Cholangiocarcinoma is a highly lethal disease with a 5-year overall survival rate of 7-20%. A minority of patients present with resectable disease, and relapse rates remain high. Emerging data from next generation sequencing analysis have identified various actionable mutations which drive the different disease courses opening door to precision medicine and targeted therapies. This review focuses on the clinical significance of genetic alterations as well as the role of systemic therapies, immunotherapy and targeted therapies for intrahepatic cholangiocarcinoma.

Futibatinib is a small, potent, covalent, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor that has been added as a new standard of care for previously treated unresectable and/or advanced FGFR2 fusion/rearrangement-positive BTC. FGFR2 fusions/rearrangements play a key role in BTC survival, proliferation, invasion, and development of distant metastasis. The inhibition of this pathway is an important target in the treatment of BTC.

The article covers the development of futibatinib for the treatment of refractory unresectable/advanced BTC, its mechanism of action, and key pharmacodynamic/pharmacokinetic data with a focus on the safety profile. Data are based on published clinical trials, pooled analysis, and retrospective studies indexed in PubMed (2010-2024).

Futibatinib is an FDA and EMA approved FGFR2 inhibitor for the treatment of patients with refractory BTC with FGFR2 fusions/rearrangements. Ongoing drug development strategies are centered on designing new FGFR2 fusion inhibitors able to overcome on-target and off-target resistances coupled with a high target selectivity to spare the most common treatment-related adverse events (hyperphosphatemia, stomatitis, alopecia, nail toxicity, skin reactions, eye toxicity).

While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC50 value of 2.8 nM, and was much less active against BaF3-FGFR1 and parental BaF3 cells with IC50 values of >1000 nM. Kinase selectivity profiling revealed that BW710 completely abolished FGFR2 enzymatic activity and was selective against other 75 tyrosine kinases including FGFR1, FGFR3, and FGFR4 at 1 μM. The covalent binding mode between BW710 and FGFR2 was confirmed by MS spectrometry. Further evaluation showed that BW710 potently suppressed the FGFR2 signaling and selectively inhibited FGFR2-driven cancer cell proliferation. Additionally, BW710 also displayed reasonable pharmacokinetic properties with an oral bioavailability of 29 % in mice. Taken together, this study provides a potent, selective and orally bioavailable FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. As with many targeted therapies, however, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.

This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.

Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared with those without clinical benefit (65% versus 10%, P < 0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.

Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.

This network meta-analysis (NMA) aims to provide evidence-based guidance for selecting the second-line chemotherapy for biliary tract cancer (BTC).

A comprehensive literature search was conducted on PubMed, Cochrane, and EMBASE through July 2024. Inclusion criteria involved: (1) patients underwent second-line chemotherapy following platinum-based first-line therapy, (2) intervention/comparator groups consisted of various chemotherapeutic agents, and (3) outcomes measured as hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) in randomized controlled trials (RCTs) and cohort studies.

Outcomes were measured as HR of OS and PFS in RCTs and cohort studies. The eight studies consisting of 1621 patients were selected. In the NMA for OS, 5FU_plus_Plat (fluorouracil plus oxaliplatin or cisplatin; HR 0.52, 95% confidence interval [CI]: 0.30-0.91), nal-IRI_5FU_LV (nano-liposomal irinotecan plus fluorouracil and LV; HR 0.54 [95% CI: 0.32-0.92]), and FOLFOX (fluorouracil plus oxaliplatin; HR 0.69 [95% CI: 0.50-0.96]) demonstrated significant benefits in OS when compared to control. For PFS, nal-IRI_5FU_LV (HR 0.61 [95% CI: 0.44-0.85]) provided a significant advantage over 5FU.

Second-line chemotherapy for BTC after the failure of gemcitabine plus platinum as first-line therapy, nal-IRI_5FU_LV appears to be the most promising second-line therapy in terms of both OS and PFS.

Cholangiocarcinoma (CCA) is an extremely malignant and aggressive primary liver tumor that has become increasingly prevalent in recent years. Unfortunately, the prognosis for patients diagnosed with CCA remains exceptionally poor. Currently, the primary treatment options include surgery and chemotherapy. However, the effectiveness of postoperative chemotherapy is limited, characterized by a brief duration of remission and high rates of recurrence and metastasis, resulting in minimal survival benefits for patients. Therefore, there is an urgent need to develop new therapeutic strategies that are both safer and more effective. In recent years, as oncology research has progressed, Claudin 18.2 (CLDN18.2)-targeted therapy has emerged, showing promise for improving the survival of patients with CLDN18.2-positive cancers. Studies suggest that combining new agents targeting CLDN18.2 with standard cytotoxic therapies offers significant survival benefits in CLDN18.2-positive solid tumors, which is expected to provide a more effective treatment option for patients with advanced cholangiocarcinoma. While existing immune checkpoints or therapeutic targets have limitations, such as low positivity rates and minimal absolute improvement in patient survival time, drugs that target FGFR, IDH, and Her-2, along with antiangiogenic agents, have shown promise for patients with advanced malignancies affecting the bile ducts. Therefore, exploring these novel therapeutic strategies may yield new insights for precision treatment of cholangiocarcinoma in the future. This review aims to focus on the potential application of CLDN18.2 in treating solid tumors, particularly cholangiocarcinoma, to systematically summarize research progress related to this target and thoroughly examine its value in diagnosing, treating, and assessing the prognosis of cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence supports CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.

Cholangiocarcinoma (CCA) is an aggressive and heterogeneous malignancy of the biliary tree that carries a poor prognosis. Multiple features at the genetic, epigenetic, and microenvironmental levels have been identified to better characterize CCA carcinogenesis. Genetic alterations, such as mutations in IDH1/2, BAP1, ARID1A, and FGFR2, play significant roles in CCA pathogenesis, with variations across different subtypes, races/ethnicities, and causes. Epigenetic dysregulation, characterized by DNA methylation and histone modifications, further contributes to the complexity of CCA, influencing gene expression and tumor behavior. Furthermore, CCA cells exchange autocrine and paracrine signals with other cancer cells and the infiltrating cell types that populate the microenvironment, including cancer-associated fibroblasts and tumor-associated macrophages, further contributing to an immunosuppressive niche that supports tumorigenesis. This review explores the multifaceted genetic, epigenetic, and microenvironmental drivers of CCA. Understanding these diverse mechanisms is essential for characterizing the complex pathways of CCA carcinogenesis and developing targeted therapies to improve patient outcomes.

Cholangiocarcinoma (CCA) is a highly fatal malignancy with an increasing prevalence, a high mortality rate, poor overall survival, and limited responsiveness to conventional chemoradiotherapy. Targeted therapies addressing specific gene mutations have expanded treatment options for some patient populations. The introduction of chimeric antigen receptor-modified T-cell (CAR-T) immunotherapy and personalized vaccines have opened up a new avenue for managing various cancers. Considerable efforts have been dedicated to preclinical research and ongoing clinical trials of immunotherapeutic approaches including CAR-T therapy, vaccines, and antibody-based therapies such as antibody drug conjugates. However, the potential of CAR-T therapy and vaccines in treating advanced unresectable/metastatic cholangiocarcinoma remains largely unexplored. This article offers an overview of the current landscape of antibody-based immunotherapy, particularly CAR-T therapy and vaccines in the context of cholangiocarcinoma treatment. It outlines a framework for selecting CAR-T and vaccine targets and delves into the biology of promising targetable antigens, as well as potential future therapeutic targets.

Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood.

We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing.

A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes.

iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.

Intrahepatic cholangiocarcinoma is a malignant tumor that starts from the epithelium of the bile duct and has a poor prognosis. They are characterized by poor response to chemotherapy and lack of effective targeted therapies; thus, therapeutic options are limited.

A 59-year-old man was admitted to the hospital for a workup of abnormal CA19-9 levels. He was diagnosed with ICC, underwent surgery and was found to have pT1bNx disease. He developed rapid disease recurrence on adjuvant gemcitabine + capecitabine. Following recurrence, he received first-line systemic pembrolizumab + lenvatinib and second-line pembrolizumab + lenvatinib + chemotherapy and had mild tumor regression followed by progression. Next-generation sequencing was performed on the baseline surgical sample. This revealed a novel RBPMS-MET fusion, and based on the literature, crizotinib 250 mg twice a day was administered. After 3 months of crizotinib treatment, magnetic resonance imaging revealed a significant reduction in liver lesions, and 4 months after initiating treatment, scans demonstrated a partial response.

Our case report strengthens the evidence that crizotinib may be a viable treatment option for patients with ICC with a c-MET tyrosine kinase fusion, necessitating additional clinical investigation.

Pemigatinib demonstrated efficacy in fibroblast growth factor receptor (FGFR)-altered cholangiocarcinoma (CCA) in the FIGHT-202 trial. However, limited real-world evidence exists on treatment patterns and outcomes in this setting.

Patient characteristics, treatment patterns, and outcomes of US adults who received pemigatinib for unresectable, locally advanced or metastatic CCA were collected via retrospective physician-abstracted chart review. Results were summarized using descriptive statistics.

Data from 120 patients (49.2% male; 55.0% White; 19.2% Hispanic; median age at initial pemigatinib prescription, 64.5 years) were collected from 18 physicians/practices. At the time of prescribing, 90.0% of patients had metastatic disease. FGFR2 testing was completed for 92.5% of patients; of those, all but one (result unknown) tested positive, and 95.5% were tested using next-generation sequencing. Pemigatinib was prescribed as second- and third-line therapy among 94.2% and 5.8% of patients, respectively. The most common starting dosage was 13.5 mg daily for 14 days of 21-day cycles (87.5% of patients). Among 60 patients (50.0% of the full cohort) who discontinued pemigatinib during the 6.5-month median study follow-up period, 68.3% discontinued due to disease progression. The median real-world progression-free survival (rwPFS) from the date of pemigatinib initiation was 7.4 months (95% CI: 6.4-8.6), and the real-world overall response rate (rwORR) was 59.2% (95% CI: 50.0%-68.4%).

This study complements the FIGHT-202 clinical trial by assessing the use of pemigatinib among a diverse population of patients with CCA under real-world conditions. Findings support the clinical benefit of pemigatinib demonstrated in FIGHT-202.

Fibroblast growth factors (FGFs) have diverse functions in the regulation of cell proliferation and differentiation in development, tissue maintenance, wound repair, and angiogenesis. The goal of this review paper is to (i) deliberate on the role of FGFs and FGF receptors (FGFRs) in different cancers, (ii) present advances in FGF-targeted cancer therapies, and (iii) explore cell signaling mechanisms that explain how FGF expression becomes dysregulated during cancer development. FGF is often mutated and overexpressed in cancer and the different FGF and FGFR isoforms have unique expression patterns and distinct roles in different cancers. Among the FGF members, the FGF 15/19 subfamily is particularly interesting because of its unique protein structure and role in endocrine function. The abnormal expression of FGFs in different cancer types (breast, colorectal, hepatobiliary, bronchogenic, and others) is examined and correlated with patient prognosis. The classification of FGF ligands based on their mode of action, whether autocrine, paracrine, endocrine, or intracrine, is illustrated, and an analysis of the binding specificity of FGFs to FGFRs is also provided. Moreover, the latest advances in cancer therapeutic strategies involving small molecules, ligand traps, and monoclonal antibody-based FGF inhibitors are presented. Lastly, we discuss how the dysregulation of FGF and FGFR expression affects FGF signaling and its role in cancer development.

Cholangiocarcinoma (CCA) is a bile duct malignancy. Our previous comprehensive analysis showed that ferroptosis-related genes can stratify CCA patients into low-risk and high-risk groups based on survival time. Here, we explored the role of ferroptosis in CCA by analyzing mRNA expression in CCA patients from public databases. We identified acyl-CoA synthetase long chain family member 3 (ACSL3) as a potential ferroptosis suppressor in high-risk CCA patients. Using a panel of CCA cell lines, we confirmed ACSL3 upregulation in CCA cell lines associated with high-risk CCA, correlating this with resistance to the ferroptosis inducer RSL3. Lipidomic analysis revealed increased monounsaturated fatty acid (MUFA)-containing phospholipids in resistant cell lines. ACSL3 silencing sensitized these cells to RSL3. Resistance to ferroptosis was also dependent on exogenous MUFAs and was enhanced by lipid droplet biogenesis inhibition. These findings highlight ACSL3 as a promising target for therapeutic strategies aimed at overcoming ferroptosis resistance in CCA.

FGFR2 fusions or rearrangements occur in 13%-20% of patients with intrahepatic cholangiocarcinoma (iCCA). Pemigatinib, a representative FGFR inhibitor, is commonly used for targeted therapy in such patients. Additionally, brain metastasis (BM) is extremely rare in advanced iCCA, and there is currently no standard treatment strategy for advanced iCCA patients with BM. Stereotactic body radiation therapy (SBRT) combined with immune checkpoint inhibitors (ICIs) may exhibit synergistic antitumor effects, presenting a promising approach for advanced iCCA.

The patient, a 58-year-old male, experienced a recurrence of iCCA following surgery and chemotherapy, with multiple metastases in the liver, lungs, and brain. Genetic testing revealed FGFR2-TXLNG-fusion, and the patient was treated with pemigatinib in combination with tislelizumab and SBRT for the BM, resulting in significant tumor shrinkage. Adverse events (AEs) such as liver dysfunction, nail loss, and dry mouth were observed during treatment, which were considered to be related to pemigatinib. These AEs were significantly alleviated after dose reduction and symptomatic treatment.

This case presented a rare occurrence of FGFR2 fusion-positive iCCA with BM, with extremely limited data on treatment options and survival outcomes in such patients. Our study was the first to report the application of the treatment strategy combining pemigatinib with ICI and SBRT in this specific case. The combined therapy proved effective and well-tolerated, providing new insights for future treatment considerations.

Cholangiocarcinoma is the rare and aggressive tumor with poor prognosis and limited therapeutic options. Recently, there have been promising developments in molecular targeted therapies for patients following the progression of first-line chemotherapy and immunotherapy combinations. Dysregulation of fibroblast Growth Factor Receptor (FGFR) signaling is significantly associated with tumorigenesis of intrahepatic cholangiocarcinoma and has been identified as a targetable alteration. This was possible through the discovery of crucial insights into the biochemical mechanisms and pathophysiology of the FGFR pathway.

This review summarizes the current state of FGFR targeted therapies, mechanisms of resistance, and future directions for FGFR-targeted therapies in patients with cholangiocarcinoma.

Currently, pemigatinib and futibatinib are FDA approved FGFR-targeted therapies that have demonstrated remarkable responses. However, there is still a significant proportion of patients whose disease remains intrinsically resistant to treatment and most patients eventually develop secondary resistance after an initial response. Additionally, unique side effects of FGFR inhibitors may limit their efficacy in clinical practice and can have detrimental effects on quality of life. Several novel FGFR inhibitors are currently being investigated to overcome resistance mechanisms and reduce toxicities.

Ten-eleven translocation protein 1 (TET1) functions as an epigenetic regulatory molecule, mediating the majority of DNA demethylation, and plays a role in the development of different types of cancers by regulating the expression of proto-oncogenes and oncogenes. Here it is found that TET1 is highly expressed in cholangiocarcinoma (CCA) and is associated with a poor prognosis. In addition, TET1 promotes claudin-3 (CLDN3) transcription by targeting the CLDN3 promoter region between -16 and 512 for demethylation. PPM1G functions as a protein dephosphorylase, catalyzing the dephosphorylation of TET1. This results in the destabilization of the TET1 protein, thereby impairing the targeting of the CLDN3 promoter for demethylation. Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA.

Intrahepatic Cholangiocarcinoma (iCCA) with FGFR alterations is relatively rare, and its identification is important in the era of targeted therapy. We collected a large series of FGFR-altered cases in the Chinese population and characterized their clinicopathological and genetic features. Among the 18 FGFR-altered cases out of 260 iCCAs, 10 were males and 8 were females, ranging in age from 35 to 74 years (mean, 57.3 years; median, 58 years). Pathologically, they include 9 cases of large duct (LD, 50 %) and small duct (SD, 50 %) types each. All of them (100 %, 18/18) showed microsatellite stable (MSS) and low tumor mutation burden (TMB). Genetically, FGFR alterations involved FGFR1 (20 %), FGFR2 (70 %), and FGFR3 (10 %), with FGFR2 rearrangement accounting for the most (11/18). The most frequently altered genes/biological processes were development/proliferation-related pathways (44 %), chromatin organization (20 %), and tumor suppressors (32 %). Our study further revealed the clinicopathological and genetic features of FGFR-altered iCCA and demonstrated that its occurrence may show regional or ethnic variability and is less common in the Chinese population. A significant number of LD-type iCCA cases also have FGFR alterations rather than the SD type.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the sixth leading cause of cancer death worldwide, and it is urgent to find safe and effective drugs for treatment. As an important therapeutic method, small-molecule drugs are continually being updated to achieve improved therapeutic effects. The purpose of this study was to investigate the structural effects of various FDA-listed small-molecule drugs sorafenib, cabozantinib, lenvatinib, and regorafenib on the corresponding HCC targets and possible structural optimization methods, and to explore the mechanism for identifying potential therapeutic drugs that offer better efficacy and fewer side effects.

The structure-activity relationship, pharmacological actions, and clinical applications of small-molecule drugs were reviewed by referencing MEDLINE, Web of Science, CNKI, and other databases, summarizing and integrating the relevant content.

The results showed that small-molecule drugs can inhibit HCC primarily by forming hydrogen bonds with Glu885, Asp1046, and Cys919 on the HCC target. HCC can be targeted by inhibiting the activation of multiple pathways, blocking the conduction of downstream signaling, and reducing the formation of tumor blood vessels. In general, small-molecule drugs primarily target four key receptors in HCC: VEGFR, PDGFR, EGFR, and FGFR, to achieve effective treatment.

By revealing their structure-activity relationships, pharmacological actions, and clinical trials, small-molecule drugs can offer broad prospects for the development of new medications.

Patients with chemotherapy-responsive advanced biliary tract cancers (BTCs) are usually observed after 6 months of gemcitabine-based therapy. There is limited prospective evidence for maintenance strategies after chemotherapy.

This investigator-initiated, open-label, randomized, integrated phase II-III study enrolled adult patients with advanced BTC from two cancer centers in India. Patients with histologically confirmed advanced biliary tract adenocarcinoma who had at least disease stabilization after 6 months of gemcitabine-based chemotherapy were randomly assigned (1:1) to either active surveillance or switch maintenance, which was a combination of bevacizumab 5 mg/kg intravenous once every 21 days plus erlotinib 100 mg once daily. Both arms were continued until disease progression, unacceptable toxicity, or patient decision to withdraw. The primary end point of the phase II component of the trial was investigator-evaluated progression-free survival. This trial is registered with Clinical Trials Registry of India (CTRI/2019/05/019323I).

From May 2021 to November 2022, 98 patients were randomly assigned to active surveillance (n = 49) or bevacizumab-erlotinib (n = 49). A majority of patients had gallbladder cancer (80%). The median follow-up was 13.4 months. The median progression-free survival was 3.1 months (95% CI, 2.47 to 3.64) in the active surveillance group versus 5.3 months (95% CI, 3.53 to 7.04) in the bevacizumab-erlotinib group (hazard ratio, 0.51 [95% CI, 0.33 to 0·74]; P = .0013). The most common grade 3 class-specific adverse events associated with bevacizumab-erlotinib were acneiform rash 1 (2%) and oral stomatitis 1 (2%) with erlotinib and bleeding 1 (2%) with bevacizumab.

The combination of bevacizumab and erlotinib as switch maintenance improves progression-free survival with an acceptable safety profile compared with active surveillance in patients with advanced BTCs in this phase II study. The trial moves on to the phase III component to evaluate improvement in overall survival.

Biliary tract cancers (BTC) are a heterogeneous group of cancers that continue to present a particularly poor prognosis. BTC treatment is rapidly evolving yet facing many challenges to improve patient outcomes and maximize benefit from treatment. Only a minority of patients are diagnosed with early-stage disease and are suitable for curative resection. Current surgical strategies are limited by a high relapse rate, and despite extensive efforts focused on adjuvant strategies, the development of more effective adjuvant strategies remains a challenge. In addition, the role of locoregional strategies, liver transplant, and neoadjuvant treatment remains unclear. Systemic treatment in the advanced setting is based on three main pillars: first, cytotoxic chemotherapy options; second, the addition of immunotherapy to chemotherapy; and third, targeted therapies. The role of targeted therapies is oriented by many promising targets, including IDH1 mutations, FGFR2 fusions, BRAF-V600E mutations, and HER2 amplifications. The aim of this review is to provide an overview of current facts and future hopes in the management of BTC, including an overview of the unmet need, and particularly focus on systemic therapies.

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations.

The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC.

Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis.

The incidence of biliary tract cancer is increasing in developed countries and is generating renewed interest in the scientific community due to the evidence of a high percentage (approximately 40%) of potentially targetable molecular alterations. However, to date, patient selection and the development of therapeutic approaches remain challenging due to the need for accurate diagnosis, adequate sampling, a specialized team for molecular analysis, centralization of patients in high-volume centers capable of supporting the high cost of these methods, and the feasibility of clinical studies on diseases with aggressive onset and poor prognosis. In this article, we would like to provide a detailed overview of the necessary tools for diagnostic framing and the various therapeutic scenarios being investigated concerning the most frequently detected molecular alterations.

Cholangiocarcinoma (CCA) is a rare type of digestive tract cancer originating from the epithelial cells of the liver and biliary tract. Current treatment modalities for CCA, such as chemotherapy and radiation therapy, have demonstrated limited efficacy in enhancing survival rates. Despite the revolutionary potential of immunotherapy in cancer management, its application in CCA remains restricted due to the minimal infiltration of immune cells in these tumors, rendering them cold and unresponsive to immune checkpoint inhibitors (ICIs). Cancer cells within cold tumors deploy various mechanisms for evading immune attack, thus impeding clinical management. Recently, combination immunotherapy has become increasingly essential to comprehend the mechanisms underlying cold tumors to enhance a deficient antitumor immune response. Therefore, a thorough understanding of the knowledge on the combination immunotherapy of cold CCA is imperative to leverage the benefits of immunotherapy in treating patients. Moreover, gut microbiota plays an essential role in the immunotherapeutic responses in CCA. In this review, we summarize the current concepts of immunotherapy in CCA and clarify the intricate dynamics within the tumor immune microenvironment (TIME) of CCA. We also delve into the evasion mechanisms employed by CCA tumors against the anti-tumor immune responses. The context of combination immunotherapies in igniting cold tumors of CCA and the critical function of gut microbiota in prompting immune responses have also been annotated. Furthermore, we have proposed future directions in the realm of CCA immunotherapy, aiming to improve the clinical prognosis of CCA patients.

FGFR genomic aberrations occur in approximately 5-10% of human cancers. Erdafitinib has previously demonstrated efficacy and safety in FGFR-altered advanced solid tumors, such as gliomas, thoracic, gastrointestinal, gynecological, and other rare cancers. However, its efficacy and safety in Asian patients remain largely unknown. We conducted a multicenter, open-label, single-arm phase IIa study of erdafitinib to evaluate its efficacy in Asian patients with FGFR-altered advanced cholangiocarcinoma, non-small cell lung cancer (NSCLC), and esophageal cancer.

Patients with pathologically/cytologically confirmed, advanced, or refractory tumors who met molecular and study eligibility criteria received oral erdafitinib 8 mg once daily with an option for pharmacodynamically guided up-titration to 9 mg on a 28-day cycle, except for four NSCLC patients who received erdafitinib 10 mg (7 days on/7 days off) as they were recruited before the protocol amendment. The primary endpoint was investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints included progression-free survival, duration of response, disease control rate, overall survival, safety, and pharmacokinetics.

Thirty-five patients (cholangiocarcinoma: 22; NSCLC: 12; esophageal cancer: 1) were enrolled. At data cutoff (November 19, 2021), the objective response rate for patients with cholangiocarcinoma was 40.9% (95% CI, 20.7-63.6); the median progression-free survival was 5.6 months (95% CI, 3.6-12.7) and median overall survival was 40.2 months (95% CI, 12.4-not estimable). No patient with RET/FGFR-altered NSCLC achieved objective response and the disease control rate was 25.0% (95% CI, 5.5-57.2%), with three patients with stable disease. The single patient with esophageal cancer achieved partial response. All patients experienced treatment-emergent adverse events, and grade ≥ 3 treatment-emergent adverse events were reported in 22 (62.9%) patients. Hyperphosphatemia was the most frequently reported treatment-emergent adverse event (all-grade, 85.7%).

Erdafitinib demonstrated efficacy in a population of Asian patients in selected advanced solid tumors, particularly in those with advanced FGFR-altered cholangiocarcinoma. Treatment was tolerable with no new safety signals.

This trial is registered with ClinicalTrials.gov (NCT02699606); study registration (first posted): 04/03/2016.

Significant advancements in our understanding and clinical treatment of cholangiocarcinoma (CCA) have been achieved over the past 5 years. Groundbreaking studies have illuminated the immune landscape and pathological characteristics of the tumor microenvironment in CCA. The development of immune- and metabolism-based classification systems has enabled a nuanced exploration of the tumor microenvironment and the origins of CCA, facilitating a detailed understanding of tumor progression modulation. Despite these insights, targeted therapies have not yet yielded satisfactory clinical results, highlighting the urgent need for innovative therapeutic strategies. This review delineates the complexity and heterogeneity of CCA, examines the current landscape of therapeutic strategies and clinical trials, and delves into the resistance mechanisms underlying targeted therapies. Finally, from a single-cell and spatial transcriptomic perspective, we address the challenge of therapy resistance, discussing emerging mechanisms and potential strategies to overcome this barrier and enhance treatment efficacy.

In the last decade, targeted therapies have shown rapid advancement in biliary tract cancer (BTC). Today, many targeted agents are available and under investigation for patients with BTC. More recently, immune checkpoint inhibitors (ICI) such as durvalumab and pembrolizumab in combination with gemcitabine plus cisplatin (gem/cis) have resulted in improved overall survival and progression-free survival in the first-line setting. However, the efficacy benefit of these novel therapeutics is often short-lived, with literature outlining concerns about both primary and secondary resistance to these agents. Investigators also need to consider toxicity profiles that can emerge using this strategy. There have been efforts to reduce evolving resistance through combinatory approaches, both pre-clinically and in early clinical settings. This review summarizes the emerging targeted therapies in BTC, evolving biomarkers of resistance, strategies to overcome them, and an analysis of ongoing clinical trials of patients with advanced BTC.

Multiple FGFR inhibitors have demonstrated significant activity in pretreated advanced FGFR2 fusion-positive intrahepatic cholangiocarcinoma. The irreversible pan-FGFR inhibitor futibatinib has the potential to overcome acquired resistance to ATP-competitive FGFR inhibitors in a subset of patients. We present a case of prolonged clinical benefit using FGFR inhibitors sequentially, initially an ATP-competitive inhibitor followed by futibatinib upon progression, for a total of 36 months of FGFR-targeting therapy. This case supports sequential FGFR-targeting therapies for FGFR2 fusion-positive cholangiocarcinoma, with futibatinib acting as rescue therapy after failure of ATP-competitive inhibitors.

Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

To assess the impact of concurrent inhibition of the FGFR and PI3K/mTOR signaling pathways on oncogenic characteristics in cholangiocarcinoma (CCA) cells, including proliferation, autophagy, and cell death.

KKU-213A, KKU-100, and KKU-213C cells were treated with either infigratinib or PKI-402 alone or in combination. Cell viability and cell death were evaluated using the sulforhodamine B (SRB) assay and acridine orange/ethidium bromide (AO/EB) staining. Cell cycle progression and apoptotic cell death were analyzed by flow cytometry. Western blotting was performed to assess the expression of proteins involved in cell cycle regulation and autophagy. Additionally, AO staining was employed to assess autophagic induction.

The combination of infigratinib and PKI-402 showed a remarked synergistic suppression in cell viability in both CCA cell lines compared to treatment with single inhibitors. This antiproliferative effect was associated with cell cycle arrest in the G2-M phase and a decrease in the expression of cyclin A and cyclin B1 in CCA cells. Furthermore, the combination treatment induced apoptotic cell death to a greater extent than treatment with a single inhibitor. Infigratinib enhanced the induction of autophagy by PKI-402, as evidenced by marked increases of autophagic vacuoles stained acridine orange, levels of LC3B-II and suppression of levels of p-mTOR and. Notably, inhibition of autophagic flux by chloroquine prevented cell death induced by the combination treatment.

This study demonstrated that concurrent inhibition of the key FGFR/PI3K/mTOR pathways in CCA carcinogenesis enhances the suppression of CCA cells. The present findings indicate potential clinical implications for using combination treatment modalities in CCA therapy.

Biliary tract cancer (BTC) is a rare cancer with poor prognosis, characterized by considerable pathophysiological and molecular heterogeneity. While this makes it difficult to treat, it also provides targeted therapy opportunities. Current standard-of-care is chemotherapy ± immunotherapy, but several targeted agents have recently been approved. The current investigational landscape in BTC emphasizes the importance of biomarker testing at diagnosis. MDM2/MDMX are important negative regulators of the tumor suppressor p53 and provide an additional target in BTC (∼5-8% of tumors are MDM2-amplified). Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown antitumor activity in preclinical studies and promising results in early clinical trials; enrollment is ongoing in a potential registrational trial for patients with BTC.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood.

To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue.

Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs.

This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.

Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA.

Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day.

In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments.

Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management.

To evaluate safety and effectiveness of selective internal radiation therapy (SIRT) using yttrium-90 for localized and locally advanced intrahepatic cholangiocarcinoma (iCCA).

A retrospective review was performed of patients with localized iCCA treated with SIRT at a single institution. Overall survival (OS), local tumor response, progression-free survival (PFS), and toxicity were collected. Stratified analysis was performed based on surgical resection. Predictor analysis of OS was performed using the Fine-Grey regression analysis model with patients bridged to surgery regarded as competing events.

A total of 28 consecutive patients with localized iCCA were treated with a total of 38 sessions of SIRT (17 segmental, 13 lobar, and 8 combined deliveries) and a mean dominant target dose per session of 238.4 ± 130.0 Gy. The cumulative radiologic response rate was 16/28 (57.1%) with a median PFS of 265 days. Median survival time (MST) was 22.9 months for the entire cohort with 1-year and 3-year survival of 78.4% and 45.1%, respectively. Ten patients (34.5%) were downstaged to surgical intervention (7 resection, 3 transplant) and showed longer OS (p = 0.027). The 1-year and 3-year OS for patients who received surgery were 100% and 62.5% (95% CI: 14.2-89.3%), respectively. Age (p = 0.028), Eastern Cooperative Oncology Group performance status (p = 0.030), and objective radiologic response (p=0.014) are associated with OS. Two ≥grade 3 hyperbilirubinemia, anemia, and one pleuro-biliary fistula occurred post-SIRT.

SIRT for localized iCCA is safe and effective in achieving radiological response, downstaging to surgery and transplant, and resulting in pathologic necrosis.

Selective internal radiation therapy should be considered for patients with localized and locally advanced intrahepatic cholangiocarcinoma.

• The effectiveness of radioembolization for intrahepatic cholangiocarcinoma (iCCA) can be underestimated given the inclusion of extrahepatic disease. • Radioembolization is safe and effective for local and locally advanced iCCA. Age, Eastern Cooperative Oncology Group performance status, and radiologic response are associated with survival. • Radioembolization should be considered for patients with localized and locally advanced iCCA.