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1.
CA Cancer J Clin ; 73(2): 198-222, 2023 03.
Article in English | MEDLINE | ID: mdl-36260350

ABSTRACT

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor and remains a fatal malignancy in the majority of patients. Approximately 20%-30% of patients are eligible for resection, which is considered the only potentially curative treatment; and, after resection, a median survival of 53 months has been reported when sequenced with adjuvant capecitabine. For the 70%-80% of patients who present with locally unresectable or distant metastatic disease, systemic therapy may delay progression, but survival remains limited to approximately 1 year. For the past decade, doublet chemotherapy with gemcitabine and cisplatin has been considered the most effective first-line regimen, but results from the recent use of triplet regimens and even immunotherapy may shift the paradigm. More effective treatment strategies, including those that combine systemic therapy with locoregional therapies like radioembolization or hepatic artery infusion, have also been developed. Molecular therapies, including those that target fibroblast growth factor receptor and isocitrate dehydrogenase, have recently received US Food and Drug Administration approval for a defined role as second-line treatment for up to 40% of patients harboring these actionable genomic alterations, and whether they should be considered in the first-line setting is under investigation. Furthermore, as the oncology field seeks to expand indications for immunotherapy, recent data demonstrated that combining durvalumab with standard cytotoxic therapy improved survival in patients with ICC. This review focuses on the current and future strategies for ICC treatment, including a summary of the primary literature for each treatment modality and an algorithm that can be used to drive a personalized and multidisciplinary approach for patients with this challenging malignancy.


Subject(s)
Antineoplastic Agents , Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/surgery , Treatment Outcome , Antineoplastic Agents/therapeutic use , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics
2.
Genes Dev ; 35(15-16): 1123-1141, 2021 08 01.
Article in English | MEDLINE | ID: mdl-34301768

ABSTRACT

Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB)-specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at ∼80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2'-O-methylation of spliceosomal snRNAs, identifying CBs as the site of scaRNP catalysis. Additionally, alternative splicing patterns change indicating that these modifications in U1, U2, U5, and U12 snRNAs safeguard splicing fidelity. Given the importance of CK2 in this pathway, compromised splicing could underlie the mode of action of small molecule CK2 inhibitors currently considered for therapy in cholangiocarcinoma, hematological malignancies, and COVID-19.


Subject(s)
Interstitial Cells of Cajal/metabolism , Methylation , Nuclear Proteins/metabolism , Phosphoproteins/metabolism , RNA Splicing , RNA, Small Nuclear/metabolism , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Cholangiocarcinoma/drug therapy , Hematologic Neoplasms/drug therapy , Humans , Phosphorylation , RNA, Small Nuclear/chemistry , Ribonucleoproteins/metabolism , Spliceosomes/genetics , COVID-19 Drug Treatment
3.
N Engl J Med ; 388(3): 228-239, 2023 01 19.
Article in English | MEDLINE | ID: mdl-36652354

ABSTRACT

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).


Subject(s)
Antineoplastic Agents , Bile Duct Neoplasms , Bile Ducts, Intrahepatic , Cholangiocarcinoma , Protein Kinase Inhibitors , Receptor, Fibroblast Growth Factor, Type 2 , Aged , Humans , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Quality of Life , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Antineoplastic Agents/administration & dosage
4.
Annu Rev Med ; 74: 293-306, 2023 01 27.
Article in English | MEDLINE | ID: mdl-36170665

ABSTRACT

Biliary tract cancer (BTC) is the second most common primary liver cancer after hepatocellular carcinoma and accounts for 2% of cancer-related deaths. BTCs are classified according to their anatomical origin into intrahepatic (iCCA), perihilar, or distal cholangiocarcinoma, as well as gall bladder carcinoma. While the mutational profiles in these anatomical BTC subtypes overlap to a large extent, iCCA is notable for the high frequency of IDH1/2 mutations (10-22%) and the nearly exclusive occurrence of FGFR2 fusions in 10-15% of patients. In recent years, FGFR2 fusions have become one of the most promising targets for precision oncology targeting BTC, with FGFR inhibitors already approved in Europe and the United States for patients with advanced, pretreated iCCA. While the therapeutic potential of nonfusion alterations is still under debate, it is expected that the field of FGFR2-directed therapies will be subject to rapid further evolution and optimization. The scope of this review is to provide an overview of oncogenic FGFR signaling in iCCA cells and highlight the pathophysiology, diagnostic testing strategies, and therapeutic promises and challenges associated with FGFR2-altered iCCA.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Precision Medicine , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/diagnosis , Mutation , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/therapeutic use
5.
Hepatology ; 79(4): 941-958, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-37018128

ABSTRACT

Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.


Subject(s)
Arachnodactyly , Bile Duct Neoplasms , Biliary Tract , Cancer-Associated Fibroblasts , Cholangiocarcinoma , Contracture , Humans , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic , Tumor Microenvironment
6.
Hepatology ; 79(4): 798-812, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-37505213

ABSTRACT

ABSTRACT AND AIM: Cholangiocarcinoma (CCA) is a highly aggressive and lethal cancer that originates from the biliary epithelium. Systemic treatment options for CCA are currently limited, and the first targeted drug of CCA, pemigatinib, emerged in 2020 for CCA treatment by inhibiting FGFR2 phosphorylation. However, the regulatory mechanism of FGFR2 phosphorylation is not fully elucidated. APPROACH AND RESULTS: Here we screened the FGFR2-interacting proteins and showed that protein tyrosine phosphatase (PTP) N9 interacts with FGFR2 and negatively regulates FGFR2 pY656/657 . Using phosphatase activity assays and modeling the FGFR2-PTPN9 complex structure, we identified FGFR2 pY656/657 as a substrate of PTPN9, and found that sec. 14p domain of PTPN9 interacts with FGFR2 through ACAP1 mediation. Coexpression of PTPN9 and ACAP1 indicates a favorable prognosis for CCA. In addition, we identified key amino acids and motifs involved in the sec. 14p-APCP1-FGFR2 interaction, including the "YRETRRKE" motif of sec. 14p, Y471 of PTPN9, as well as the PH and Arf-GAP domain of ACAP1. Moreover, we discovered that the FGFR2 I654V substitution can decrease PTPN9-FGFR2 interaction and thereby reduce the effectiveness of pemigatinib treatment. Using a series of in vitro and in vivo experiments including patient-derived xenografts (PDX), we showed that PTPN9 synergistically enhances pemigatinib effectiveness and suppresses CCA proliferation, migration, and invasion by inhibiting FGFR2 pY656/657 . CONCLUSIONS: Our study identifies PTPN9 as a negative regulator of FGFR2 phosphorylation and a synergistic factor for pemigatinib treatment. The molecular mechanism, oncogenic function, and clinical significance of the PTPN9-ACAP1-FGFR2 complex are revealed, providing more evidence for CCA precision treatment.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Morpholines , Pyrimidines , Pyrroles , Humans , Cholangiocarcinoma/drug therapy , Epithelium , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic , Receptor, Fibroblast Growth Factor, Type 2 , GTPase-Activating Proteins
7.
Hepatology ; 79(1): 96-106, 2024 Jan 01.
Article in English | MEDLINE | ID: mdl-37505216

ABSTRACT

BACKGOUND AND AIMS: In advanced, liver-only intrahepatic cholangiocarcinoma (iCCA), selective internal radiation therapy (SIRT) has been suggested as promising in nonrandomized studies. We aimed to compare data from patients with advanced, liver-only iCCA treated in the first line in clinical trials with either chemotherapy alone or the combination with SIRT. APPROACH AND RESULTS: We collected individual patients' data from the ABC-01, ABC-02, ABC-03, BINGO, AMEBICA, and MISPHEC prospective trials. Data from patients with liver-only iCCA treated in chemotherapy-only arms of the first 5 trials were compared with data from patients treated with SIRT and chemotherapy in MISPHEC. Emulated target trial paradigm and Inverse Probability of Treatment Weighting (IPTW methods) using the propensity score were used to minimize biases. We compared 41 patients treated with the combination with 73 patients treated with chemotherapy alone, the main analysis being in 43 patients treated with cisplatin-gemcitabine or gemcitabine-oxaliplatin. After weighting, overall survival was significantly higher in patients treated with SIRT: median 21.7 months (95% CI: 14.1; not reached) versus 15.9 months(95% CI: 9.8; 18.9), HR = 0.59 (95% CI: 0.34; 0.99), p = 0.049. Progression-free survival was significantly improved: median 14.3 months (95% CI: 7.8; not reached) versus 8.4 months (95% CI: 5.9; 12.1), HR = 0.52 (95% CI: 0.31; 0.89), p < 0.001. Results were confirmed in most sensitivity analyses. CONCLUSIONS: This analysis derived from prospective clinical trials suggests that SIRT combined with chemotherapy might improve outcomes over chemotherapy alone in patients with advanced, liver-only iCCA. Randomized controlled evidence is needed to confirm these findings.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Gemcitabine , Prospective Studies , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/radiotherapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/radiotherapy
8.
Mol Ther ; 32(8): 2762-2777, 2024 Aug 07.
Article in English | MEDLINE | ID: mdl-38859589

ABSTRACT

This study demonstrates the potential of using biological nanoparticles to deliver RNA therapeutics targeting programmed death-ligand 1 (PD-L1) as a treatment strategy for cholangiocarcinoma (CCA). RNA therapeutics offer prospects for intracellular immune modulation, but effective clinical translation requires appropriate delivery strategies. Milk-derived nanovesicles were decorated with epithelial cellular adhesion molecule (EpCAM) aptamers and used to deliver PD-L1 small interfering RNA (siRNA) or Cas9 ribonucleoproteins directly to CCA cells. In vitro, nanovesicle treatments reduced PD-L1 expression in CCA cells while increasing degranulation, cytokine release, and tumor cell cytotoxicity when tumor cells were co-cultured with T cells or natural killer cells. Similarly, immunomodulation was observed in multicellular spheroids that mimicked the tumor microenvironment. Combining targeted therapeutic vesicles loaded with siRNA to PD-L1 with gemcitabine effectively reduced tumor burden in an immunocompetent mouse CCA model compared with controls. This proof-of-concept study demonstrates the potential of engineered targeted nanovesicle platforms for delivering therapeutic RNA cargoes to tumors, as well as their use in generating effective targeted immunomodulatory therapies for difficult-to-treat cancers such as CCA.


Subject(s)
B7-H1 Antigen , Cholangiocarcinoma , Immunotherapy , RNA, Small Interfering , Cholangiocarcinoma/therapy , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/immunology , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , Animals , Humans , Mice , Cell Line, Tumor , Immunotherapy/methods , RNA, Small Interfering/genetics , RNA, Small Interfering/administration & dosage , Nanoparticles/chemistry , Bile Duct Neoplasms/therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/immunology , Tumor Microenvironment/immunology , Disease Models, Animal , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Gemcitabine
9.
Gut ; 73(3): 496-508, 2024 Feb 23.
Article in English | MEDLINE | ID: mdl-37758326

ABSTRACT

OBJECTIVE: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. DESIGN: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. RESULTS: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. CONCLUSIONS: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Animals , Mice , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Gene Expression Profiling , Transcriptome , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism
10.
Semin Liver Dis ; 44(2): 159-179, 2024 May.
Article in English | MEDLINE | ID: mdl-38806159

ABSTRACT

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Hepatocellular , Cholangiocarcinoma , Drug Resistance, Neoplasm , Immune Checkpoint Inhibitors , Liver Neoplasms , Tumor Microenvironment , Humans , Immune Checkpoint Inhibitors/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/immunology , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/drug therapy , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/immunology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/immunology , Tumor Escape/drug effects , Immunotherapy/methods , Animals
11.
Am J Physiol Cell Physiol ; 327(1): C11-C33, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38708523

ABSTRACT

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.


Subject(s)
Liver Neoplasms , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Animals , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Immunotherapy/methods , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Drug Resistance, Neoplasm/drug effects , Protein Kinase Inhibitors/therapeutic use , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/immunology , Cholangiocarcinoma/pathology , Epigenesis, Genetic/drug effects
12.
J Cell Mol Med ; 28(17): e18585, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39223878

ABSTRACT

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Tryptophan Hydroxylase , Xenograft Model Antitumor Assays , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/metabolism , Animals , Tryptophan Hydroxylase/metabolism , Tryptophan Hydroxylase/antagonists & inhibitors , Humans , Cell Line, Tumor , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/metabolism , Mice , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Cell Proliferation/drug effects , Gemcitabine , Cisplatin/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Synergism , Disease Models, Animal , Serotonin/metabolism , Female
13.
Br J Cancer ; 131(1): 117-125, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38806725

ABSTRACT

BACKGROUND: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. PATIENTS AND METHODS: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). RESULTS: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). DISCUSSION: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.


Subject(s)
Adenocarcinoma , Duodenal Neoplasms , Humans , Male , Female , Chemotherapy, Adjuvant , Middle Aged , Aged , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Duodenal Neoplasms/drug therapy , Duodenal Neoplasms/pathology , Duodenal Neoplasms/surgery , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/surgery , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Ampulla of Vater/pathology , Pancreaticoduodenectomy , Cohort Studies , Common Bile Duct Neoplasms/drug therapy , Common Bile Duct Neoplasms/surgery , Common Bile Duct Neoplasms/pathology , Common Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/surgery , Retrospective Studies , Capecitabine/therapeutic use , Capecitabine/administration & dosage
14.
J Hepatol ; 80(2): 322-334, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37972659

ABSTRACT

BACKGROUND & AIMS: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA). METHODS: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro. RESULTS: On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance. CONCLUSIONS: These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi. CLINICAL TRIAL NUMBER: NCT02052778. IMPACT AND IMPLICATIONS: We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Animals , Humans , Mitogen-Activated Protein Kinases/metabolism , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins B-raf/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Proto-Oncogene Proteins p21(ras)/therapeutic use , Retrospective Studies , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Mutation , Bile Ducts, Intrahepatic/pathology , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Protein Kinase Inhibitors/adverse effects , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism
15.
Funct Integr Genomics ; 24(3): 114, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38862667

ABSTRACT

With advances in radioactive particle implantation in clinical practice, Iodine-125 (125I) seed brachytherapy has emerged as a promising treatment for cholangiocarcinoma (CCA), showing good prognosis; however, the underlying molecular mechanism of the therapeutic effect of 125I seed is unclear. To study the effects of 125I seed on the proliferation and apoptosis of CCA cells. CCA cell lines, RBE and HCCC-9810, were treated with reactive oxygen species (ROS) scavenger acetylcysteine (NAC) or the p53 functional inhibitor, pifithrin-α hydrobromide (PFTα). Cell counting kit-8 (CCK-8) assay, 5-bromo-2-deoxy-uridine (BrdU) staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry assay were performed to test the radiation-sensitivity of 125I seed toward CCA cells at different radiation doses (0.4 mCi and 0.8 mCi). 2,7-dichlorofluorescein diacetate (DCF-DA) assay, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot analysis were performed to assess the effect of 125I seed on the ROS/p53 axis. A dose-dependent inhibitory effect of 125I seeds on the proliferation of CCA cells was observed. The 125I seed promoted apoptosis of CCA cells and induced the activation of the ROS/p53 pathway in a dose-dependent manner. NAC or PFTα treatment effectively reversed the stimulatory effect of 125I seed on the proliferation of CCA cells. NAC or PFTα suppressed apoptosis and p53 protein expression induced by the 125I seed. 125I seed can inhibit cell growth mainly through the apoptotic pathway. The mechanism may involve the activation of p53 and its downstream apoptotic pathway by up-regulating the level of ROS in cells.


Subject(s)
Apoptosis , Cell Proliferation , Cholangiocarcinoma , Iodine Radioisotopes , Reactive Oxygen Species , Tumor Suppressor Protein p53 , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/radiotherapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/genetics , Cholangiocarcinoma/drug therapy , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Reactive Oxygen Species/metabolism , Apoptosis/drug effects , Cell Proliferation/drug effects , Humans , Cell Line, Tumor , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/radiotherapy , Acetylcysteine/pharmacology , Benzothiazoles/pharmacology , Signal Transduction/drug effects
16.
Oncologist ; 29(8): 725-730, 2024 Aug 05.
Article in English | MEDLINE | ID: mdl-39036962

ABSTRACT

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. METHODS: We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. RESULTS: Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. CONCLUSION: This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Isocitrate Dehydrogenase , Poly(ADP-ribose) Polymerase Inhibitors , Humans , Isocitrate Dehydrogenase/genetics , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Female , Male , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Middle Aged , Retrospective Studies , Aged , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Mutation , Adult
17.
Oncologist ; 29(4): e514-e525, 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38297981

ABSTRACT

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy. RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours. CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.


Subject(s)
Antineoplastic Agents , Cholangiocarcinoma , Hypertension , Neoplasms , Prostatic Neoplasms, Castration-Resistant , Triple Negative Breast Neoplasms , Male , Humans , Triple Negative Breast Neoplasms/drug therapy , Bayes Theorem , Prostatic Neoplasms, Castration-Resistant/drug therapy , Vascular Endothelial Growth Factor A , Neoplasms/drug therapy , Neoplasms/genetics , Antineoplastic Agents/adverse effects , Cholangiocarcinoma/drug therapy , Hypertension/chemically induced , Maximum Tolerated Dose
18.
J Gene Med ; 26(5): e3689, 2024 May.
Article in English | MEDLINE | ID: mdl-38676365

ABSTRACT

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.


Subject(s)
Cholangiocarcinoma , Cisplatin , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Y-Box-Binding Protein 1 , beta Catenin , Animals , Female , Humans , Male , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , beta Catenin/metabolism , beta Catenin/genetics , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/mortality , Cisplatin/pharmacology , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/genetics , Neoplastic Stem Cells/metabolism , Prognosis , Proto-Oncogene Proteins c-akt/metabolism , Wnt Signaling Pathway , Xenograft Model Antitumor Assays , Y-Box-Binding Protein 1/metabolism , Y-Box-Binding Protein 1/genetics
19.
Cancer Immunol Immunother ; 73(12): 249, 2024 Oct 03.
Article in English | MEDLINE | ID: mdl-39358645

ABSTRACT

BACKGROUND: Treatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC. METHODS: This retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted. RESULTS: A total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5-13.1) and 5.4 (95% CI: 3.8-7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016). CONCLUSION: Lenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Bile Duct Neoplasms , Biomarkers, Tumor , Cholangiocarcinoma , Phenylurea Compounds , Quinolines , Humans , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/genetics , Cholangiocarcinoma/mortality , Male , Female , Quinolines/therapeutic use , Quinolines/administration & dosage , Quinolines/adverse effects , Middle Aged , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/adverse effects , Phenylurea Compounds/administration & dosage , Aged , Retrospective Studies , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/genetics , Adult , Prognosis , Aged, 80 and over
20.
BMC Med ; 22(1): 165, 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38637772

ABSTRACT

BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases. METHODS: In this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: From December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%). CONCLUSIONS: External radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation. TRIAL REGISTRATION: NCT03898895. Registered 2 April 2019.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Drug-Related Side Effects and Adverse Reactions , Humans , Immunotherapy/adverse effects , Drug Therapy, Combination , Cholangiocarcinoma/drug therapy , Cholangiocarcinoma/radiotherapy , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/radiotherapy , Bile Ducts, Intrahepatic
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