Abstract
Background:
Cholangiocarcinoma (CCA) is a cancer with a low survival rate. New drugs targeting molecular alterations, oncogenic mutations, and gene fusions are being tested as second-line treatments.
Objectives:
This systematic review aims to summarize the results obtained with three new targeted therapies—pemigatinib, futibatinib, and ivosidenib—for the treatment of CCA, evaluating their safety and tolerability profiles in patients, compared to current standard therapies.
Data sources and methods:
A systematic literature search was performed with a cutoff date of July 24, 2023, in MEDLINE, Embase, and the Cochrane Library. The authors also conducted an advanced search in the ClinicalTrials.gov database, evaluated conference abstracts, article bibliographies, and drug monographs. Studies involving the treatment of patients with pemigatinib, futibatinib, and ivosidenib were considered. The selected studies had to report adverse events (AEs) that occurred during treatment with these therapies.
Results:
The most common AEs observed with pemigatinib, futibatinib, and ivosidenib were alopecia, diarrhea, fatigue, and dysgeusia. In addition, hyperphosphatemia, hypophosphatemia, and ocular disorders were observed with fibroblast growth factor receptor (FGFR) inhibitors, while the isocitrate dehydrogenase 1 (IDH1) inhibitor was associated with dose-dependent prolongation of the corrected QT interval (QTc). These AEs were effectively managed through dose adjustments.
Conclusion:
FGFR2 and IDH1 inhibitors have good tolerability in the population examined. All AEs were optimally managed with dose modulation. Future studies should focus on identifying the most effective dosages to further enhance treatment safety.
Plain language summary
Keywords
Introduction
Cholangiocarcinoma (CCA) refers to a diverse group of malignant tumors arising from the intrahepatic and extrahepatic bile ducts within the liver. 1
CCA may be classified according to its anatomical location as intrahepatic (iCCA, those in the bile ducts that are proximal to second-order ducts) or extrahepatic (i.e., those occurring between the second-order ducts and the Ampulla of Vater). Extrahepatic CCA is further classified as either perihilar (pCCA) or ductal (dCCA). CCA subtypes are varied, showing differences in clinical presentation, associated risk factors, diagnostic pathways, and management strategies, along with distinct epidemiological, molecular, genetic, and clinical profiles. 2 Patients with CCA disease present heterogeneous characteristics, due to different genomic alterations that involve the tumor process. Alterations such as fusions, rearrangements, mutations, and overexpressions are oncogenic events that promote tumor progression. 3
CCA is a rare disease in Western countries, with an incidence of less than 1% of all human cancers and about 10%–15% of primary liver cancers. 4
A high mortality rate is reported for CCA due to its rapid progression, late diagnosis, and resistance mechanisms related to immunoregulatory abilities. 5
Although CCA is defined as a rare tumor pathology, recent epidemiological data suggest a global increase in recent decades, with increasing annual rates of incidence (0.3–6/100,000 inhabitants) and mortality (1–6/100,000 inhabitants). 6
Surgical resection with lymph node dissection at the hepato-duodenal ligament is the optimal treatment for CCA when achievable. For patients with unresectable or metastatic disease, systemic chemotherapy serves as the cornerstone of palliative therapy. A meta-analysis of Valle et al. 7 combining the results from two randomized trials (ABC-02, phase III and BT22, phase II) reported that the combination of cisplatin and gemcitabine chemotherapy reduces the risk of progression or death (defined by progression-free survival (PFS) event) by 36%; and risk of death by 35%, compared with gemcitabine monotherapy.
Clinical trials assessing the gemcitabine–oxaliplatin combination have shown a median overall survival (OS) of 8.3–12.4 months, with response rates ranging from 15% to 50%, and oxaliplatin presenting a more favorable toxicity profile compared to cisplatin. In addition, fluoropyrimidine-based chemotherapy has demonstrated effectiveness in advanced biliary tract cancers; however, a direct comparison between gemcitabine-based and fluoropyrimidine-based regimens remains unavailable. 7 Recently, further studies have led to the introduction and enhancement of first-line Cisplatin–Gemcitabine (CIS-GEM) therapy. The addition of durvalumab, the anti-Programmed Death-Ligand 1 (PD-L1) antibody based on the phase III study TOPAZ-1, 8 highlighted that the antibody, which acts as an immune checkpoint inhibitor (ICI), reported an OS median of 12.8 months. 9
Subsequently, the phase III ABC-06 clinical trial showed a benefit in treatment with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) as a second line of therapy for patients diagnosed with advanced biliary tract cancer (72% CCA). Patients had already progressed on first-line cisplatin–gemcitabine treatment, with OS as the primary endpoint. 10
In recent years, the emergence of targeted therapies has demonstrated improvements in the survival of CCA patients with relevant genetic alterations. These innovative therapies have changed the landscape of possible treatment avenues.
ICIs have led to a targeted therapeutic approach that has improved the quality of life (QoL) of patients. The most prevalent genomic alterations involve mutations in isocitrate dehydrogenase 1 (IDH1) with a frequency rate of 15%–20%, fibroblast growth factor receptor 2 (FGFR2) fusions at 10%, Erb-b2 receptor tyrosine kinase 2 (ERBB2) for 5%–10%, and mutations of the BRAF gene involved in the MAPK/ERK signaling pathway for 3%. 11 Other mutations and rearrangements that have been found with a lower frequency rate involve the family of tyrosine kinase receptors NTRK (neurotrophic tyrosine receptor kinase) at 1%, the RET gene (Rearranged during Transfection) at 1%, and the KRAS gene (Kirsten Rat Sarcoma Virus) at 1%. 11
The most promising target molecules are ivosidenib in patients with mutations in IDH1, and pemigatinib, infigratinib, and futibatinib in patients with fusions or rearrangements of the FGFR2. 11 Currently, at the end of May 2024, the Food and Drug Administration (FDA) has announced the withdrawal of approval of infigratinib (Truseltiq) for previously treated, locally advanced unresectable or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. 12 In this systematic review of the literature, we analyze the safety profiles of pemigatinib, futibatinib, and ivosidenib. Figure 1 lists the signaling pathways considered in this review.
Mechanism of action of pemigatinib, futibatinib, and ivosidenib.
Study drugs
In this systematic review, the drugs monitored and adverse reactions assessed were pemigatinib, futibatinib, and ivosidenib. Pemigatinib is an oral FGFR tyrosine kinase inhibitor that was recently granted accelerated approval by the FDA in April 2020 and obtained a conditional approval from the European Medicines Agency (EMA). The marketing authorization was issued on March 26, 2021, for the treatment of adults with previously treated drugs, unresectable locally advanced or metastatic CCA with FGFR2 fusion or rearrangement. 13
Pemigatinib is predominantly metabolized by CYP3A4 in vitro and is a CYP3A4 substrate; moderate and strong CYP3A4 inducers should be avoided during pemigatinib therapy. 14 The pharmacokinetics profile suggests that at steady state, pemigatinib concentrations increased proportionally over a 1–20 mg dose range and may be administered with or without food. 15 The median time to achieve peak pemigatinib plasma concentration was 1.13 h. The effect of severe renal impairment, renal dialysis in end-stage renal disease, or severe hepatic impairment on pemigatinib exposure remains unknown. Pemigatinib is excreted with 82.4% of the dose in feces (1.4% as unchanged) and 12.6% in urine (1% as unchanged). 16
Another important FGFR1–4 inhibitor is futibatinib, also known as TAS-120.17,18 The treatment dose of futibatinib is one 20 mg oral dose per day, has a half-life of 2.9 h, and is 95% bound to plasma proteins. Its metabolism occurs mainly via cytochrome CYP3A, to a small extent via CYP2C9 and CYP2D6.19,20 The compound is well absorbed and does not present dose accumulation in the body after daily administration. Furthermore, the results demonstrate that no dose adjustment is necessary for mild, moderate, or severe hepatic impairment in patients treated with futibatinib. 21 The EMA report showed that the mean elimination half-life (t1/2) of futibatinib was 2.94 (CV of 26.5%) hours, and its excretion after a single oral dose of 20 mg occurs for approximately 64% in feces and 6% in urine. In September 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced, or metastatic iCCA with FGFR2 fusions or other rearrangements and obtained conditional approval from the EMA, and the marketing authorization was issued on July 4, 2023.
Patients with CCA may present numerous genomic alterations these mutations also including those of the IDH1. Ivosidenib (AG-120) is an oral, potent, targeted IDH1 variant inhibitor approved for the treatment of adult patients with previously treated locally advanced or metastatic CCA with an IDH1 mutation.22,23 In the ClarIDHy treatment trial, patients received a 500 mg dose of ivosidenib per day, equivalent to two tablets, for 28 consecutive days. The mean apparent clearance of ivosidenib at steady state is 6.1 L/h (31%) with a mean terminal half-life of 129 h (102%). Metabolism occurs through CYP3A4, of which it is a strong inducer, and to a lesser extent through N-dealkylation and hydrolytic pathways. Its elimination occurs by 77% via feces (67% unchanged) and 17% in urine (10% unchanged). 22
On August 25, 2021, the FDA approved ivosidenib for the treatment of CCA; ivosidenib is the first IDH1 inhibitor recommended for approval in Europe, and the marketing authorization was issued on May 4, 2023.
Aims and objectives
The greatest challenge in the research and development of drugs that can specifically target mutations or alterations/rearrangements in CCA may lie in managing adverse effects and potential drug tolerance. A further understanding of the safety profiles of these new targeted therapies could help evaluate their toxicity profiles and facilitate treatment choice based on the scientific evidence produced. This systematic review explores the safety profiles of pemigatinib, futibatinib, and ivosidenib across phase II and III clinical trials. The topic chosen in this systematic review was recently discovered, and the drugs mentioned are approved by the FDA and EMA drug regulatory agencies in recent years. These premises determine a limitation of the number of articles available in the literature that can be included in the review. The research was conducted by reviewing the available gray literature, but no records met the inclusion criteria. This opens the search to integrations of safety data that can be extrapolated from the trials.
Methods
Data selection
The study was conducted from May 2023 to July 24, 2023, using the Medline, Cochrane Library, and Embase databases. A screening of all the data available in the literature was performed, given the innovativeness of pemigatinib, futibatinib, and ivosidenib. We conducted the research following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 24 The data collected were selected based on the PICOS framework (participants, interventions, comparisons, outcomes, and study design), as shown in Table 1. The development of the desired PICO for the research of this review is available in the Supplemental Material. The database search sought to identify cases of suspected adverse events (AEs) associated with the use of pemigatinib, futibatinib, and ivosidenib that emerged during treatment.
Formulation of the participants, interventions, comparisons, and outcomes question for the systematic review.
FGFR2, fibroblast growth factor receptor 2; IDH1, isocitrate dehydrogenase 1.
We also performed searches using Medical Subject Headings (MeSH), such as “cholangiocarcinoma,” “biliary tract cancer,” “FGFR inhibitors,” “IDH1 inhibitors,” “pemigatinib,” “futibatinib,” “ivosidenib,” “drug-related side effects and adverse reactions,” and “adverse reactions.”
An advanced search of the ClinicalTrials.gov database was also conducted by selecting the following filters: Condition or disease: “cholangiocarcinoma.” Other terms: “pemigatinib,” “futibatinib,” “ivosidenib.” Eligibility criteria: “adult,” “over 18,” “elderly adult.” Type of study: “interventional studies” (clinical studies). Study results: “studies with results.” Status: “finished” and “completed.”
There were no limitations on language or geographic location; Rayyan software was used to import and manage all the research results. The process of collection, selecting, and confirming the records involved a triple check by three reviewers based on the results obtained. It was deemed appropriate not to perform a meta-analysis, as the number of studies found was too small for statistical analysis, and the trials were of different types. Therefore, the aim of this paper is a critical analysis of drug safety.
Inclusion and exclusion criteria
In this systematic review, common eligibility criteria were defined for pemigatinib, futibatinib, and ivosidenib. Study characteristics such as stage three or four of the tumor, age, and previous chemotherapy treatments were examined. The reviewers, given the innovative nature of drugs, did not limit the search to the English language alone, and the selection process involved several phases. Detailed inclusion criteria are presented in Table 2.
Inclusion criteria.
Literature selection and submission of materials
A comprehensive systematic review of the literature was carried out according to the inclusion criteria.
The initial search was conducted by two authors, and to ensure the accuracy and reliability of the search strategy, a third author independently re-ran the database search and verified the number of citations identified. The specific search strategy, as elaborated for each mentioned database, is available as Supplemental Material.
To identify additional articles relevant to understanding the drugs’ safety profiles, citation monitoring was performed by examining the references of the identified studies, monitoring citations, and appropriately evaluating related articles. Finally, a follow-up search was conducted on gray literature sources to best complete the update phases of the study.
In the first screening phase, after collecting all the records, duplicates were eliminated with the help of Rayyan software and reviewers.
A second-level screening was based on reading the titles and abstracts; all references that were ineligible and not compliant with the scope of this systematic review were eliminated following the eligibility criteria defined upstream and set on the PICOS model defined previously. Finally, in the third screening phase, the full text of potentially eligible studies was reviewed to identify which were eligible and which were to be excluded as they did not meet the characteristics. The title and abstract screening process was carried out by three researchers, and any discrepancies were discussed and resolved, allowing for consistency of records according to the inclusion criteria.
Risk of bias assessment and quality assessment
In this systematic review, the potential risk of bias was assessed to ensure the highest possible methodological quality of the included studies. The evaluation was performed independently by two reviewers, with any discrepancies resolved through discussion and, when necessary, with the involvement of a third reviewer to reach consensus.
For randomized controlled trials (RCTs), the Cochrane Risk of Bias tool, version 2 (RoB 2) was employed. 25 This tool was applied exclusively for one study conducted, as it was the only RCT included in the review.
Non-randomized studies evaluating the effects of interventions play a pivotal role in assessing the efficacy and safety of healthcare interventions, particularly in the early phases of oncological clinical research (i.e., phase I and II studies). However, the methodological tools currently available for risk of bias assessment have been primarily developed for comparative study designs and are therefore unsuitable or suboptimal for use in single-arm studies. At present, no universally accepted and validated instrument exists for assessing the risk of bias in non-comparative studies.
To address this methodological gap, the ROBINS-I (Risk Of Bias In Non-randomized Studies—of Interventions) 26 tool was introduced. This tool allows for a structured and systematic evaluation of risk of bias even in single-arm cohort studies, thus representing a significant methodological advancement in the context of systematic reviews that include evidence from non-randomized observational research. In the present review, this tool was applied to assess three non-randomized studies. The complete risk of bias assessment is available as Supplemental Material (Figures S1 and S2).
Results
In the literature search process, 729 studies potentially relevant to this systematic review were initially identified. In the next phase, following an initial screening, a total of 174 duplicates were removed. In the subsequent screening, starting from 555 records, a total of 546 records were excluded after title and abstract selection. These studies did not meet the eligibility criteria; furthermore, many of them were only descriptive of the molecules under examination and did not provide sufficient original data. In this systematic review, only nine studies followed a process of reading the full text to evaluate the eligibility criteria. No further studies were identified by the literature search. After reading the full text, five studies were excluded. Studies were excluded as they did not meet the inclusion criteria, such as explaining safety data. Finally, four studies were included in this systematic review. The flowchart of the literature retrieval and screening process, along PRISMA lines, is presented in the flowchart in Figure 2. Table 3 presents a summary of the four included studies, which include one RCT study and three multicenter phase II observational studies.
Flowchart of the screening process for included studies.
Summary of the four included studies.
DCR, Disease control rate; DOR, duration of response; FGFR2, fibroblast growth factor receptor 2; IDH1, isocitrate dehydrogenase 1; IQR, interquartile range; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life.
Study characteristics
The characteristics of the included studies are shown in Table 3. In total, four studies were included for the systematic review, including two for pemigatinib27,28 and one for futibatinib 29 and ivosidenib, 30 respectively. Of these, only one ivosidenib study features an RCT design, while the remaining three are observational studies. The sample size ranges from 31 to 187 patients diagnosed with stage 3/4 CCA with FGFR2 rearrangement or IDH-1 mutation. Furthermore, in the selected studies, women had a higher percentage than men, considering the three drugs included.
For pemigatinib, the data collected come from Asia, the United States, Europe, and the Middle East. The study is single-arm, multicenter, and phase II. 27 Patients in the first study were divided into three groups: with FGFR2 fusion or rearrangement, with other FGFR fusion or rearrangement, or without FGFR alteration. In the second included study, 28 31 patients were enrolled, and all had an alteration of FGFR2.
For futibatinib, 29 there is a phase II, multicenter, single-arm study with a population of 103 people enrolled, from North America, Japan, Europe, Asia, and the Pacific with positive FGFR2 fusion or positive FGFR2 rearrangement.
For ivosidenib, 30 a total of 187 treated patients belonged to a single multicenter, double-blind, placebo-controlled phase III study. All enrolled patients have a histologically confirmed IDH1 mutation. In the informative Figure 3, the data for the three drugs are summarized.
Main drug characteristics.
Risk of bias of included studies
The evaluation revealed that, although certain risks of bias were present—particularly in domains related to outcome measurement and missing data—the studies demonstrated several methodological strengths. Notably, the transparent selection of participants, the accurate classification of interventions, and the absence of selective outcome reporting represent robust methodological features that enhance the credibility of the findings. As such, the included studies offer a valid and informative contribution to the current understanding of the effectiveness of the interventions under investigation. Further details are provided in the Supplemental Materials.
Safety profile of pemigatinib
The systematic review considered two studies on pemigatinib, the first produced by Abou-Alfa et al., published in
FIGHT-202 25 is a multicenter, open-label, single-arm, multicohort, phase II study involving three cohorts of patients who received an oral dose of 13.5 mg of pemigatinib once daily for 21-day cycles. All patients had received prior systemic anticancer therapies for their advanced/metastatic disease. The median duration of treatment was 7.2 months (3.9–10.9) in patients with FGFR2 fusions or rearrangements, 1.4 months (1.0–6.1) in patients with other FGF/FGFR alterations, and 1.3 months (0.7–1.9) in patients without FGF/FGFR alterations. 27
FIGHT-202 was assessed for safety using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
31
In this study, safety was assessed in three stages: at screening, during treatment (days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles), at the end of treatment, and during follow-up (30 days after stopping treatment). Patients in the three cohorts (
The second study of pemigatinib 28 is a multicenter, single-arm, phase II study that was conducted in 14 hospitals in China. The dose of pemigatinib administered to patients corresponds to 13.5 mg orally once a day, with a cycle of 21 days. Patients treated with pemigatinib, belonging to a single cohort, previously received systemic therapy for advanced and metastatic disease. AEs were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v5.0. 32
The most common AEs were hyperphosphatemia (77.4%), of which one (3.2%) was grade ⩾ 3, dry mouth (54.8%), and alopecia (54.8%). Serious AEs occurred in three (9.7%) patients: rectal polyps, abnormal liver function, and biliary tract infection. A total of four patients (12.9%) had dose interruption due to hypercalcemia, pain in the extremity, abnormal liver function, and vomiting, respectively.
In this study, as in FIGHT-202, both nail toxicity occurred in 16 patients (51.6%), and retinal detachment occurred in 3 (9.7%) patients. Hypophosphatasemia occurred in 7 (22.6%) patients, and changes in 25-hydroxyvitamin D and blood calcium were modest for most patients during treatment. 28 The median PFS, calculated using Kaplan–Meier estimates, was 6.9 months (95% CI: 6.2–9.6) in patients with FGFR2 rearrangements. Durable responses were observed in 35.5% of patients with FGFR2 alterations, with a complete response in 2.8% and a partial response in 32.7%. Data from both studies suggest that QoL, assessed using validated tools such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol 5-Dimension 5-Level (EQ-5D-5L)—which measure parameters including physical, functional, and emotional well-being—was preserved through a proactive approach to AE management. This approach allowed many patients to continue treatment without compromising their daily activities.
Safety profile of futibatinib
FOENIX-CCA2 29 is a multinational, open-label, phase II study conducted at 47 centers in 13 countries. Enrolled patients received an oral futibatinib dose of 20 mg once daily continuously.
The safety profile of the drug was evaluated from the first dose of futibatinib until 30 days after the last dose or until starting a new agent.
AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. 31 The safety profiles were evaluated from the first dose of futibatinib administration, and the observation time was up to 30 days after the last dose or, alternatively, until the start of a new chemotherapy agent.
The AEs that occurred were of variable grade, in the article, with a grade ranging from 1 to 4. Hyperphosphatemia occurred in 85% of patients, alopecia in 33%, dry mouth in 30%, diarrhea in 28%, dry skin in 27%, and fatigue in 25% of cases. Grade three adverse reactions occurred, of which hyperphosphatemia was the most common, approximately 30% of patients under treatment, defined as a serum phosphate level equal to or greater than 7 mg per deciliter. In patients undergoing treatment, the occurrence of hyperphosphatemia occurred with a median of 5 days and was treated with a diet based on hypophosphate in 78% of cases, with dose reduction or interruptions in administration; however, no one discontinued treatment due to this adverse reaction, which on average resolved in 7 days. When serum phosphate levels were ⩾5.5 mg/dL, patients temporarily interrupted treatment. This was accompanied using phosphate-lowering therapies, such as phosphate binders, to control serum phosphate levels effectively.
Toxic effects that occur when FGFR inhibitors are administered occurred in 47% of patients with nail disorders and 8% with retinal disorders.
Increased alanine aminotransferase level was the only grade 4 reaction occurring in 1% of cases. Overall, treatment-related AEs led to dose interruptions in 52 patients (50%) and dose reductions in 56 patients (54%). They have not been reported as grade 5. 29 The OS associated with futibatinib treatment was reported with a median value of 21.7 months and a 12-month survival rate of 72%. The median PFS was 9.0 months, with a 6-month progression-free survival rate of 66% and a 12-month rate of 40%. These data indicate that futibatinib significantly prolongs survival compared to the SoC.
In patients experiencing AEs, futibatinib treatment was managed gradually. Initially, the dose was reduced to 16 mg per day. If AEs persisted, a further reduction to 12 mg per day was implemented. Ultimately, treatment was discontinued if AEs remained unresolved. Futibatinib demonstrated a robust objective response rate (ORR) of 42% (95% CI, 32–52) in patients with advanced iCCA. The median duration of response (DOR) was 9.7 months (95% CI, 7.6–17.1), reflecting the durability of clinical benefit in this molecularly defined population. Notably, 72% of patients maintained their response for at least 6 months, and 14% experienced responses lasting 12 months or longer. These data highlight futibatinib’s sustained anti-tumor activity in a setting where therapeutic options are otherwise limited and often poorly tolerated.
Safety profile of ivosidenib
ClarIDHy 30 is a multicenter, randomized, double-blind, placebo-controlled phase III study. The patients included in this study came from 49 hospitals in 6 different countries for a total of 126 treated with ivosidenib and 61 with placebo. All patients had histologically confirmed advanced CCA with IDH1 mutation and had been treated with prior therapy.
In the study, ivosidenib or placebo, randomized 2:1, was administered orally once daily for a continuous 28-day cycle. Treatment safety and tolerability were assessed from the first dose, and treatment-emergent AEs were classified by severity and type according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. 31 Grade 1–5 reactions were identified in the study for both protocols: ivosidenib or placebo.
The most common grade 3 AE was ascites, which occurred in 11 (9%) patients who received ivosidenib and 4 (7%) patients who received placebo. In addition, grade 3 or higher anemia was more common in 8 (7%) patients versus 0 patients; increased blood bilirubin levels in 7 patients (6%) versus 1 patient (2%), and hyponatremia in 7 patients (6%) versus 6 patients (10%).
Another adverse reaction that occurred in 12 patients (10%) treated with ivosidenib and in 2 patients (3%) treated with placebo was a prolongation of the QT interval on the electrocardiogram.
In total, only 5 patients (4%) in the ivosidenib group had serious AEs that led to a dose reduction, while 9 patients (7%) had to completely discontinue treatment. Treatment discontinuation, but not dose reduction, occurred with placebo in 5 (8%) of patients.
30
This study shows the positive outcome of treatment with ivosidenib; in fact, the survival rate at 12 months of therapy was 43% versus 36% for the drug. Furthermore, according to the results published by Zhu et al., the median PFS was statistically significantly higher in the ivosidenib group than in the placebo group (2.7 months vs 1.4 months (HR, 0.37; 95% CI, 0.25–0.54;
In patients experiencing grade ⩾3 AEs related to drug administration, such as QT interval prolongation, significant hepatic toxicity (e.g., elevated transaminases or serum bilirubin), or severe gastrointestinal effects (including persistent nausea, vomiting, or diarrhea), the dose was reduced to 250 mg daily or temporarily suspended until resolution or improvement of the event. These measures positively impacted health-related quality of life (HRQoL), as demonstrated by outcomes from the EORTC QLQ-C30 (a QoL questionnaire for oncology patients) and the EORTC QLQ-BIL21 (a questionnaire specific to biliary tract cancers). 30 In ClarIDHy trial, it is reported a modest ORR of 2%. Although the median DOR was not specifically reported, the clinical benefit of ivosidenib was evident through significant improvement in PFS and disease stabilization rates compared to placebo.
Discussion
Relevance to patient care and clinical practice
This review provides a comprehensive update on the treatment of CCA, incorporating evidence from clinical trials published up to July 2023. A key advancement discussed is the integration of targeted therapies for patients with specific genetic alterations, such as FGFR2 fusions or rearrangements and IDH1 mutations. This marks a significant shift from traditional first- and second-line treatments toward more personalized, genomics-based approaches.
The diagnosis of CCA remains challenging. Many patients are diagnosed only upon the onset of symptoms such as jaundice, abdominal pain, anorexia, weight loss, and night sweats. Due to the nonspecific nature of these symptoms, diagnosis often occurs incidentally through imaging studies conducted for other causes of symptomatic biliary obstruction. 33 Recent analyses suggest that 20–40% of patients with intrahepatic CCA are diagnosed incidentally. 34 Currently, there is no standardized protocol for prevention and early detection. However, screening indicators have been proposed. For example, the American Association for the Study of Liver Diseases (AASLD) recommends annual magnetic resonance imaging or magnetic resonance cholangiopancreatography, with or without serum biomarkers, for patients with primary sclerosing cholangitis. 35
From a clinical perspective, incorporating genetic testing for FGFR2 and IDH1 alterations into routine diagnostic and therapeutic workflows is essential. Identification of these biomarkers enables healthcare providers to personalize treatment strategies, improve efficacy, and reduce reliance on less effective standard therapies. These findings emphasize the potential of targeting specific genetic alterations to achieve more tailored and effective treatment strategies, moving beyond the limitations of conventional chemotherapy.
From a clinical perspective, incorporating genetic testing for FGFR2 and IDH1 alterations into routine diagnostic and therapeutic workflows is essential. Identifying these biomarkers enables healthcare professionals to personalize treatment strategies, enhance efficacy, and reduce reliance on less effective standard therapies. These findings underscore the potential of targeting specific genetic alterations to achieve more tailored and effective treatment strategies, overcoming the limitations of conventional chemotherapy.
One of the main distinguishing features of targeted therapies such as pemigatinib, futibatinib, and ivosidenib is their favorable tolerability profile compared to conventional chemotherapy. For pemigatinib, the most frequently reported AE was hyperphosphatemia, occurring in approximately 60% of patients in the FIGHT-202 trial, and up to 26% of grade ⩾3 cases in the Chinese cohort. Despite its high incidence, hyperphosphatemia was largely manageable with dietary modifications, phosphate binders, and dose adjustments, and rarely led to treatment discontinuation. Other common AEs included stomatitis, fatigue, and ocular toxicities, generally of mild severity. Serious treatment-related AEs were uncommon, and no deaths were attributed to the drug.
For futibatinib, the most common AE was also hyperphosphatemia, observed in 85% of patients, with 30% of cases being grade 3. This was generally successfully managed with hypophosphatemia therapy, temporary treatment interruptions, or dose reductions. All grade 3 cases resolved within a median of 7 days. Ocular events, such as retinal disorders and cataracts, were reported in 8% and 4% of patients, respectively, all of which were of mild or moderate severity.
Ivosidenib demonstrated an even more favorable safety profile in the phase III ClarIDHy trial, with a low incidence of treatment-related serious AEs (2%) and a tolerability profile comparable to placebo. Common AEs such as nausea, fatigue, and ascites were reported at manageable levels. Importantly, QTc interval prolongation, a class effect of IDH1 inhibitors, was infrequent and clinically manageable with ECG monitoring. No deterioration in HRQoL was observed compared to placebo, further supporting its suitability for long-term administration.
Across all studies, the low rate of treatment discontinuation due to toxicity and the absence of treatment-related mortality underscore the clinical feasibility of prolonged therapy with these agents. These findings are particularly relevant given the limited therapeutic options and the frailty of patients with advanced or metastatic CCA. A table of the various AEs compared is present in the Supplemental Materials (Table S1).
An important advantage of these agents is their oral administration, which provides significant logistical and QoL benefits for patients with advanced CCA. Unlike standard chemotherapy regimens that require repeated hospital-based infusions, these drugs can be taken at home, reducing the burden of hospital visits and facilitating integration into daily life.
This administration mode is especially beneficial for patients with compromised general conditions or functional limitations, offering greater autonomy in treatment management. Furthermore, oral therapies have been shown to improve patients’ perceived sense of control, reduce the psychological stress associated with treatment, and enhance adherence when supported by appropriate education and clinical follow-up.36,37
The review acknowledges several limitations. Among these is the overall heterogeneity in the methodological quality of the included studies, particularly in outcome measurement and control of confounding factors, which are notoriously complex in observational research. However, the overall assessment did not reveal biases sufficient to invalidate the results. The number of study participants for the three drugs remains limited and not fully representative of the general patient population. This is partly due to diagnostic challenges and the relatively rare incidence of CCA. The limited number of studies and the lack of control arms in many of them weaken the strength of the evidence. For pemigatinib, only two single-arm studies met the inclusion criteria. For futibatinib, only one non-comparative study was included. For ivosidenib, only one study met the criteria—the only RCT in the review, which included a placebo comparison. In addition, the predominance of female participants in some studies may limit generalizability.
Further evidence and real-world data are needed to better understand the optimal use of pemigatinib, futibatinib, and ivosidenib in patients with locally advanced or metastatic CCA. A multidisciplinary team is essential for the effective management of FGFR inhibitor therapy. Pharmacists play a central role not only in drug procurement but also in monitoring adherence, managing drug interactions, ensuring prescription continuity, and minimizing financial toxicity. In parallel, nurses and physician assistants monitor patients during outpatient visits and through regular phone follow-ups, supporting clinical management and AE monitoring. Optometrists are critical for the early identification and management of ocular toxicities associated with FGFR inhibitors. Dietitians provide essential nutritional support, particularly in managing hyperphosphatemia through low-phosphate diets. Nurse coordinators and navigators serve as consistent points of contact for patients throughout therapy, facilitating communication within the care team. Social workers further support patients’ overall well-being by offering psychosocial assistance and practical resources.
It is important to note that multidisciplinary team structures may vary across institutions. Clearly defining roles and responsibilities is crucial to avoid gaps in care and ensure coordinated patient management, while maintaining regular communication between patients and their primary care providers to ensure continuous and integrated support.
Addressing these organizational aspects would contribute to more consistent safety data collection and enhance our understanding of individual responses to targeted therapies. Overall, this review offers valuable insights into the benefits and challenges of targeted treatments, reinforcing the role of precision medicine in improving outcomes for patients with cholangiocarcinoma.
Conclusion
This is the latest and among the first systematic reviews of the literature, including recent trials on pemigatinib, futibatinib, and ivosidenib. The studies included are phase II and III, with only one concerning ivosidenib being randomized, double-blind. The choice of these three drugs is due to careful research into what are becoming effective second-line therapies for CCA.
In the future, new trials are being advanced for pemigatinib. The objective is to evaluate the efficacy and safety of pemigatinib compared to chemotherapy with gemcitabine plus cisplatin in the first-line treatment of participants with unresectable or metastatic CCA with FGFR2 rearrangement. For futibatinib, an ongoing, multinational, randomized, open-label phase II study confirms the clinical benefit of 20 mg futibatinib and evaluates the safety and efficacy of 16 mg futibatinib in previously treated CCA harboring FGFR2 gene fusions and other rearrangements. A phase III research study is underway for ivosidenib to consolidate data that ivosidenib is safe and effective in adult patients with previously treated, locally advanced or metastatic CCA.
In conclusion, based on the evidence of the present analysis, pemigatinib, futibatinib, and ivosidenib may be a useful treatment option for selected patients with advanced cholangiocarcinoma. The risk of developing grade 3 and 4 adverse reactions is limited, and these AEs that occurred during the trial were easily contained. A thorough evaluation of the studies included in this systematic review highlighted effective patient management. The AEs for pemigatinib, futibatinib, and ivosidenib were handled optimally, with severe reactions addressed through dose adjustments or temporary therapy suspension when necessary, enabling patients to continue treatment without permanent discontinuation. Future studies should aim to analyze the effects of these new target therapies with larger population arms, to broaden knowledge of safety data and modulate dosing. It is hoped that this review can be of real help to all healthcare professionals who have to treat this rare disease, simply by providing a broad view of the adverse reactions reported for drugs/genomic alterations.
Supplemental Material
sj-docx-1-taw-10.1177_20420986251347376 – Supplemental material for Safety profiles of the new target therapies—pemigatinib, futibatinib, and ivosidenib—for the treatment of cholangiocarcinoma: a systematic review
Supplemental material, sj-docx-1-taw-10.1177_20420986251347376 for Safety profiles of the new target therapies—pemigatinib, futibatinib, and ivosidenib—for the treatment of cholangiocarcinoma: a systematic review by Giulia Matranga, Anna Carollo, Miriam Alaimo, Sofia Cutaia, Sergio Rizzo and Alessio Provenzani in Therapeutic Advances in Drug Safety
Supplemental Material
sj-docx-2-taw-10.1177_20420986251347376 – Supplemental material for Safety profiles of the new target therapies—pemigatinib, futibatinib, and ivosidenib—for the treatment of cholangiocarcinoma: a systematic review
Supplemental material, sj-docx-2-taw-10.1177_20420986251347376 for Safety profiles of the new target therapies—pemigatinib, futibatinib, and ivosidenib—for the treatment of cholangiocarcinoma: a systematic review by Giulia Matranga, Anna Carollo, Miriam Alaimo, Sofia Cutaia, Sergio Rizzo and Alessio Provenzani in Therapeutic Advances in Drug Safety
Footnotes
References
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