggest the potential of cell-free tumor DNA sequencing of blood samples as a noninvasive method to assess tumor heterogeneity and acquisition of resistance mutations.^17,18 Dr. Roychowdhury recommended caution when using this method for diagnosis of cholangiocarcinoma, however. “I'm not certain it’s adequately sensitive to detect FGFR fusions because it is a DNA-based approach,” he said. “For the time being, until we learn more about liquid biopsy, I recommend at a minimum to do a tumor biopsy–based approach for genomic testing.”

Timing and Selection of FGFR2 Inhibitors

Some patients are refractory or resistant to chemotherapy or unable to tolerate its toxicity, leading to a switch to a targeted agent. For those who do receive chemotherapy initially, there is no clear benefit for second-line chemotherapy following disease progression, regardless of FGFR status, nor does addition of a biologic agent significantly prolong survival.^5,7 In contrast to the continued use of chemotherapy, earlier initiation of FGFR inhibitor therapy may result in a higher response rate, as seen in the infigratinib phase II trial (objective response rate of 34.0% for patients with no more than one previous line of therapy vs 13.8% in those with more than one previous line of therapy). Notably, the third- or later-line therapy subgroup encompassed patients who received two to eight prior lines of treatment. Durable responses in this more refractory subgroup support meaningful clinical activity in this population.⁷ Preliminary data also suggest that some patients who progress on one FGFR2 inhibitor might respond to another. In a trial of futibatinib in 45 patients with advanced cholangiocarcinoma (including 13 treated with at least one prior FGFR inhibitor), 71% of patients with FGFR2 fusions had tumor shrinkage.¹⁹ The efficacy of infigratinib in patients previously treated with other FGFR inhibitors is also being evaluated in an ongoing phase II trial (ClinicalTrials.gov identifier NCT02150967).⁷ These intriguing results, and their applicability to other sequences of FGFR2 inhibitors, require further study.

Certain factors may influence choice of agent for FGFR2-altered advanced cholangiocarcinoma. Patient-specific factors and comorbidities should be considered since some could impact drug selection. Manufacturer support, including any available drug rebates, financial assistance, and/or patient support programs, might also be important. Differences in dosing schedule may also be a consideration (ie, daily for 21 days followed by a 7-day rest with infigratinib vs daily for 14 days followed by a 7-day rest with pemigatinib).^13,14

Currently approved FGFR inhibitors are indicated for treatment of patients with cholangiocarcinoma bearing an FGFR2 fusion or other rearrangement, but there is interest in their broader potential use given their inhibition of FGFR1, 2, and 3. “We also see patients who have an atypical FGFR gene alteration in cholangiocarcinoma for which existing FGFR inhibitors are not yet approved,” said Dr. Roychowdhury. “We try to enroll those patients in clinical trials, and we predict that they are likely to benefit from a first-generation selective FGFR inhibitor as well.” The ongoing phase II trial is evaluating the efficacy of infigratinib in patients with FGFR genetic alterations other than FGFR2 gene fusions or rearrangements.

Adverse Events and Management

FGFR inhibitors are associated with a variety of on-target toxicities including alterations in phosphate homeostasis, nail and skin toxicities, and ocular adverse events. In the pemigatinib pivotal trial, the most common treatment-related adverse events (≥ 30%; all-grade) were hyperphosphatemia (55%), alopecia (46%), dysgeusia (38%), diarrhea (34%), and fatigue (31%).⁸ Overall, 64% of patients (N = 146) had a grade ≥ 3 adverse event. Gastrointestinal toxicity was common, with grade 1/2 dysgeusia (38%), diarrhea (34%), and nausea (23%). Serous retinal detachment was noted in 4% of patients. In the infigratinib phase II trial, the most common treatment-related adverse events (≥ 30%; all-grade) were hyperphosphatemia (74%), stomatitis (51%), alopecia (32%), and palmar-plantar erythrodysesthesia syndrome (PPES; 32%), and dry eye (31%); other gastrointestinal toxicities included dysgeusia (26%) and diarrhea (18%).⁷ Grade ≥ 3 adverse events were seen in 56% of patients (N = 108). Central serous retinopathy–like and retinal pigment epithelial detachment–like events occurred in 17% of patients, which were grade 1/2 in nearly all cases.

Hyperphosphatemia, a class effect of FGFR inhibitors, occurred in 55% to 81% of patients in cholangiocarcinoma pivotal trials.⁴ It can be managed by dietary modification and use of phosphate-lowering therapies, with dose reductions if necessary (Table 1). Patients should be educated about the risk of hyperphosphatemia and approaches to reducing dietary phosphate while on FGFR inhibitors.²⁰

Gastrointestinal adverse events such as diarrhea, nausea, and vomiting can occur with FGFR inhibitors. The incidence of diarrhea ranges from 15% to 60%, with mostly low-grade events.⁴ Diarrhea can often be controlled by optimizing fluid intake and use of probiotics and loperamide. Additionally, oral mucosal effects such as stomatitis and dry mouth may occur. Low-grade stomatitis is often managed using dexamethasone elixir or other nonalcoholic oral rinses, while dry mouth may be treated with gustatory/masticatory stimulants and lubricants.²¹

Dermatologic toxicities including dry skin, PPES, and alopecia are frequently observed with FGFR inhibitor therapy and may increase with duration of treatment. Skin and hair adverse events can be managed by standard measures such as topical lotions and moisturizers (containing urea for PPES or severe dry skin), and minoxidil or high-potency corticosteroids for alopecia.²¹ Reported nail toxicities include onycholysis, paronychia, and nail hypertrophy and discoloration. Paronychia can be treated with a topical antiseptic or antibiotic, while oral antibiotics are indicated for infection associated with onycholysis. A dermatology consultation or referral may be appropriate for more severe toxicities.

Ocular toxicities including dry eye, blurry vision, and floaters can occur with many FGFR inhibitors, although most adverse events are low grade.²⁰ Dry eye was fairly common in the pemigatinib and infigratinib clinical trials (22% and 34%, respectively, all-grade).^7,8 More serious retinal issues such as central serous retinopathy and retinal detachment have been reported, though nearly all were grade 1/2. Because early identification of retinal changes is essential, patients should be monitored by comprehensive ophthalmologic examinations before and during FGFR inhibitor therapy.

I think we have gotten smarter and better at understanding the class effects of these drugs, and to be more proactive about mitigating and managing their side effects, which can absolutely impact the patient's quality of life. Rachna Shroff, MD

Increased risk of these toxicities requires careful monitoring, supportive care measures, dietary modification, and/or dose reduction or interruption. Permanent discontinuation of the FGFR inhibitor is recommended for any grade 4 event and for some other toxicities of lesser grade.^13,14 Overall, however, management of drug-related adverse events has improved. According to Dr. Shroff, “I think we have gotten smarter and better at understanding the class effects of these drugs, and to be more proactive about mitigating and managing their side effects, which can absolutely impact the patient's quality of life.”

Future Directions of FGFR Inhibition in Advanced Cholangiocarcinoma

In light of the efficacy of FGFR inhibitors in previously treated patients with advanced cholangiocarcinoma, ongoing trials are evaluating these agents as first-line therapy in patients with FGFR2 gene fusions or rearrangements (Table 2).²² The PROOF 301 Phase III trial, for example, is comparing infigratinib with gemcitabine-cisplatin as first-line therapy in patients with unresectable locally advanced or metastatic cholangiocarcinoma bearing FGFR2 gene fusions/translocations (Figure 1; NCT03773302).

These agents are also under further evaluation in the second-line or greater setting. Additionally, clinical trials are evaluating FGFR inhibitors in many other solid tumors including hepatocellular carcinoma, breast cancer, high-grade glioma, and gastric cancer/gastroesophageal junction tumors, and as solid tumor–agnostic therapy for FGFR-altered malignancies. Trials are also testing FGFR inhibitors in combination with other targeted agents or immunotherapy in advanced cholangiocarcinoma and other tumor types to further increase efficacy.

Conclusion

FGFR dysregulation occurs in a significant proportion of patients with advanced cholangiocarcinoma. Increased use of FGFR inhibitors in patients with these molecular alterations has led to improved response rates and decreased toxicity compared with chemotherapy and may increase survival. “I think it is really exciting that we have these drugs available to us and can effectively treat patients with a rare tumor, with great clinical benefit,” remarked Dr. Shroff. Results of trials evaluating FGFR inhibitors as first-line therapy are eagerly awaited since, if positive, they could establish a new frontline standard of care for advanced cholangiocarcinoma bearing FGFR2 gene fusions/rearrangements. In both settings, knowledge of treatment-related adverse events and approaches for management is essential to optimize use of FGFR inhibitors. Efforts are also under way to identify potential biomarkers that could aid in assessing response to these agents or detect early development of resistance.