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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 22-29

FGFR inhibitors: Emerging treatments in advanced or metastatic cholangiocarcinoma


1 Medical Oncology Department, St Vincent’s University Hospital, Dublin, Ireland
2 Medical Oncology Department, Mid-Western Cancer Centre, University Hospital Limerick, Limerick, Ireland

Date of Submission19-Dec-2020
Date of Acceptance12-Mar-2021
Date of Web Publication31-Jul-2021

Correspondence Address:
Dr. Yasar Ahmed
Medical Oncology Department, St Vincent’s University Hospital, Merrion Rd, Dublin 4 D04 N2E0.
Ireland
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_45_20

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  Abstract 

Cholangiocarcinoma (CCA) is an aggressive cancer with poor prognosis, where the median overall survival remains less than 1 year with standard treatment for unresectable or metastatic disease. This highlights the need for new therapeutic approaches. The fibroblast growth factor receptor (FGFR) family of transmembrane receptors, which are implicated in tumorigenesis, may represent one such target. In this article, we summarize the therapeutic rationale for targeting these receptors in CCA and the role of molecular testing to identify potential responders to treatment. We examine the current available safety and efficacy data on the several small molecule tyrosine kinase inhibitors under investigation for this disease. With a move toward identifying and targeting tumor specific mutations, FGFR inhibitors represent an exciting development which may be available for patients in the near future.

Keywords: Biliary tract cancer, FGFR, precision oncology, translational medicine


How to cite this article:
Ahmed Y, Khan R, O’Reilly M, O’Sulivan S, Mahgoub T. FGFR inhibitors: Emerging treatments in advanced or metastatic cholangiocarcinoma. J Curr Oncol 2021;4:22-9

How to cite this URL:
Ahmed Y, Khan R, O’Reilly M, O’Sulivan S, Mahgoub T. FGFR inhibitors: Emerging treatments in advanced or metastatic cholangiocarcinoma. J Curr Oncol [serial online] 2021 [cited 2021 Nov 30];4:22-9. Available from: https://www.journalofcurrentoncology.org/text.asp?2021/4/1/22/322895




  Introduction Top


Cholangiocarcinoma (CCA) is an aggressive and deadly cancer of the epithelial cells of the bile ducts.[1] CCAs are typically classified into intrahepatic (ICCA) and extrahepatic (ECCA) depending on whether they originate from inside or outside the liver, respectively.[2] Importantly, because some ICCAs are classified as “cancer of unknown primary” or as “primary liver cancer,” accurate estimates of CCA incidence are difficult to ascertain.[3] According to current estimates, ICCA represents approximately 10% of all primary hepatobiliary cancers, making it the second most common malignancy arising from the liver.[4],[5] Each year, roughly 23,000 cases of CCA are diagnosed worldwide, and the incidence of biliary tract cancers appears to be increasing, possibly because of the rising rate of ICCA.[1],[2],[4] In addition, CCA can be challenging to diagnose and is often misclassified; therefore, its actual incidence is likely higher than reported.[5]

Survival rates of individuals with CCA vary depending on the cancer subtype, stage at diagnosis, performance status, and liver function.[2],[5],[6] The median overall survival (OS) of individuals with CCA is typically less than 2 years.[1] The 5-year survival rates for ICCA and ECCA are 8% and 10%, respectively.[5] Surgical resection can potentially be curative; unfortunately, many patients with CCA present with advanced, unresectable, or metastatic disease, thereby limiting the number of available treatment options.[1],[4],[7] For patients with unresectable or metastatic disease, the prognosis remains poor with a median OS of no more than 1 year, even with the standard treatment of gemcitabine and cisplatin[8],[9]

The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signaling networks that drive and sustain cholangiocarcinogenesis.

This article explores emerging clinical data and insights related to the potential use of fibroblast growth factor receptor (FGFR) inhibitors in CCA. It addresses the challenges and limitations of emerging FGFR inhibitors, discusses current research on using genomic biomarkers and their potential to predict response to FGFR inhibitors.


  Targeting Fibroblast Growth Factor Receptor Fusions Top


Next-generation DNA sequencing has identified several actionable gene signatures in CCA, including genomic alterations in the FGFR signaling pathway.[6],[10] The FGFR family consists of 4 transmembrane receptors (FGFR1-4) and 18 ligands (FGF1-10 and FGF16-23).[10],[11],[12] FGFR signaling is involved in various biological processes including cell proliferation, migration, and survival, as well as phosphate and vitamin D homeostasis.[1],[13] Aberrations in FGFR signaling contribute to tumorigenesis, including invasion and the promotion of tumor angiogenesis; therefore, they have been implicated in the pathogenesis of CCA.[11],[14],[15]

In an analysis by Helsten et al.[16] of 4853 patients with solid tumors, the overall frequency of FGFR aberrations was 7.1%. Aberrations in FGFR1 were the most common, accounting for 49% of total aberrations. FGFR2, FGFR3, and FGFR4 aberrations represented 19%, 26%, and 7% of total aberrations, respectively. The majority of FGFR aberrations were gene amplifications (66%), followed by gene mutations (26%) and gene rearrangements (8%).[16]

In approximately 20% of ICCA cases and 5% of ECCA cases, the FGFR signaling pathway is dysregulated through various genomic alterations, including gene fusions, point mutations, insertions, deletions, and copy-number amplifications.[2],[11],[17]FGFR2 translocations have been reported in 13%–17% of ICCA cases, and FGFR1-3 fusions and arrangements have been reported in approximately 11% of ICCA cases.[6],[14],[15],[18]FGFR2-BICC1 fusion was one of the first targetable FGFR gene fusions discovered in CCA. Subsequent studies have identified several other gene partners of FGFR2 fusions.[19],[20]

CCA tumors with genomic alterations in the FGFR signaling pathway are associated with a better prognosis than those with wild-type FGFR.[21]FGFR genetic aberrations, specifically, may be associated with a favorable prognosis, and patients with these alterations often present at an earlier disease stage.[11]FGFR2 fusions have also been found in patients with early stage, nonadvanced CCA following surgical resection, suggesting that FGFR2 fusions may be an early oncogenic event.[17] Together, these studies support the potential role of FGFR2 fusions as a predictive and prognostic marker in CCA.

Research suggests that FGFR2 fusions are associated with better survival rates in patients with CCA.[22] Indeed, a study that examined the prognostic implications of FGFR alterations in biliary tract cancers found that FGFR2 fusions or mutations in ICCA are associated with significantly improved OS (P = 0.001).[22]


  Predictive Role Of Fibroblast Growth Factor Receptor Inhibitors: Emerging Treatments in Clinical Trials Top


Increasing knowledge of the functional consequences of genetic modifications along the FGFR signaling pathway has led to the targeting of this pathway for therapeutic purposes. Several drugs that target the FGFR signaling pathway, including FGFR inhibitors, are being evaluated in clinical trials in FGFR2 fusion-positive CCA. In some early-phase clinical trials, the presence of FGFR2 fusions correlated with initial clinical responses to FGFR inhibitors, with overall response rates (ORRs) ranging from 19% to 40% and median progression-free survival (PFS) rates of 5–9 months.[23],[24],[25],[26],[27] All of the following agents have been shown to inhibit FGFR1-4 in vitro, though some are less potent against FGFR4 [Table 1].[23],[24],[25],[26],[28]
Table 1: Selective inhibition as measured by IC50 nM of emerging FGFR inhibitors

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Debio 1347 mechanism of action

Debio 1347 is an investigational, oral, selective, adenosine triphosphate (ATP)-competitive pan-FGFR inhibitor. It has been shown to inhibit FGFR1–4 in vitro, although it is less potent against FGFR4 [Table 1]; it has also been shown to be effective in several in vivo tumor models that express FGFR alterations.

Efficacy

A dose-escalation phase-1 trial (NCT01948297) assessed Debio 1347 in individuals with advanced solid tumors and FGFR alterations The most common gene alterations observed were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 participants (21%) had FGFR fusions. Among the 57 participants who were evaluated for tumor responses, 6 achieved a partial response and 16 achieved stable disease.[29]

Safety

The most common treatment-related AEs of all grades are Nail changes included onychomadesis, onychoclasis, onychalgia, nail dystrophy, nail bed disorders, and nail discoloration.[30] The most common severe AEs (of grade 2 or higher) were hyperphosphatemia, anemia, hyponatremia, and dyspnea. Both the incidence and severity of hyperphosphatemia were dose-dependent. Dose-limiting toxicities (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis) were reported in five participants. Notably, the maximum tolerated dose was not reached, but dermatologic toxicity was sometimes dose-limiting. AEs requiring dose modifications occurred in 52% of participants, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%).[29],[31]

Ongoing trials

A phase-2 trial (NCT03834220) has enrolled patients with advanced solid tumors harboring FGFR fusions to investigate the efficacy of Debio 1347.

Derazantinib mechanism of action

Derazantinib is an investigational, oral, ATP-competitive pan-FGFR kinase inhibitor with potent activity against FGFR-dependent cancer cell lines and tumors.[32] It has been shown to inhibit FGFR1-4 in vitro, though it is somewhat less potent against FGFR4.[32]

Efficacy

An open-label, dose-escalation phase 1/2 trial (NCT01752920) evaluated derazantinib in individuals with advanced solid tumors and FGFR2 alterations.[32] This study enrolled 29 participants with advanced or inoperable FGFR2 fusion-positive CCA, including 27 individuals whose disease progressed after at least 1 prior systemic therapy and 2 treatment-naïve individuals.

In a post hoc outcome analysis of the trial, the ORR, disease control rate (DCR), tumor shrinkage, and PFS in individuals with advanced CCA with FGFR2 fusions who were treated with derazantinib in the first- or second-line setting (n = 15) were compared with those in individuals who received derazantinib after two or more prior lines of therapy (n = 14).[32] Outcomes were similar irrespective of treatment line.

Safety

AEs (all grades) occurred in 27 participants (93%) and are. AEs of grade 3 or higher occurred in eight participants (28%) and included hyperphosphatemia (n = 3), eye toxicity of dry eye and/or blurred vision (n = 2), and serious treatment-unrelated upper gastrointestinal hemorrhage (n = 1).

Ongoing trials

A phase-2 trial (NCT03230318) evaluating the antitumor activity of derazantinib in inoperable or advanced ICCA with FGFR2 alterations (fusions, mutations, or amplifications) is now underway.

Erdafitinib mechanism of action

Erdafitinib is an oral, selective, pan-FGFR kinase inhibitor with potent tyrosine kinase inhibitory activity against FGFR1-4.[33] It is approved by the United States Food and Drug Administration (FDA) for use in select adults with locally advanced or metastatic urothelial carcinoma, but its use in CCA is off label.[34]

Efficacy

An open-label, dose-escalation phase-1 trial (NCT01703481) evaluated erdafitinib in 65 participants with advanced refractory solid tumors with or without FGFR alterations.[35] In individuals with FGFR2 or FGFR3 fusions with glioblastoma or urothelial or endometrial cancer, four confirmed responses and one unconfirmed partial response were reported. Another 16 evaluable patients had stable disease. Notably, no response to erdafitinib was observed in the 36 individuals whose tumors harbored no known or unknown FGFR alterations.

As part of the NCT01703481 phase 1 trial, erdafitinib was also evaluated in an expansion cohort of 187 individuals with advanced refractory solid tumors with or without FGFR alterations.[36]

Safety

Treatment-related AEs were reported in 63 participants (97%), 36 Treatment-related AEs of grade 3 or higher were observed in 27 participants (42%) and included abnormal hepatic function, nail toxicity, abdominal pain, and palmar-plantar erythrodysesthesia.[36] In the expansion cohort, 88 participants (47%) experienced serious treatment-related AEs.[26] Anemia was the most frequently reported grade 3 treatment-related adverse event, followed by stomatitis, general physical health deterioration, asthenia, increased aspartate aminotransferase, and hyponatremia.[26]

Other clinical studies

In 12 evaluable Asian participants with FGFR-altered CCA who were treated with erdafitinib in a phase-2a trial (NCT02699606), the ORR was 50%, and the median PFS was 5.59 months.[37] In 10 evaluable Asian participants with FGFR2 alterations, the ORR was 60%, and median PFS was 12.35 months. The most common treatment-related AEs were hyperphosphatemia, dry mouth, stomatitis, and dry skin. Grade 3 or higher AEs were reported in nine participants, of which seven were drug-related. These results are consistent with those observed in participants from other ethnic populations.[37]

Ongoing trials

The aforementioned ongoing phase-2 trial (NCT02699606) is evaluating the clinical efficacy of erdafitinib in various FGFR-mutated cancers, including CCA.

Infigratinib mechanism of action

Infigratinib is an investigational, oral, selective, ATP-competitive pan-FGFR kinase inhibitor with activity against cancer cell lines expressing FGFR alterations.[37] It has been shown to inhibit FGFR in vitro, though it is less potent against FGFR4.[24]

Efficacy

Results from a phase-2 trial of infigratinib (NCT02150967) included clinical data on 61 participants with metastatic or advanced CCA that expressed FGFR2 alterations (48 with fusions, 8 with mutations, and 3 with amplifications) whose disease progressed despite prior treatment with first-line chemotherapy.[37] At the prespecified data cutoff of June 30, 2016, the overall ORR was 14.8%, and the DCR was 75.4% (partial response in 9 participants and stable disease in 37 participants). All responsive tumors harbored FGFR2 fusions; in this subgroup (n = 48), the ORR was 18.8%, and the DCR was 83.3%.[37]

According to updated results from this phase-2 trial, at the prespecified data cutoff of August 8, 2018, 71 participants with advanced FGFR2 fusion-positive CCA achieved a DCR of 83.6% and an ORR of 31% with infigratinib treatment.[24],[38]

Safety

As of June 30, 2016, treatment-related AEs were reported in 56 participants (92%) Treatment-related AEs of grade 3 or 4 occurred in 25 participants (41%) and included hyperphosphatemia, stomatitis, palmar-plantar erythrodysesthesia, increased lipase, and hypophosphatemia. Toxicity was generally manageable.[24]

As of August 8, 2018, the most common treatment-related AEs were hyperphosphatemia (73%), fatigue (49%), stomatitis (45%), alopecia (38%), and constipation (35%).[36] Grade 3 or 4 treatment-related AEs occurred in 47 participants (66%) and included hypophosphatemia (14%), hyperphosphatemia (13%), and hyponatremia (11%).

Ongoing trials

A phase-3 trial (NCT03773302) directly comparing infigratinib to traditional chemotherapy (gemcitabine and cisplatin) is now underway.

Pemigatinib mechanism of action

Pemigatinib is an investigational, oral, selective, ATP-competitive pan-FGFR inhibitor that has shown potent selective pharmacologic activity against cancer cells expressing FGFR alterations.[25],[28] It has been shown to inhibit FGFR1-4 in vitro, although it is less potent against FGFR4.[27]

Efficacy

A phase-2 study evaluated pemigatinib (NCT02924376) in 107 individuals with advanced refractory FGFR2 fusion-positive CCA.[26] The ORR was consistent when stratified by the number of prior lines of therapy and by FGFR2 gene fusion partner.[27] At the time of data cutoff (March 22, 2019), the median OS was 21.1 months (95% CI, 14.8 months to not reached) in participants with FGFR2 fusions compared with 6.7 months in participants with other FGF/FGFR alterations (n = 20) and 4 months in the cohort with no FGF/FGFR alterations (n = 18).[25],[26]

Safety

Treatment-related AEs of grade 3 or higher that were observed in more than 5% of participants included hypophosphatemia (14%), hyponatremia (8%), abdominal pain (7%), and arthralgia (7%).[26] Importantly, five participants had AEs causing death, but none of these fatalities were related to treatment.[26]

Ongoing trials

A phase-3 trial (NCT03656536) of pemigatinib versus gemcitabine plus cisplatin in the first-line setting in patients with CCA and FGFR2 fusions is ongoing.

TAS-120 mechanism of action

TAS-120 is an investigational, oral, selective, irreversible pan-FGFR inhibitor that covalently binds to a highly conserved P-loop cysteine residue in the ATP pocket of FGFRs.[20] It has been shown to inhibit FGFR1-4 in vitro [Table 1].[31]

Efficacy

A phase 1/2 basket trial (NCT02052778) evaluated TAS-120 in individuals with advanced refractory solid tumors.[32] Results showed an ORR of 25% and a DCR of 78.6% (7 confirmed partial responses and 15 stable diseases) in 28 participants with FGFR2 fusion-positive CCA, including 13 who had received prior therapy with an FGFR inhibitor

Safety

Common AEs of all grades occurred in 98% of patients[31] and includes. Grade 3 or higher treatment-related AEs were reported in 51% of participants; the most common were hyperphosphatemia (22%) and increased alanine aminotransferase (7%).[32]

Other clinical studies

TAS-120 showed clinical benefit in four participants with FGFR2 fusion-positive CCA whose disease progressed after treatment with infigratinib or Debio 1347.[20] These findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and circulating tumor DNA (ctDNA) analysis, may prolong the duration of benefit from FGFR inhibition in FGFR2 fusion-positive CCA.[20]

Ongoing trials

As part of the basket trial (NCT02052778), a phase-2 study examining the efficacy of TAS-120 in individuals with FGFR2 fusion-positive CCA is now underway.

Selected clinical trials of anti-FGFR drugs in advanced CCA are summarized in [Table 2].
Table 2: Selected clinical trials of anti-FGFR drugs in advanced cholangiocarcinoma

Click here to view



  Practical Clinical Considerations Top


Molecular testing may have an increasingly important role in selecting therapy for advanced or unresectable CCA.[15] Available data suggest that the clinical characteristics and treatment outcomes of FGFR-altered CCA are distinct and include a disproportionately high number of young women. FGFR-altered CCA also seems to be associated with a relatively indolent disease course.[21] Given the emerging evidence regarding actionable targets for targeted therapy in CCA, the National Comprehensive Cancer Network (NCCN) guidelines recommend considering molecular testing of unresectable and metastatic tumors.[39]

Results reported last year from a phase-2 trial of pemigatinib (NCT02924376) highlight the importance of genomic profiling in CCA.[40] In this study, molecular profiling was performed on tumor samples from 1104 participants. Approximately 8% of participants had FGFR2 fusions involving 44 unique partner genes, 84% of which were observed only once. The most prevalent FGFR2 fusion gene partner was BICC1 (31%). FGFR2-activating point mutations were found in 1% of participants. Of 1,091 evaluable samples for microsatellite instability (MSI) or tumor mutational burden (TMB), 13 (1%) had high TMB and 10 (1%) had high MSI (MSI-H).[40]

Considerations for treatment selection

The prognosis of patients with advanced CCA is poor, and the median survival for those who receive supportive care alone is dismal.[4] According to the NCCN guidelines, the available treatment options for patients with advanced biliary tract cancers include the following:[39]

  • Enrollment in a clinical trial


  • Systemic therapy (gemcitabine- or fluoropyrimidine-based chemotherapy, or pembrolizumab [for MSI-H tumors])


  • Fluoropyrimidine-based chemoradiotherapy


  • Radiotherapy alone


  • Best supportive care


  • Importantly, current second-line therapies for CCA have limited efficacy, with a median PFS of 2.6–3.2 months, a median OS of 6.2–7.2 months, and an ORR of less than 9.5%.[28] Therefore, enrollment in clinical trials should be considered for all eligible patients. Notably, CCA tumors should be evaluated prior to the initiation of therapy, as elucidating the specific molecular profile of the patient’s cancer can help ensure referral to the appropriate clinical trial.

    FGFR2 fusion is contemplated to be a promising marker for CCA and FDA has approved pemigatinib in unresectable, locally advanced or metastatic CCA harboring FGFR2 gene fusions. This was based on the results of phase-2 FIGHT‐202 trial.[26]

    Resistance to fibroblast growth factor receptor inhibitors

    ICCA has considerable intratumoral genetic heterogeneity, which contributes to resistance and presents a significant challenge to delivering targeted therapy for this type of cancer.[41] Furthermore, study findings show that CCA tumors develop acquired resistance to treatment with FGFR inhibitors via multiple secondary mutations in the FGFR2 kinase domain.[41]

    Goyal et al.[41] examined the mechanisms of resistance to an ATP-competitive FGFR inhibitor by evaluating cell-free ctDNA and tumor tissue of three individuals with progressive disease after an initial documented response to treatment with infigratinib. Targeted gene panel sequencing with a commercial assay to analyze ctDNA revealed an FGFR2 V564F gatekeeper mutation in the ctDNA of all three participants, as well as several additional FGFR2 kinase domain mutations in the ctDNA of two of the individuals.[41]

    In another study, Goyal et al.[26] examined whether the irreversible, third-generation pan-FGFR inhibitor TAS-120 can overcome acquired resistance to ATP-competitive FGFR inhibitors. Enrolled individuals were initially treated with infigratinib or Debio 1347 and received treatment with TAS-120 after disease progression. All participants were reevaluated for FGFR2 mutations after their disease progressed again following treatment with TAS-120. The authors reported that the spectrum of secondary FGFR2 resistance mutations detected after disease progression differed across the various FGFR inhibitors, indicating that resistance profiles may evolve under the selective pressure of sequential FGFR inhibitors.[26]


      Conclusion Top


    CCA confers a poor prognosis in patients with advanced or unresectable disease. The FGFR signaling pathway is dysregulated in approximately 20% of ICCA cases and 5% of ECCA cases, and clinical trials are currently evaluating whether targeting this pathway with FGFR inhibitors is safe and effective. Increased understanding of the emerging molecular pathways that drive oncogenesis has led to the development of novel therapies targeting FGFR fusions in CCA.

    Preliminary results are encouraging and suggest that FGFR inhibitors may provide a new personalized treatment approach for FGFR-altered CCA.

    Financial support and sponsorship

    Nil.

    Conflicts of interest

    There are no conflicts of interest.



     
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