Cholangiocarcinoma is a cancer of the bile duct epithelium, arising from the intrahepatic or extrahepatic biliary tract. An estimated 8,000 to 10,000 new cases are diagnosed in the United States annually, although this may be an underestimate since such tumors are difficult to accurately diagnose and classify.1 Because cholangiocarcinoma is a rare disease that is challenging to recognize, patients are often not diagnosed until they have progressed to an advanced stage, which is associated with poor survival.
Limited systemic treatment options exist for patients with advanced unresectable or metastatic cholangiocarcinoma not amenable to locoregional therapy or surgery. Standard first-line chemotherapy consists of gemcitabine plus cisplatin, which results in a median overall survival of 1 year or less and median progression-free survival of approximately 8 months.2 The Advanced Biliary Tract (ABC)-02 phase III trial compared the combination of gemcitabine and cisplatin to gemcitabine alone as first-line systemic therapy. A significant increase in median overall survival was seen with the doublet (11.7 months vs 8.1 months), although patients with an ECOG performance status of 2 (PS2) did not live longer with the combination regimen.3 Efforts to improve survival with gemcitabine plus cisplatin by the addition of biologics such as cediranib (ABC-03 trial) or cetuximab (BINGO trial) have not been successful.2 The immune checkpoint inhibitor pembrolizumab can be used in patients with microsatellite instability–high or mismatch repair–deficient tumors.
Few effective treatment options exist following disease progression on gemcitabine/cisplatin. A retrospective analysis of patients with advanced cholangiocarcinoma (most of whom had received first-line gemcitabine-based treatment) found that outcomes were poor with various second-line chemotherapy regimens, including FOLFOX and FOLFIRI; median progression-free survival was just 2.7 months, with a median overall survival of 13.8 months.4 Keeran R. Sampat, MD, of Virginia Cancer Specialists, in Arlington, Virginia, noted that “Beyond surgery, standard chemotherapy options, particularly for those with metastatic disease, are limited so having that [genomic] information is really critical as we’re learning more about the different genomic subtypes.”
Beyond surgery, standard chemotherapy options, particularly for those with metastatic disease, are limited so having that [genomic] information is really critical as we're learning more about the different genomic subtypes.Keeran R. Sampat, MD
A retrospective analysis of patients with cholangiocarcinoma bearing FGFR2 fusions who received second-line chemotherapy indicated a median progression-free survival of 4.6 months (95% confidence interval [CI] = 2.7–7.2) and best overall response of 5.4% (95% CI = 0.7–18.2).1 Current second-line options include gemcitabine plus a fluoropyrimidine, FOLFOX or FOLFIRI, or gemcitabine plus platinum if not received in the first-line setting.4 In the ABC-06 trial, addition of modified FOLFOX to best supportive care improved survival in the second-line setting compared with best supportive care alone, yet the 12-month overall survival rate was only approximately 25% with the combination.5 Together, these results highlight the need for more effective therapeutic options in first-line setting and beyond. (Figure 1).
*Pemigatinib is FDA-approved as second-line treatment for FGFR-altered previously treated, unresectable locally advanced or metastatic cholangiocarcinoma.
Abbreviations: FDA, U.S. Food and Drug Administration; TKIs, tyrosine kinase inhibitors.
The FGFR family of transmembrane receptors, including FGFR1 through FGFR4, can bind 18 known FGF ligands. In normal cells, binding of ligand triggers FGFR dimerization and kinase activation, which then signals through intracellular downstream pathways (RAS/RAF/MEK, JAK/STAT, PI3K/AKT) to promote cell growth, differentiation, survival, and angiogenesis.6 In many cholangiocarcinoma tumors, FGFR is constitutively activated due to FGFR gene amplification, missense mutations or fusions in coding regions, alterations in noncoding domains, or epigenetic modifications. FGFR gene fusions in particular (especially those involving FGFR2) have been found in many types of solid tumors, including cholangiocarcinomas.
Next-generation sequencing has identified actionable genetic alterations with oncogenic potential (mutations, fusions, gene amplification, or overexpression) in more than one-half of all patients with intrahepatic cholangiocarcinoma tumors. These involve IDH (20%–25% of cases), FGFR (15%–20%), HER2 overexpression (10%–20%), PIK3CA (4%–9%), and BRAF (1%–5%).7-12 Genomic alterations appear to segregate according to tumor subtype. FGFR2, IDH1/2, and BRAF are more common in intrahepatic tumors (with FGFR2 fusions found in 13%–17% of cases), while KRAS, TP53, and CDKN2A/B are affected more often in extrahepatic tumors.
All patients with confirmed unresectable or metastatic disease who have adequate performance status should be tested prospectively [for genomic alterations], said Dr. Sampat. “Early genomic testing is critical since it can impact second-line and subsequent lines of therapy for patients with cholangiocarcinoma,” he emphasized.
Alexander Spira, MD, PhD, FACP, of the Virginia Cancer Specialists, Fairfax, Virginia, supports early genomic testing. “With any tumor that is metastatic, and especially with cholangiocarcinomas, almost all patients should be tested for genetic alterations as soon as possible since FGFR inhibitors should be considered sooner rather than later,” he said.
Since there are very few other treatments, I think it's important to have [FGFR inhibitors] as an option. Plus, patients like the idea of a targeted therapy that is directed against a specific mutation.Alexander Spira, MD, PhD, FACP
FGFR fusions are thought to occur in 10% to 20% of cholangiocarcinomas; fusions involving FGFR2 are found in up to 50% of intrahepatic cholangiocarcinomas but not in extrahepatic tumors. A retrospective analysis of 377 patients with cholangiocarcinoma revealed that one-quarter had FGFR genetic alterations (78% affecting FGFR2). FGFR alterations were more common in younger patients (≤ 40 years), women, those with advanced disease, and patients with intrahepatic tumors, and were associated with a longer overall survival compared with patients lacking FGFR alterations.6 Patients with cholangiocarcinomas harboring FGFR alterations typically have normal CA19-9 levels, a high rate of bone metastases, and a short median time on first-line palliative gemcitabine/cisplatin chemotherapy.12
Several FGFR tyrosine kinase inhibitors (TKIs) have been identified and characterized including pemigatinib, infigratinib, futibatinib, erdafitinib, and derazantinib (Figure 1). Most target multiple members of the FGFR family but with varying degrees of specificity (Table 1). With infigratinib, for example, the IC50 (50% inhibitory concentration) for FGFR1 is over 60-fold lower compared with FGFR4 (0.9 nM vs 60 nM). In general, these agents have greater specificity for FGFR compared with other multikinase TKIs, and less off-target toxicity as well.
In a retrospective analysis, FGFR-directed therapy (as well as surgery and radiation therapy) was shown to significantly improve overall survival compared to standard chemotherapy in patients with FGFR-altered cholangiocarcinoma.6 Importantly, cholangiocarcinomas with FGFR fusions show greater sensitivity to FGFR TKIs than those without such alterations, proving the rationale for use of such agents in patients with FGFR2-altered cholangiocarcinoma.
Table 1: In Vitro Selectivity of FGFR Inhibitors*
|IC50 Value (nM)||Infigratinib||Pemigatinib13||Erdafitinib||Rogaratinib||Futibatinib||Derazantinib|
*Note: data are from separate studies, not head-to-head comparisons.
Abbreviation: IC50, 50% inhibitory concentration.
Dr. Spira said, “Since there are very few other treatments, I think it’s important to have [FGFR inhibitors] as an option. Plus, patients like the idea of a targeted therapy that is directed against a specific mutation.”
Several FGFR inhibitors have demonstrated clinical efficacy in advanced cholangiocarcinoma with altered FGFR (Table 2). Currently, pemigatinib (which targets FGFR1–3) is the only FGFR inhibitor approved in the United States. Pemigatinib is indicated for patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma having an FGFR rearrangement.13 Approval was based on results of a phase II trial of pemigatinib in 146 patients with advanced/metastatic or surgically unresectable cholangiocarcinoma with FGFR2 fusion or other rearrangement (as detected by a U.S. Food and Drug Administration–approved test) for whom at least one prior treatment had failed. A total of 107 patients had FGFR2 fusions or rearrangements. With a median follow-up of 17.8 months, the overall response rate (ORR) was 36% (95% CI = 27%–45%) and median duration of response was 6.9 months.13
Table 2. Key Clinical Trials of FGFR Inhibitors in FGFR-Altered Cholangiocarcinoma
|Infigratinib10, 11 (n = 71)||Pemigatinib13 (n = 107)||Futibatinib15 (n = 24)|
|Prior lines of therapy|
|Stage IV at enrollment||96%||66%||NR|
|mPFS||6.8 months||6.9 months||NR|
|mOS||12.5 months||21.1 months||NR|
Abbreviation: DCR, disease control rate; mPFS, median progression-free survival; mOS, median overall survival; NR, not reported; ORR, objective response rate.
Infigratinib was shown to be efficacious in a phase II trial of 71 patients with cholangiocarcinoma with FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. The ORR (the primary efficacy endpoint) was 26.9%, with a 83.6% disease control rate (DCR).11 Median progression-free survival was 6.8 months (95% CI = 5.3–7.6).10, 11 While both this and the preceding trial of pemigatinib enrolled previously treated patients, comparison of efficacy is confounded by the fact that those in the infigratinib study had received more prior lines of therapy (≥ 2 lines: 68% vs 39%). Additionally, 96% of patients in the infigratinib trial had stage IV disease (compared with 66% in the pemigatinib study).
Erdafitinib is an FGFR TKI that may have particular clinical benefit in Asian patients with FGFR-altered advanced cholangiocarcinoma who have had disease progression after one or more prior treatments. Preliminary data on 12 Asian patients from a phase II trial indicated there were 6 confirmed partial responses, including 4 patients with stable disease, and 2 patients who achieved a partial response. In 10 patients with FGFR2 alterations, 6 of 10 patients (60%) achieved a partial or complete response.14
In the FOENIX-CCA2 phase II trial, the FGFR inhibitor futibatinib was evaluated in patients with locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma harboring FGFR2 rearrangements who had disease progression after at least one prior line of systemic therapy (including gemcitabine plus platinum-based chemotherapy).15 For the 67 patients with at least 6 months of follow-up, an interim analysis reported an ORR of 34.3%, with a median duration of response of 6.2 months. Of note, the time to response was rapid in responders (median = 1.6 months; range = 1.0–4.9 months).15
Derazantinib is an inhibitor with pan-FGFR activity that has demonstrated preliminary activity against FGFR2 fusion–positive intrahepatic cholangiocarcinoma.16 In a phase II trial of derazantinib in this patient population, an ORR of 20% was obtained in the first- and second-line settings, with a DCR of 80% and median progression-free survival of 5.5 months.16
The PROOF 301 phase III randomized trial is comparing infigratinib monotherapy to gemcitabine/cisplatin as first-line therapy in patients with FGFR2 gene fusions/translocations (Figure 2). Several additional clinical trials of FGFR inhibitors for advanced cholangiocarcinoma harboring FGFR alterations are ongoing (Table 4). A single-arm phase II trial is also assessing infigratinib in patients with FGFR2 fusions/translocations or other FGFR alterations who are intolerant to gemcitabine-based chemotherapy or for whom such treatment has failed. Two other phase III trials, FIGHT-302 and FOENIX-CCA3, are comparing pemigatinib and futibatinib, respectively, to gemcitabine/cisplatin as first-line treatment of advanced cholangiocarcinoma with FGFR2 rearrangements. The FGFR inhibitor derazantinib is being evaluated in patients with FGFR2 gene fusions/mutations/amplification-positive, inoperable or advanced intrahepatic cholangiocarcinoma following at least one prior systemic regimen.
Abbreviations: ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PS, performance status.
Table 4. Selected Ongoing Trials of FGFR Inhibitors in FGFR-Altered Advanced Cholangiocarcinoma
|NCT Trial Number (Acronym)||Agent/Regimen||Phase||Setting||No. Patients||Primary Outcome Measure||Estimated Primary Completion Date|
|NCT03230318 (FIDES-01)||Derazantinib (following ≥ 1 prior regimen of systemic therapy)||II||Inoperable or advanced intrahepatic cholangiocarcinoma with FGFR2 fusions/mutations/amplification||143||PFS, ORR||July 2020|
|NCT04093362 (FOENIX-CCA3)||Futibatinib vs gemcitabine/cisplatin (first-line treatment)||III||Advanced cholangiocarcinoma with FGFR2 rearrangement||216||PFS||March 2022|
|NCT02150967||Infigratinib (failure or intolerant to gemcitabine-based chemotherapy)||II||Advanced cholangiocarcinoma with FGFR2 gene fusions/translocations (± prior FGFR inhibitor therapy) or other FGFR alterations||160||ORR||March 2022|
|NCT03773302 (PROOF 301)||Infigratinib (first-line treatment)||III||Advanced cholangiocarcinoma with FGFR2 gene fusions/translocations||384||PFS||September 2023|
|NCT03656536 (FIGHT-302)||Pemigatinib vs gemcitabine/cisplatin (first-line treatment)||III||Unresectable or metastatic cholangiocarcinoma with FGFR2 rearrangement||432||PFS||October 2023|
Abbreviations: CCA, cholangiocarcinoma; NCT, National Clinical Trial; ORR, objective response rate; PFS, progression-free survival.
FGFR inhibitors are generally tolerable. Class effects include hyperphosphatemia, fatigue, stomatitis, diarrhea, and dermatologic toxicities (Table 3). Differences in adverse event profiles do exist among FGFR inhibitors, due in part to differences in specificity for the various receptors. For example, hyperphosphatemia is associated with FGFR1 inhibition, whereas diarrhea and other gastrointestinal toxicities are more common with agents such as pemigatinib with greater FGFR4 inhibition. Ocular toxicities such as dry eye can occur in up to one third of patients treated with FGFR inhibitors. While few serious ocular adverse events have been reported with infigratinib, retinal pigment epithelial detachment was noted in 6% of patients across all pemigatinib trials.13,14,18
Table 3. Most Common Treatment-Emergent Adverse Events for Selected FGFR Inhibitors
|Adverse Event (any grade), n (%)||Infigratinib10 (n = 71)||Pemigatinib13,19 (n = 146)||Futibatinib34 (n = 45)|
|Hyperphosphatemia||52 (73)||88 (60)||36 (80)|
|Alopecia||27 (38)||72 (49)||NR|
|PPE||19 (26)||22 (15)||9 (22)|
|Stomatitis||32 (45)||51 (35)||9 (22)|
|Dry eye||23 (32)||51 (35)*||NR|
|Diarrhea||17 (24)||68 (47)||14 (31)|
|Peripheral edema||8 (12)||26 (18)||NR|
*Retinal pigment epithelial detachment reported in 6% of patients (0.6% Grade ≥3).
Abbreviation: NR, not reported; PPE, palmar-plantar erythrodysesthesia.
Overall, FGFR inhibitors are thought to result in less toxicity and better quality of life compared with cytotoxic chemotherapy. Additionally, the lower incidence of off-target toxicity with selective FGFR inhibitors compared to VEGF and multikinase inhibitors reduces the incidence of side effects that can adversely affect patient quality of life.
“The major side effects I’ve seen are eye toxicity, fingernail and skin changes, and some electrolyte abnormalities with calcium and phosphorus,” noted Dr. Spira.
In addition to these FGFR inhibitors, other agents are being investigated for advanced cholangiocarcinoma including novel FGFR inhibitors, multikinase TKIs, and immune checkpoint inhibitors. Debio 1347, an FGFR inhibitor, has demonstrated preliminary efficacy in patients with advanced refractory solid tumors harboring an FGFR1–3 gene fusion.19 In one study, FGFR4 expression was increased in cholangiocarcinoma tumors and was found to be an independent prognostic factor for poor prognosis, suggesting its potential as a therapeutic target.20 A phase I study of H3B-6527, an inhibitor of the FGFR4/FGF19 pathway, has demonstrated preliminary activity in patients with advanced intrahepatic cholangiocarcinoma or hepatocellular carcinoma,21 and another FGFR4 inhibitor (fisogatinib) demonstrated clinical benefit and tumor regression in patients with hepatocellular carcinoma showing aberrant FGF19 expression.22
A recent phase III trial (ClarIDHy) evaluated ivosidenib, an inhibitor of mutated IDH1, in previously treated patients with IDH1-mutated cholangiocarcinoma. Ivosidenib significantly improved median progression-free survival (2.7 months vs 1.4 months; P < .0001); however, crossover from the placebo arm upon disease progression confounded determination of any overall survival benefit with ivosidenib.23
In an ongoing phase II, open-label basket trial (ROAR), 43 patients with BRAFV600E-mutated locally advanced or metastatic biliary tract cancer were treated with the combination of dabrafenib and trametinib. More than 90% of patients had cholangiocarcinoma and all had received previous systemic treatment. In an interim analysis, the investigator-assessed overall response was 51%, and toxicity was considered to be manageable. These results suggest that this combination regimen could be effective in the 5% of cholangiocarcinoma patients whose tumors bear this mutation.24
A phase II randomized trial (TreeTopp) of capecitabine combined with the pan-HER inhibitor varlitinib or placebo as second-line therapy found no significant difference in ORR, progression-free survival, or overall survival, although a progression-free survival benefit was noted in some patient subgroups (eg, those with gallbladder cancer and females).25 Bintrafusp alfa, a fusion protein targeting TGF-β and PD-L1, demonstrated preliminary activity in pretreated patients with cholangiocarcinoma and is now being evaluated as first-line therapy in combination with gemcitabine/cisplatin for locally advanced or metastatic disease.26 Lastly, trials of immunotherapy including durvalumab, pembrolizumab, and nivolumab plus ipilimumab have shown some efficacy in advanced cholangiocarcinoma, suggesting a possible role for immunotherapy in combination with chemotherapy in this setting.27-30
Recent studies have evaluated the use of liquid tumor biopsies for assessment of genomic alterations in cholangiocarcinoma by measuring circulating tumor cells or plasma circulating tumor DNA (ctDNA). In the phase III ClarIDHy study, mutant IDH1 could be detected in both tumor tissue and plasma ctDNA (92% concordance), supporting the use of ctDNA when tumor tissue is not available.31 Moreover, in a subset of patients, IDH1 mutation clearance from plasma correlated with longer progression-free survival, suggesting its potential as a predictive marker of response to ivosidenib therapy. At present, however, use of liquid biopsies for FGFR inhibitor therapy is investigational.
FGFR alterations are present in a significant proportion of patients with cholangiocarcinoma and can thus serve as a therapeutic target. The clinical development of FGFR-specific inhibitors, and the recent approval of one such agent for FGFR2-rearranged advanced cholangiocarcinoma, support the efficacy and safety of this approach. These agents have greater specificity compared with multikinase inhibitors and may therefore result in greater efficacy and less nonspecific toxicity, potentially improving survival and enhancing quality of life.
Rapid genomic testing and accurate diagnosis are critical in order to identify cholangiocarcinoma patients with FGFR alterations who may be candidates for FGFR inhibitor therapy. Next-generation sequencing is recommended for all patients with cholangiocarcinoma who undergo a core biopsy or surgical resection in order to inform the use of FGFR inhibitors in those whose disease has FGFR alterations. Early initiation of such therapy could obviate the need for chemotherapy, reducing toxicity and increasing the likelihood of a response.
To potentially expand the use of FGFR inhibitors beyond cholangiocarcinoma, these agents also are under evaluation in other tumor types with FGFR alterations such as bladder cancer, hepatocellular carcinoma, melanoma, and glioblastoma. An ongoing phase III trial of infigratinib as adjuvant therapy for invasive urothelial carcinoma with susceptible FGFR3 alterations is underway, as is a phase II basket trial of infigratinib for advanced or metastatic solid tumors with FGFR mutations. Combination regimens of FGFR inhibitors with other anticancer modalities such as immune checkpoint inhibitors, other TKIs, and radiotherapy also are being explored and may further increase their therapeutic benefit.
“Dr. Sampat concluded, “Given the lack of progress in this field, we are excited to finally have targeted therapies for these rare but aggressive cancers.”
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