Metastatic Cholangiocarcinoma Research Articles

In brief: A new indication for pemigatinib (Pemazyre).

The oral kinase inhibitor pemigatinib (Pemazyre – Incyte) has been approved by the FDA for treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangements. It is the first targeted therapy to be approved in the US for this indication. The drug received accelerated approval from the FDA in 2020 for treatment of adults with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements.

Futibatinib (Lytgobi) for cholangiocarcinoma.

The oral kinase inhibitor futibatinib (Lytgobi – Taiho) has received accelerated approval from the FDA for treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions or other rearrangements. Accelerated approval was based on the overall response rate and duration of response. Futibatinib is the second drug to be approved for this indication; pemigatinib (Pemazyre) was approved earlier.

Abstract CT153: Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma Including FGFR2 fusion or rearrangement: Updated overall survival from an open-label, single-arm, multicenter Phase II study

Abstract Background: Pemigatinib is a selective FGFR inhibitor that showed effectiveness and tolerability in patients with cholangiocarcinoma (CAA) with FGFR2 fusion or rearrangement. Data from prior data cutoffs (primary: Jan 29th, 2021; initial update: Dec 20th, 2021) showed that patients receiving pemigatinib had durable responses. Confirmed objective response rate (ORR) (60%) met the primary endpoint, median duration of response (DOR) was 8.3 months, median progression-free survival (PFS) was 9.1 months at the initial update (G-M. Shi et al. ASCO 2022). Safety results were also consistent with previously reported data on pemigatinib. Here we report updated overall survival (OS) results. Methods: Patients aged 18 years or older with recurrent or metastatic CCA that failed at least one prior systemic therapy were enrolled. Thirty-one subjects with documented FGFR2 fusion or rearrangement received 13.5 mg pemigatinib. The primary efficacy endpoint was ORR assessed by the independent radiological review committee (IRRC) per RECIST V1.1. And the second endpoints included disease control rate (DCR), DOR, PFS, and OS. Updated OS were evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Results: At data cutoff (December 28th, 2022), a total of 30 patients were assessed (1 participant excluded due to inadequate FGFR2 aberrant frequency). Median age was 56 years (range, 28-68).With a median OS follow-up of 25.6 months (95% CI, 23.0-25.8), the median OS was 23.9 months (95% CI, 15.2-NC), with 16 (53.3%) OS events. Estimated OS rate at 12 month, 18 month and 24 month were 73.3% (95% CI, 53.7%-85.7%), 66.5% (95% CI, 46.7%-80.4%), and 41.4% (95% CI, 22.4%-59.4%), respectively. No new safety signals were observed. Conclusions: These updated results demonstrated encouraging and durable survival benefit of pemigatinib in Chinese patients with recurrent or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement. Clinical trial identification: NCT04256980. Editorial acknowledgment: Guoming Shi and Xiaoyong Huang contributed equally to this work. Jian Zhou is the corresponding author. Citation Format: Guoming Shi, Xiaoyong Huang, Tianfu Wen, Tianqiang Song, Ming Kuang, Haibo Mou, Lequn Bao, Haitao Zhao, Hong Zhao, Xielin Feng, Bixiang Zhang, Tao Peng, Yubao Zhang, Xiangcheng Li, Hongsheng Yu, Yu Cao, Yang Luo, Ye Chen, Mingxia Chen, Jia Fan, Jian Zhou. Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma Including FGFR2 fusion or rearrangement: Updated overall survival from an open-label, single-arm, multicenter Phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT153.

Abstract CT192: Phase 1, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib in adult subjects

Abstract Background: Futibatinib, an irreversible FGFR1-4 inhibitor, is indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements. As the primary elimination pathway for futibatinib is hepatic metabolism, we conducted a phase 1 study to evaluate the effect of hepatic impairment (HI) on futibatinib pharmacokinetics (PK) and safety in healthy adults. Methods: A single oral dose of 20 mg futibatinib was administered to adult subjects with mild (Child-Pugh score, 5-6), moderate (7-9), or severe (10-15) HI. Control healthy subjects were matched to each HI cohort according to age, body mass index, and sex. Intensive PK samples were collected up to 72 hours post-dose. Exposure measures (AUC0-inf, AUC0-t, and Cmax) in subjects with HI were compared with matching control cohorts and with the overall healthy-control cohort. Relationships between plasma PK and HI were examined graphically via scatter/regression plots of PK parameters versus baseline Child-Pugh score, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase. Results: Overall, 38 subjects were enrolled (mild HI, n = 8; moderate HI, n = 8; severe HI, n = 6; healthy controls, n = 16). Following the administration of futibatinib, no trend was observed between the severity of HI and the extent of futibatinib exposure increase. Compared with matched controls, AUC0-inf increased by 21%, 20% and 18%, and Cmax by 43%, 15%, and 10% in subjects with mild, moderate, and severe HI, respectively. Changes in exposure were not considered clinically relevant as geometric mean ratios were within 80-125% bioequivalence limits, except for Cmax in subjects with mild HI (43%). Futibatinib PK parameters and HI measures did not appear to be associated based on visual inspection or statistical evaluation of regression plots (p-values all > 0.05). No subjects discontinued from the study due to treatment-emergent adverse events (TEAEs). Overall, two (12.5%) subjects in the healthy-control cohort reported one Grade 1 TEAE each (dyspepsia and headache) and two (25.0 %) subjects in the mild HI cohort each reported one Grade 1 TEAE (toothache and headache). All TEAEs were considered related to treatment. No subjects with moderate/severe HI reported TEAEs. Conclusions: No clinically meaningful differences in the systemic plasma exposure of futibatinib were observed based on the severity of HI. Single oral doses of futibatinib were well tolerated among subjects with varying degrees of HI and matched healthy adult subjects in this study. The data suggest that dose adjustment may not be necessary in patients with HI receiving futibatinib 20 mg QD for its approved indication. Citation Format: Ling Gao, Ikuo Yamamiya, Mark Pinti, Juan Carlos Rondón, Thomas Marbury, Gareth Tomlinson, Lukas Makris, Nanae Hangai, Volker Wacheck. Phase 1, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib in adult subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT192.

Specific recognition of an FGFR2 fusion by tumor infiltrating lymphocytes from a patient with metastatic cholangiocarcinoma

BackgroundMetastatic cholangiocarcinoma (CC), a form of gastrointestinal cancer that originates from the bile ducts, cannot be cured by currently available therapies, and is associated with dismal prognosis. In a previous...

Clinical outcomes of immune checkpoint inhibitors in unresectable or metastatic combined hepatocellular-cholangiocarcinoma.

Immune checkpoint inhibitors (ICIs) have been demonstrated to be effective for unresectable or metastatic hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA) in prior prospective trials. However, the clinical outcomes of ICIs in patients with combined HCC-CCA (cHCC-CCA) have not been investigated. Accordingly, we retrospectively evaluated the effectiveness and safety of ICIs in patients with unresectable or metastatic cHCC-CCA. Among 101 patients with histologically documented cHCC-CCA who received systemic therapy, 25 received ICIs between January 2015 and September 2021 and were included in the current analysis. Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were retrospectively evaluated. The median age was 64years (range 38-83) and 84% (n = 21) of patients were males. Most patients had Child-Pugh A liver function (n = 22, 88%) and hepatitis B virus infection (17, 68%). Nivolumab (n = 17, 68%) was the most frequently used ICI, followed by pembrolizumab (n = 5, 20%), atezolizumab plus bevacizumab (n = 2, 8%), and ipilimumab plus nivolumab (n = 1, 4%). All patients, except one, had previously received systemic therapy; median two lines (1-5 lines) of systemic therapy were administered prior to ICIs. With a median follow-up duration of 20.1months (95% CI 4.9-35.2months), the median PFS was 3.5months (95% CI 2.4-4.8months), and the median OS was 8.3months (95% CI 6.8-9.8months). The ORR was 20.0% (n = 5, nivolumab for 2 patients, pembrolizumab for 1, atezolizumab plus bevacizumab for 1, and ipilimumab plusnivolumab for 1) and the duration of response was 11.6months (95% CI 11.2-12.0months). ICIs displayed clinical anti-cancer effectiveness, aligning with the results of prior prospective studies for HCC or CCA. Further international studies are required to define the optimal strategies for managing unresectable or metastatic cHCC-CCA.

Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.

Deregulating fibroblast growth factor receptor (FGFR) signaling is a promising strategy for cancer therapy. Herein, we report the discovery of compound 5 (TAS-120, futibatinib), a potent and selective covalent inhibitor of FGFR1-4, starting from a unique dual inhibitor of mutant epidermal growth factor receptor and FGFR (compound 1). Compound 5 inhibited all four families of FGFRs in the single-digit nanomolar range and showed high selectivity for over 387 kinases. Binding site analysis revealed that compound 5 covalently bound to the cysteine 491 highly flexible glycine-rich loop region of the FGFR2 adenosine triphosphate pocket. Futibatinib is currently in Phase I-III trials for patients with oncogenically driven FGFR genomic aberrations. In September 2022, the U.S. Food & Drug Administration granted accelerated approval for futibatinib in the treatment of previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring an FGFR2 gene fusion or other rearrangement.

Lack of pharmacokinetic interaction between derazantinib and naringin in rats

Context Derazantinib—an orally bioavailable, ATP competitive, multikinase inhibitor—has strong activity against fibroblast growth factor receptors (FGFR)2, FGFR1, and FGFR3 kinases. It has preliminary antitumor activity in patients with unresectable or metastatic FGFR2 fusion-positive intrahepatic cholangiocarcinoma (iCCA). Objective This experiment validates a novel sensitive and rapid method for the determination of derazantinib concentration in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and applies it to the study of drug-drug interaction between derazantinib and naringin in vivo. Materials and methods A Xevo TQ-S triple quadrupole tandem mass spectrometer was used for mass spectrometry monitoring in selective reaction monitoring (SRM) mode with transitions of m/z 468 96 → 382.00 for derazantinib and m/z 488.01 → 400.98 for pemigatinib, respectively. The pharmacokinetics of derazantinib (30 mg/kg) was investigated in Sprague-Dawley (SD) rats divided into two groups (with the oral pretreatment of 50 mg/kg naringin or not). Results The newly optimized UPLC-MS/MS method was suitable for the determination of derazantinib in rat plasma. It was also successfully employed to evaluate the effect of naringin on derazantinib metabolism in rats. After pretreatment with naringin, there was no significant difference in the pharmacokinetic parameters (AUC0→t, AUC0→∞, t1/2, CLz/F, and Cmax) of derazantinib when compared with derazantinib alone. Conclusion Co-administration of naringin with derazantinib was not associated with significant changes in pharmacokinetic parameters. Thus, this study suggests that the combination of derazantinib with naringin can safely be administered concomitantly without dose adjustment.

Bone Metastases from Intrahepatic Cholangiocarcinoma Confer Worse Prognosis

Metastatic intrahepatic cholangiocarcinoma still has a dismal prognosis. The aim of our study was to investigate the prognostic role of bone metastases in patients affected by intrahepatic cholangiocarcinoma. A total of 186 metastatic intrahepatic cholangiocarcinoma patients were retrospectively reviewed. Clinicopathologic and survival data were collected and reviewed, in particular overall survival, progression-free survival after first-line treatment and time from end of first-line therapy to cancer death. Around 11% of intrahepatic cholangiocarcinoma patients developed bone metastases. This subgroup of patients showed no differences in progression-free survival to first-line chemotherapy but had a shorter median overall survival of 4 months compared to the group with liver involvement only (p = 0.03). If treated, the outcome for ECOG PS 2 patients with bone metastases was worse in comparison to patients with liver involvement only with poor performance status (p = 0.003). The presence of bone metastases, poor performance status and no subsequent second-line treatment was associated with a worse outcome in multivariate analysis. Patients with intrahepatic carcinoma and bone metastases with poor ECOG performance status might be treated with best supportive care and not active chemotherapy treatment, the decisions which have to be shared with patients.

Phase II study of FGFR1-3 inhibitor tinengotinib as monotherapy in patients with advanced or metastatic cholangiocarcinoma: Interim analysis.

539 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor with a unique FGFR-binding mechanism. It potently inhibits FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and early clinical studies in cholangiocarcinoma (CCA). Here we present the preliminary efficacy and safety of tinengotinib (TT-00420) in a phase II trial TT420C1206 (NCT04919642). Methods: Eligible patients (pts) with advanced/metastatic CCA exhausting standard treatment options received tinengotinib 10 mg QD. Pts were enrolled into four cohorts using historical FGFR alteration status: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor (FGFRi) (A1) or progression after prior response to FGFRi (acquired resistance) (A2); non-fusion FGFR alteration(s) (B); or FGFR wild-type (FGFRwt, C). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Safety, PK parameters, and biomarker profile were evaluated and reviewed jointly with the efficacy outcomes. Adverse events (AEs) were graded per CTCAE version 5.0. Results: As of Sep 13, 2022, 25 pts with CCA were enrolled and dosed; 7 in A1, 6 in A2, 2 in B and 10 in C. Median age 61 [range 24-82] years old, 64% female, 93.3% had ≥ 3 prior treatment lines. 13 patients with ECOG 0 and 12 patients with ECOG 1 at baseline. Among 15 patients with historical FGFR alterations (13 fusions/rearrangement and 2 mutations), 93.3% had ≥ 1 prior FGFRi, and 3 pts (20.0%) had 2 prior FGFRi treatments. Eighteen pts were evaluable for tumor assessment at data cutoff date, including 4 in A1, 6 in A2, 1 in B and 7 in C. The median follow up was 15 weeks. In A2, 2 out of 6 pts (33%) achieved PR with tumor reductions of 34% and 54%. Overall DCR (CR or PR+SD) was 90% (9/10) in FGFR2 fusion/rearrangement pts; 100% in FGFR primary mutation pt (1/1); and 71% (5/7) in FGFRwt pts. One PR and 5 SDs lasted for more than 16 weeks. Among 25 treated pts, drug-related AEs occurred in 20 (80%) pts, including 7 (28%) with Grade (G) 1-2 AEs, 12 (48%) with G3 AEs, and 1 (4%) with G4 AE. Most frequently occurred G3/4 AEs were hypertension in 6 (24%) pts, including 5 (20%) with G3 and 1 (4%) with G4, G3 fatigue in 2 (8%) and G3 neutrophil count decreased in 2 (8%) pts. No drug-related G5 was observed. The efficacy and safety results observed were consistent with the previous reported data ( NCT03654547 ) in CCA pts. The preliminary biomarker analysis suggests loss of resistant FGFR mutation on liquid biopsy post tinengotinib therapy. Further biomarker analysis will be updated at the presentation. Conclusions: Tinengotinib may result in promising clinical benefit for CCA pts in the setting of FGFRi-resistance. Tinengotinib-related toxicities were manageable. An ongoing phase II study will further provide safety, efficacy and biomarker evaluations for both FGFR resistant and FGFRwt CCA. Clinical trial information: NCT04919642 .

Therapeutic effect of regional chemotherapy in diffuse metastatic cholangiocarcinoma

Background: Current therapeutic options in diffuse metastatic cholangiocarcinoma (CCC) are limited with unsatisfactory results. We evaluated the efficacy of regional chemotherapy (RegCTx) using arterial infusion (AI), hypoxic stop-flow abdominal perfusion (HAP), upper abdominal perfusion (UAP) and isolated-thoracic perfusion (ITP) in 36 patients with metastatic perihilar and intrahepatic CCC.

Gunagratinib, a highly selective irreversible FGFR inhibitor, in patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR pathway alterations: A phase IIa dose-expansion study.

572 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR 1, 2, 3 and 4 activities irreversibly by covalent binding. Here we present data from an ongoing phase IIa dose-expansion study (ICP-CL-00301 NCT03758664) of gunagratinib in patients with cholangiocarcinoma (CCA). Methods: Eligible participants were aged 18-75 years, had locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, and had disease progression after ≥1 prior treatment or intolerant of prior treatment. Patients received oral gunagratinib 20 mg QD (21-day cycle) until disease progression, intolerance, withdrawal of consent, or death. Radiological tumor evaluation was done at baseline and every 6 weeks until disease progression. Primary endpoint was objective response rate (ORR). Results: As of September 5, 2022, 18 CCA patients were enrolled and received 20 mg gunagratinib. The median age of the patients was 52.0 with 44.4% male and ECOG between 0-2. Median follow-up was 5.57 months. Among the 17 patients who have completed at least one tumor assessment, 9 patients had confirmed partial response (PR) and 7 patients had stable disease (SD). The ORR was 52.9% (9/17). The disease control rate (DCR) was 94.1% (16/17). The median progression free survival (mPFS) was 6.93 months (95% CI, 5.42–not reached) (not mature at cutoff). Among the 17 patients with safety data, 16 (94.1%) patients experienced at least one treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 35.3% of patients. Five serious TEAE were reported with only one serious treatment-related adverse event (TRAE). Discontinuation rate due to TRAEs was 0%. There were no treatment-related deaths. Conclusions: The study data demonstrated that gunagratinib is safe and well-tolerated in previously treated patients with locally advanced or metastatic CCA harboring FGFR2 gene fusions or rearrangements. The response rate in such a patient group is high comparing to other approved FGFR inhibitors. Gunagratinib is a promising second-generation FGFR inhibitor with potential for the treatment of multiple indications with FGF/FGFR pathway abnormalities. Clinical trial information: NCT03758664 . [Table: see text]

Updated survival outcomes with ivosidenib in patients with previously treated IDH1-mutated intrahepatic-cholangiocarcinoma: an Italian real-world experience.

The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations. We recently published the first data on the use of ivosidenib in a real-world setting. Here we report the updated survival results of 11 patients with locally advanced or metastatic IDH1-mutated CCA who received ivosidenib in clinical practice. Patients treated with ivosidenib as second- and third-line treatments for advanced CCA have been collected with the aim to evaluate the survival outcomes. A molecular study has been performed by next generation sequencing essay. Overall, 11 patients were included. After a median follow-up of 13.7 months, median progression-free survival from the start of treatment with ivosidenib was 4.4 months (95% CI: 2.0-5.8), whereas median overall survival was 15 months (95% CI: 6.6-15.0) regardless of treatment line. Disease control rate was 63%, with two patients achieving a partial response (18%). Eighteen percent of patients experienced at least one treatment-related adverse events (AEs), but no grade ⩾3 was reported. The most frequently observed grade 2 AEs were prolonged QT interval and hypomagnesemia. A molecular profiling was performed on 8 out of 11 patients, highlighting TP53, BAP1, CDKN2A, and CDKN2B as the most common co-altered genes in these patients. The present update confirms the results of our previous real-world experience on the use of ivosidenib in IDH1-mutated CCA. Real-world evidence on larger numbers of patients is needed to confirm our findings.

Peribiliary gland injury by floxuridine may be an early mechanistic insult en route to sclerosis

Background: Hepatic artery infusion pumps (HAIP) are being increasingly employed in the management of metastatic colorectal cancer and cholangiocarcinoma secondary to encouraging response rates in most patients. However, efficacy is limited in many patients by biliary toxicity, which requires vigilant monitoring of hepatic biochemistry and frequent dose reductions to avoid secondary sclerosing cholangitis. Although dexamethasone is employed to limit this drug-induced adverse event, little is known about the early (and possibly intervenable) mechanism(s) of toxicity. We hypothesize that mitigation of biliary sensitivity to floxuridine (FUDR) will allow patients to receive more FUDR, increasing the oncologic efficacy of therapy while simultaneously minimizing morbidity.

Robotic partial hepatectomy following immunotherapy for advanced intrahepatic cholangiocarcinoma

Background: Metastatic Intrahepatic cholangiocarcinoma (iCCA) carries a poor prognosis, with upfront hepatic resection of the primary tumor contraindicated. Response rates to systemic chemotherapy are low and confer only a modest survival benefit. Next generation sequencing (NGS) is useful for identifying potentially actionable mutations for therapeutic targets. For patients with a high tumor mutational burden, immunotherapy can produce a profound decrease in tumor size and distribution. Immunotherapy for iCCA is growing, and a dramatic response to immunotherapy may downstage previously unresectable iCCA, expanding the role for surgery in this complex biliary malignancy. There are a limited number of case reports describing successful hepatic resection of previously metastatic iCCA after immunotherapy. Herein, we report our experience performing a robotic partial hepatectomy for clearance of the only identifiable active disease 3 years after diagnosis and downstaging of metastatic iCCA with PD-1 blockage for microsatellite high instability (MSI High).

Hematological and biochemical changes in a cow with metastatic cholangiocarcinoma

We describe here hematological and biochemical findings in a cow with metastatic cholangiocarcinoma. On physical examination, apathy with congested mucous membranes, tachycardia and enlarged abdomen; hypoperistalsis in rumen, abomasum and intestines. In hematological examination, icteric plasma with leukocytosis by neutrophilia with regenerative left shift and inversion of the proportion between lymphocytes and segmented neutrophils, and hypofibrinemia. In serum biochemistry: hyperproteinemia, hypoalbuminemia, hyperglobulinemia, low albumin/globulin ratio and high levels of aspartate aminotransferase, gamma-glutamyltransferase. The cow died and in necropsy was observed a severe and diffuse increase in volume predominantly on the hepatic right lobe and moderate increase of volume in mesenteric lymph nodes. Which was diagnosed microscopically as a cholangiocarcinoma, characterized by arrangements in irregular and coalescent ducts. In conclusion, cholangiocarcinoma may cause important hematological and biochemical changes in cattle.

Futibatinib: First Approval.

Futibatinib (Lytgobi®) is an oral, covalently binding, irreversible inhibitor of fibroblast growth factor receptor (FGFR)1-4 that is being developed by Taiho Oncology and Taiho Pharmaceutical for the treatment of cancers, including cholangiocarcinoma, breast cancer, gastric cancer, urothelial cancer, oesophageal cancer and non-small cell lung cancer. Futibatinib was approved in the USA on 30 September 2022 for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harbouring FGFR2 gene fusions or other rearrangements. This article summarizes the milestones in the development of futibatinib leading to this first approval.

Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation.

Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%-50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA. We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues. This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD. Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.

S2027 Extrinsic Compression of the Hepatic Flexure from Metastatic Cholangiocarcinoma Masquerading as Cecal Bascule

Introduction: Cecal bascules are the rarest variant of cecal volvulus that involve upward folding of the cecum, without axial twisting or sigmoid involvement. We present a case in which a patient with a hepatic flexure obstruction from extrinsic compression masqueraded as a cecal bascule on imaging. Case Description/Methods: A 66-year-old woman with history of stroke, hypertension, recent obstructive cholestasis due to choledocholithiasis requiring biliary stent placement, presented with 3 days of right sided abdominal pain, 15lb weight loss and 3 weeks of constipation with thin stools. Computed Tomography (CT) revealed dilated loops of distal small bowel and cecum that folded anteriorly and superiorly with extensive pneumatosis (Figure A), consistent with cecal bascule (type III cecal volvulus). The ascending colon was dilated up to a decompressed hepatic flexure, where nonspecific bowel wall thickening was visualized. She had a normal colonoscopy a few months prior. The patient was initially managed conservatively, however a lower gastrointestinal series showed persistent obstruction at the hepatic flexure with bird-beak appearance (Figure B). She underwent an exploratory laparotomy that discovered a mass in the right upper quadrant involving the gallbladder and liver, causing extrinsic compression of the hepatic flexure and numerous omental nodules. Biopsies confirmed metastatic cholangiocarcinoma. The patient began evaluation for cancer staging, but ultimately passed one month after diagnosis. Discussion: The development of a cecal bascule is usually attributed to an abnormally mobile cecum due to improper development and insufficient fixation of the mesentery to the posterior parietal peritoneum. A mobile cecum may also be acquired in pregnancy due to enlargement of the uterus, or after abdominal surgery such as open appendectomies which require extensive division of peritoneal attachments to the cecum. Clinical presentation can be variable with abdominal pain, distention and nausea being most common symptoms and ranging to an acute abdomen and perforation. Diagnosis of type III cecal volvulus requires CT imaging confirming a distended cecum lying anterior to ascending colon. Treatment generally involves surgical resection of the affected bowel as colonoscopic detorsion may lead to recurrence. This is a unique case of an extrinsic malignant obstruction causing a cecal bascule, highlighting the importance of a comprehensive evaluation for underlying etiologies.Figure 1.: A: Cecal bascule with extensive pneumatosis on CT. B: Lower gastrointestinal series showing obstruction at hepatic flexure with bird-beak appearance.

S2062 Metastatic Cholangiocarcinoma Presenting as Colonic Obstruction: A Case Report

S2062 Metastatic Cholangiocarcinoma Presenting as Colonic Obstruction: A Case Report