Metastatic Cholangiocarcinoma Research Articles

Phase I/II clinical trial of regorafenib plus durvalumab (MEDI4736) in patients with chemotherapy-refractory advanced biliary tract cancers.

TPS581 Background: Biliary tract cancers (BTC) are a heterogeneous group of cancers affecting the epithelial lining of the intra- and extrahepatic portions of the biliary tree, ranking as the second most prevalent primary liver cancer after hepatocellular carcinoma. A subgroup of BTC was found to have an abundant tumor specific neoantigen expression, enriched expression of immune related genes and genes regulating inhibitory immune checkpoint proteins. Recent advancements in BTC treatment include the TOPZ-1 trial, which established the survival advantage of adding durvalumab to the gemzar + cisplatin regimen with an estimated 24-month overall survival rate of 24.9% versus 10.4% for placebo. The hazard ratio for progression-free survival favored durvalumab at 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates also showed improvement, with 26.7% for durvalumab and 18.7% for placebo. Furthermore, single agent regorafenib has exhibited efficacy in patients with refractory advanced metastatic cholangiocarcinoma, particularly in terms of progression-free survival, favoring regorafenib over placebo, the overall toxicity profile was as expected. Regorafenib targets multiple tyrosine kinases and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with checkpoint inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like regorafenib will have synergistic effect when combined with checkpoint-based immunotherapy like durvalumab in patients with chemo refractory BTC. Methods: This study comprises a single-arm, unblinded Phase I/II trial designed to assess the safety and efficacy of the combination therapy involving regorafenib and durvalumab in patients with chemo-refractory advanced BTC. The Phase I portion employed a 3 + 3 design with two dose levels of regorafenib (80 mg and 120 mg) administered in conjunction with 1500 mg IV durvalumab every 28 days. Phase I successfully completed, and the Data Monitoring Committee (DMC) endorsed the continuation of the trial as planned. Eligibility: Histologically confirmed unresectable or metastatic disease. Progressed on at least one line of therapy. May have received checkpoint inhibitor in the past. Inclusion criteria also include ECOG PS 0-1. Objectives:Primary Phase I: Safety of regorafenib in combination with durvalumab.Phase II: Progression-free survival (PFS).Secondary:Disease Control Rate (DCR), Overall response rate (ORR), Overall survival (OS). Statistical Plan: Interim futility testing after one year, halting if conditional power < 20%. Final analysis: PFS and OS via Weibull Regression. Enrollment is currently ongoing with 8 out of 40 patients enrolled.

Pemigatinib: A Review in Advanced Cholangiocarcinoma.

Pemigatinib (Pemazyre®), a selective, potent, reversible, oral inhibitor of fibroblast growth factor receptor (FGFR) 1-3, has received conditional (in the EU) or accelerated (in the USA) approval for the treatment of adults with previously treated, unresectable locally-advanced or metastatic cholangiocarcinoma (CCA) with an FGFR2 gene fusion or rearrangement. Over the course of a single-arm, phase 2 study (FIGHT-202), just over a third of patients with pretreated, advanced CCA [almost exclusively intrahepatic CCA (iCCA)] harbouring an FGFR2 fusion or rearrangement who received pemigatinib once daily (2 weeks on, 1 week off) had an objective response; nearly half had stable disease. Median progression-free survival and overall survival at the time of the final analysis were 7.0 months and 17.5 months, respectively. Pemigatinib was generally well tolerated and had a manageable safety profile. The most common treatment-related adverse event, hyperphosphataemia, was exclusively grade 1-2 in severity and, similarly, observed ocular and nail toxicities were rarely grade ≥3 in severity. Pending confirmation of its clinical benefits in an ongoing cisplatin plus gemcitabine-controlled, phase 3 study (FIGHT-302), pemigatinib provides a valuable targeted therapy for pretreated patients with advanced (i)CCA harbouring a FGFR2 fusion or rearrangement.

Locoregional therapy combined with systemic therapy (LRT + ST) for unresectable and metastatic intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

The outcome of systemic therapy (ST) for unresectable and metastatic intrahepatic cholangiocarcinoma (iCCA) is poor. This study aims to further evaluate the efficacy and safety of locoregional therapy combined with systemic therapy (LRT + ST) compared with only ST in unresectable and metastatic iCCA by performing a systematic literature review and meta-analysis. A comprehensive search was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 3, 2022. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Ten retrospective cohort studies with 3,791 unresectable or metastatic iCCA patients were enrolled in this study, including 1,120 who received ablation, arterially directed therapy (ADT), or external beam radiation therapy (EBRT) combined with ST. The meta-analysis showed that the LRT + ST group had a better OS (HR = 0.51; 95% CI =0.41-0.64; p value < 0.001), PFS (HR = 0.40, 95% CI = 0.22-0.71, p value = 0.002) and ORR (RR = 1.68; 95% CI = 1.17-2.42; p value = 0.005). Subgroup analysis showed that both ST combined with ADT (HR = 0.42, 95% CI = 0.31-0.56, p value < 0.001) and EBRT (HR = 0.67, 95% CI = 0.63-0.72, p value < 0.001) could improve OS. Neutropenia, thrombocytopenia, anemia, anorexia, and vomiting did not show significant differences between the groups (p value > 0.05). Compared with only ST, LRT + ST improved survival outcomes for unresectable and metastatic iCCA patients without increasing severe AEs, which can further provide a basis for guidelines.

Liquid Biopsy: A Highly Useful Tool to Decide Personalized Therapy in Veteran Patients with Metastatic Pancreaticobiliary Cancer

Abstract Introduction/Objective Pancreatic cancer is one of the leading causes of death in Veteran patients. Early detection and treatment of the pancreatic cancers are key to the successful management of pancreatic cancer with good patient outcome. The National Comprehensive Cancer Network (NCCN) recommends tumor molecular profiling in all patient cases of unresectable or metastatic pancreatic adenocarcinomas and biliary tract cancers who are candidates for chemotherapy. This testing can be performed using liquid biopsy to obtain this molecular profiling from circulating tumor cells (CTC) to obtain information that may impact treatment. However, the literature of metastatic pancreaticobiliary cancers targeted by liquid biopsies and the mutations found is sparse, particularly for the veteran population. Methods/Case Report A retrospective review was performed of all patients with a submitted liquid biopsy specimen at a Veteran Affairs Medical Center (VAMC) from April 2020 to March 3rd, 2023, to examine those patients with metastatic pancreaticobiliary cancers, specifically pancreatic adenocarcinoma, and cholangiocarcinoma. Information on mutations detected was collected. Results (if a Case Study enter NA) There were a total of 5 patient specimens with a history of metastatic pancreatic adenocarcinoma (4 cases/5) and cholangiocarcinoma (1 case/5). The first liquid biopsy from a patient with a history of metastatic pancreaticobiliary cancer was sent on April 14th, 2020, and the last was sent on November 12th, 2021. TP53 was detected on all the successfully tested pancreatic adenocarcinoma cases. Other mutations detected in the individual pancreatic adenocarcinoma cases were KRAS, TET2 BCOR, DNMT3A, FUBP1, RAD21, and STAG2. The mutations found on the single cholangiocarcinoma case included DNMT3A and TP53. 1 of the 4 cases sent on a patient with pancreatic adenocarcinoma resulted in a sample failure. Conclusion Liquid biopsies provided comprehensive molecular profiling in cases of metastatic pancreatic adenocarcinoma and biliary tract cancer in the veteran population treated at a local VAMC to help decide on personalized therapy, in compliance with the recommendations of the NCCN. The results of this pilot quality assurance study help highlight the potential of liquid biopsies to detect most commonly mutated genes such as KRAS and T53 in pancreatic cancer.

Second-Line Chemotherapy for Intrahepatic Cholangiocarcinomas: What Is the Real Gain?

The presence of actionable alterations in advanced biliary tract cancer patients opened new therapeutic possibilities for second-line treatments. However, for around 60% of the patients, chemotherapy remains the only therapeutic option. The aim of our study was to evaluate outcomes and prognostic parameters in patients with intrahepatic cholangiocarcinomas treated with second-line chemotherapy. A total of 255 consecutive metastatic intrahepatic cholangiocarcinoma (ICC) patients were retrospectively reviewed and clinicopathologic and survival data were collected. Fourty-four percent of ICC patients underwent second-line chemotherapy. In particular, younger ICC patients with better ECOG PS status, and with disease control after first-line chemotherapy were those who were treated with second-line treatments. Median progression-free survival in the patients treated with second-line chemotherapy was 3 months. Finally, the patients affected by intrahepatic cholangiocarcinoma with better ECOG PS, with prior surgical resection of the primary tumor, who responded to first-line chemotherapy, and had better progression-free survival with second-line chemotherapy, were associated with better outcomes in multivariate analysis. Not all patients seem to benefit from second-line chemotherapy. To improve therapeutic decisions, performance status and disease control with first-line chemotherapy should lead to the decision on the usefulness of second-line treatments in advanced ICC patients.

THU373 Refractory Hypoglycemia In A Patient With Metastatic Cholangiocarcinoma: Abstract

Abstract Disclosure: M.G. Fernandez: None. D.J. Selen: None. Background: Nonislet cell tumor hypoglycemia is an uncommon but severe complication of cancer. It results from tumoral overproduction of insulin-like growth factor 2 (IGF-2), which inhibits hepatic glycogenolysis and the release of glucagon and growth hormone (GH). These three mechanisms can result in severe and refractory hypoglycemia. Clinical Case: We present a case of a 57-year-old female newly diagnosed with metastatic cholangiocarcinoma who was admitted to the hospital after an episode of syncope at home in the setting of hypoglycemia with a serum blood glucose of 17 mg/dL (N &amp;gt;60 mg/dL). During the hospital admission, evaluation of hypoglycemia included a normal TSH of 1.170 (reference range [RR] 0.3-5.5 mIU/ml), fasting morning cortisol of 23.3 (RR &amp;gt;14-15 μg/dL), and a negative sulfonylurea screen. In addition, the patient had an undetectable level of Insulin &amp;lt;3.0 (RR 3-25 mU/L), Beta-hydroxybutyrate &amp;lt;0.10 (RR 0.02-0.27 mMol/L), C-peptide &amp;lt;0.1 (RR 0.5-3.3 ng/ml), and Pro-insulin &amp;lt;1.6 (RR 3-20 pmol/L). CT of the abdomen revealed disease progression with innumerable bilateral enhanced hypoattenuating masses in the liver. Management for refractory hypoglycemia required nutrition optimization, nausea control, close glucose monitoring, IV dextrose infusion, and intermittent intravenous glucagon for episodes of severe hypoglycemia (&amp;lt;40 mg/dL). During the hospitalization, the patient received the first cycle of chemotherapy with gemcitabine, cisplatin, and dexamethasone. On day 10 of admission, the IGF-2 resulted at 120 ng/ml (RR 180-580ng/ml) and IGF-1&amp;lt;10 (RR 50-317 ng/ml) with an IGF-2/IGF-1 ratio greater than 100 (cut off&amp;gt;10), diagnostic of a large nonislet cell tumor as the most likely cause of her severe hypoglycemia. Artificial nutrition did not align with this patient’s goals of care, so she was discharged from the hospital with a FreeStyle Libre 2 for continuous glucose monitoring. However, two weeks later, she returned to the emergency department with hypoglycemia (&amp;lt;40 mg/dL), ultimately choosing to pursue hospice. Conclusion: Patients with large liver tumor burden can experience hypoglycemia due to low glycogen content in the liver. In addition, these patients can have decreased oral intake and weight loss, which confounds the clinical scenario and can delay diagnostic workup. Patients with refractory hypoglycemia and nonislet cell tumors require further evaluation for IGF-2 production, and alternative temporary nutritional options should be discussed with the patient immediately. Therapeutic options depend on the ability to treat underlying cancer. Palliative chemotherapy, surgery, or radiation can be considered to control the tumor and improve hypoglycemia for quality of life when the cancer is otherwise untreatable. Presentation: Thursday, June 15, 2023

FRI553 ICI-induced Thyroid Ophthalmopathy With De Novo Graves’ Disease

Abstract Disclosure: S.I. Moctezuma: None. J. Perlman: None. J.S. Mammen: None. Background: Immune checkpoint inhibitors frequently target the thyroid gland. However, immune checkpoint inhibitor (ICI)-induced Graves’ disease (GD) is rare. To our knowledge, there are no reported cases of thyroid eye disease after immune checkpoint inhibitor therapy in patients with newly positive anti-thyroid antibodies. Clinical Case: An 81-year-old man developed thyroiditis within three weeks of a single dose of ipilimumab/nivolumab for the treatment of metastatic cholangiocarcinoma. ICI therapy was discontinued for cardiotoxicity. He presented one year later with onset of periorbital edema, pain with downgaze, redness, irritation and progressive proptosis with diplopia. He did not have a prior history of thyroid disease. Thyroid function tests before the start of ICI therapy revealed euthyroidism [TSH 2.982 uIU/mL (0.55 - 4.78)]. Symptoms of palpitations, weight loss, and hyper-defecation that characterized his initial presentation with thyroiditis were absent at the time of onset of eye disease. At presentation of thyrotoxicosis his TSH was &amp;lt;0.01 uIU/mL, free T4 3.6 ng/dL (0.89 - 1.76) total T3 190 ng/dL (60-180) Thyroid-peroxidase autoantibodies (TPOAb) and thyroid-stimulating immunoglobulin (TSI) were negative. When his visual symptoms appeared, TPOAb remained negative while a repeat TSI antibody was positive [0.64 IU/L (0.00 - 0.55)]. Thyroid ultrasound at the time of thyroiditis revealed a heterogeneous gland without discrete nodules and a normal vascular flow. Most cases of ICI-induced GD have been reported at the start of therapy, particularly in the first 6 weeks, although thyrotoxicosis has been described to occur as late as 224 days after starting PD-1 inhibitor. GD is more frequently reported with combination anti-CTLA-4 and anti-PD-1 therapy. Patients with thyroid ICI-induced adverse events experience either isolated hypothyroidism or thyroiditis spontaneously evolving towards hypothyroidism. However, ICI-induced GD is more likely to have a relapsing-remitting disease. In 2021, Peiffert et al. described the antibody profile for 243 patients with ICI-induced thyrotoxicosis. In this case series, 5 patients developed thyrotoxicosis with positive thyrotropin-receptor antibodies (TRAb). Only 2 patients had a typical clinical presentation of GD. TSI antibodies were not reported. Furthermore, none of the patients with positive TRAb had Graves’ ophthalmopathy. Conclusion: Our case demonstrates the acquisition of auto-antibodies capable of mediating Graves’ disease, and raises the possibility that thyroid eye disease-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy. These symptoms developed as late as one year after initiation of therapy. As with sporadic cases, this can occur in the absence of clinically significant hyperthyroidism. Presentation: Friday, June 16, 2023

Enhancement Patterns of Metastatic Intrahepatic Cholangiocarcinoma and Outcomes after Chemotherapy and Radiation

Patients with metastatic intrahepatic cholangiocarcinoma (M1-iCCA) have a poor prognosis with a 5-year survival rate of less than 20%. Definitive doses of radiation therapy (RT) after upfront chemotherapy (chemo/RT) in this patient population have shown to prolong survival by reducing the risk of tumor-related liver failure compared to chemotherapy alone. Our group has also identified a baseline radiographic feature, the arterial enhancement pattern, which has pathological and prognostic associations for iCCA. We tested the hypothesis that baseline arterial enhancement is independently associated with survival outcomes for patients who receive chemo/RT or chemo alone. Patients with M1-iCCA from 2010 to 2021 were included in this retrospective study. Patients were grouped into those who underwent chemo alone and those who underwent chemo/RT. The inclusion criteria included confirmed diagnosis of M1-iCCA, availability of baseline multi-phasic computed tomography (CT), and follow-up for at least six months or until death. Tumor arterial enhancement patterns were categorized as previously described into hypovascular or hypervascular, where the tumors that were hypervascular had either peripheral enhancement or central enhancement.Mean tumor density in Hounsfield units was recorded for each patient. Survival was estimated using the Kaplan Meier method, and Cox proportional models were used to adjust for prognostic variables. A total of 281 patients with iCCA were identified and 229 had evaluable CT scans. Demographic and baseline characteristics of patient groups are shown in the Table. On univariate analysis, patient age, ECOG performance status (PS) at diagnosis, treatment type, and arterial enhancement patterns associated with overall survival (OS). On multivariable analysis, the arterial enhancement pattern independently associated with OS after accounting for covariates. Patients with hypervascular tumors had prolonged OS compared to those with hypovascular tumors (HR = 0.72, [0.54 - 0.96], p = 0.02). Prolonged OS was also observed in the chemo/RT group compared to the chemo alone group (HR = 0.37, [0.25-0.54], p< 0.0001). Baseline enhancement patterns of M1-iCCA were prognostic in the contexts of chemo alone and chemo/RT.This imaging-based biomarker may improve the ability to stratify patients for therapeutic management.

Pharmacovigilance Study of Infigratinib: A Safety Analysis of the FDA Adverse Event Reporting System.

Infigratinib is a fibroblast growth factor receptor (FGFR)-specifc tyrosine kinase inhibitor indicated for the treatment of patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. However, few studies have been conducted to evaluated the safety of infigratinib in the real world. In this study, we conducted a pharmacovigilance study to evaluate the adverse events (AEs) of infigratinib by using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. OpenVigil 2.1 was employed to extract the FAERS database. Descriptive analysis was used to describe the characteristics of infigratinib-associated AE reports. Disproportionality analysis was performed by calculating the proportional reporting ratio (PRR), reporting odds ratios (ROR), and Bayesian analysis confidence propagation neural network (BCPNN) to detect positive signals. Our findings revealed 149 AE reports, among which 36 significant signals were identified. These significant AE signals were mainly observed in gastrointestinal disorders (N=26, ROR=26.03, PRR=8.44, information component [IC]=3.08) and skin and subcutaneous tissue disorders (N=21, ROR=92.13, PRR=40.41, IC=5.34). Notably, dehydration and skin exfoliation were unexpected AEs, but had relatively high signal intensities (ROR=29.75, PRR=26.64, IC=4.74; ROR=50.61, PRR=45.24, IC=5.50, respectively) despite not being listed on the drug label. Furthermore, our analysis showed that infigratinib dose differed statistically between severe and non-severe reports (113.82±16.13mg vs 125±0.00 mg, t= - 4.28; p<0.001). However, there were no significant differences in sex, age, and types of AEs between the two groups (p =0.06, p =0.86, and p=0.93, respectively). These findings suggest that gastrointestinal and skin toxicities are the most common adverse reactions for infigratinib. It is important to recognize skin exfoliation and dehydration in clinical practice, as they are unexpected AEs. Additionally, our study indicates that infigratinib dose may correlate with an increased risk of AE severity, highlighting the need for dose adjustment of infigratinib when exposure to the drug is increased due to internal or external factors.

Transarterial chemoembolization plus lenvatinib with or without a PD-1 inhibitor for advanced and metastatic intrahepatic cholangiocarcinoma: a retrospective real-world study.

Most patients with intrahepatic cholangiocarcinoma (ICC) present with locally advanced or metastatic disease. We report the combined potency of transarterial chemoembolization (TACE), lenvatinib and programmed cell death-1 (PD-1) inhibitors in patients with advanced and metastatic ICC. This retrospective study enrolled 32 patients with advanced or metastatic ICC between January 2017 and August 2021. Eligible patients had received gemcitabine-based TACE combined with lenvatinib with or without PD-1 inhibitor in any line of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Risk factors associated with OS were assessed using univariate and multivariate Cox regression analyses. Eighteen patients received a combination of TACE and lenvatinib (TL group) and 14 patients received TACE and lenvatinib plus aPD-1 inhibitor (TLP group). The median follow-up time was 19.8 months (range 1.8-37.8). The median OS was 25.3 months (95% CI 18.5-32.1) and the median PFS was 7.3 months (95% CI 4.9-9.7). Partial response was achieved in 10 patients (31.3%), and stable disease in 13 (40.6 %) with disease control rate of 71.9%. The median OS was comparable in the TL and TLP groups (22.4 vs 27.3 months, respectively; hazard ratio: 1.245, 95% CI 0.4245-3.653; p = 0.687). The regression analysis revealed that, regardless of treatment group, a favorable independent prognostic factor for OS was HBV/HCV infection (HR: 0.063, 95% CI 0.009-0.463; p = 0.007). There were no treatment-related deaths and 81.3% of study participants experienced adverse events (AEs), the majority of which were of moderate severity (71.8% Grade 1-2). Gemcitabine-based TACE plus lenvatinib with or without aPD-1 inhibitor was well tolerated and provided promising therapeutic outcomes for patients with advanced and metastatic ICC. Monotherapy with TACE, or Lenvatinib, or PD-1 inhibitors has shown limited efficacy over standard first-line chemotherapy in advanced and metastatic ICC. This work suggested the combined potency of these treatments and well-tolerance.

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date.

Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p < 0.0001) and overall survival (OS), median OS was 10.8 months for ivosidenib and 9.7 months for the placebo arm (p = 0.06) for patients with previously treated and IDH1 mutated cholangiocarcinoma. In this review article, we will address the mechanism of action of ivosidenib and data from early trials and safety from the randomized trial in cholangiocarcinoma. As a conclusion, future perspectives of IDH1 inhibition in IDH1 mutated tumors and possible strategies of sequencing and combinations will be reviewed and discussed.

Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement.

Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.

Histological and immunohistochemical features of carcinomas with pulmonary involvement in cattle.

Primary pulmonary neoplasms in cattle are rare. There are few studies on the pathological findings of these neoplasms in this species. This study aimed to describe the histological and immunohistochemical findings of primary and metastatic pulmonary carcinomas in cattle. We conducted a retrospective study of 19 cases of epithelial neoplasms with pulmonary involvement. Histologically, most of the neoplasms were classified as primary pulmonary neoplasms, including different adenocarcinoma subtypes (4/19, 21%) and adenosquamous carcinomas (3/19, 16%), followed by squamous cell carcinoma (6/19, 32%), metastatic uterine adenocarcinoma (4/19, 21%), metastatic hepatocellular carcinoma (1/19, 5%), and metastatic cholangiocarcinoma (1/19, 5%). By immunohistochemistry, all neoplasms were positive for pancytokeratin, and 4/19 (21%) were positive for vimentin. Primary pulmonary neoplasms had immunoreactivity for thyroid transcription factor-1 (6/7), while only 2 of these cases were positive for napsin A. All cases with squamous differentiation (9/9) had immunoreactivity for cytokeratin (CK) 5/6, while only 7 of these cases were positive for p40. CK20, CK7, and CK8/18 showed varied immunoreactivity in the primary and metastatic pulmonary carcinomas but were important markers to confirm the diagnosis of primary mucinous adenocarcinoma and metastatic cholangiocarcinoma. HepPar-1 was only positive in the metastatic hepatocellular carcinoma. The limited number of cases of metastatic uterine adenocarcinomas in this study precluded identification of a specific immunophenotype for this tumor. Immunohistochemistry proved to be an important tool to confirm the proper classification of these neoplasms.

Efficacy of fibroblast growth factor receptor (FGFR) inhibitors therapy in advanced cholangiocarcinoma with FGFR genes alterations: A meta-analysis of phase II clinical trials.

54 Background: Fibroblast growth factor receptor ( FGFR) gene fusions and rearrangements are involved in the pathogenesis of approximately 10 to 16 percent of patients with cholangiocarcinoma. There is no meta-analysis available of phase 2 clinical trials of FGFR inhibitors in these patients. In this article, we analyze the efficacy of FGFR inhibitors in advanced cholangiocarcinoma with FGFR gene fusions or other rearrangements. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were Objective response rate (ORR), Disease control rate (DCR), Progression-free survival (PFS), and Overall survival (OS). We calculated the pooled ORR for these studies by using weighted average ORR = Σ (ORR_i * weight_i). Calculate the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). However, it is important to note that the pooled ORR is only as reliable as the individual ORR estimates from each study and may be subject to bias or confounding factors. This method was used to calculate the pooled DCR, PFS, and OS for our study as well. All data extraction and calculations were verified by three reviewers. Results: Eight phase II clinical trials met the inclusion criteria (1-8). Outcome data were available for all eight studies, comprising 562 patients with FGFR-positive advanced cholangiocarcinoma who received FGFR-targeted treatment regimens. The pooled objective response rate (ORR) and disease control rate (DCR) were 32.6% (95% CI 28.1-37.1) and 81.86% (95% CI 74.96-88.76), respectively. The pooled weighted progression-free survival (PFS) was 7.5 months, and pooled overall survival (OS) was 17.4 months. These findings suggest that FGFR-targeted treatment regimens have a promising ORR, DCR, PFS, and OS. Conclusions: FGFR inhibitors as a class in patients with advanced or metastatic cholangiocarcinoma with FGFR gene alterations showed clinically meaningful efficacy with durable objective responses. [Table: see text]

Futibatinib (Lytgobi®)

Futibatinib (Lytgobi®)

RNA sequencing as a confirmatory assay and its impact on patient care in multiple cancer types.

e15058 Background: Increasing evidence shows the ability of RNA sequencing (RNA-seq) to detect expression of multiple biomarkers with improved sensitivity and scalability, offering a more objective and reproducible interpretation of data compared to pathological assessment methods by immunohistochemistry (IHC). Further, ongoing research demonstrating strong correlation between RNA-seq gene expression values and IHC values suggests the utility of RNA-seq as an objective diagnostic approach. Here, we highlight 4 cases where discordance in expression levels measured by IHC and RNA-seq resulted in re-evaluation of IHC values and a subsequent change in the clinical course. Methods: All patients underwent RNA and DNA sequencing of tumor tissue as part of a standard-of-care workflow. Sequencing was performed and reported with the BostonGene Tumor Portrait test, utilizing whole-exome sequencing (WES) and transcriptome sequencing data for tumor analysis. Gene expression levels were evaluated by comparison to a reference cohort of patients with a similar diagnosis. Results: In one case, a 53-year-old female was diagnosed with metastatic cholangiocarcinoma. While IHC of her biopsy reported positive HER2 (+3) expression, RNA-seq revealed low expression. A repeated IHC assay confirmed negative HER2 expression, leading to a change in therapy options. Another 61-year-old female was diagnosed with triple negative breast cancer (TNBC) (IHC: ER 0%, PR 0%, HER2 1+). Integrated WES and RNA-seq analysis detected HER2 amplification (+8 copies), ERBB2-activating mutation, high ERBB2 (HER2) expression and a HER2-enriched PAM50 subtype. IHC was repeated, now showing positive HER2 (+3) expression. In order to target HER2, systemic treatment was changed to a combination containing trastuzumab and pertuzumab, resulting in pathological complete response. In the third case of an 85-year-old female with relapsed TNBC, IHC demonstrated 1% PDL-1 staining. In contrast, RNA-seq detected high PD-L1 expression leading the treating physician to repeat IHC. Staining showed high PDL-1 (CPS50), prompting a change in therapy to an anti-PDL-1 (pembrolizumab) therapy. Lastly, while IHC of a 21-year-old female diagnosed with diffuse large B-cell lymphoma (DLBCL) showed negative CD30, subsequent RNA-seq detected relatively high CD30 expression that prompted a second IHC evaluation confirming positive CD30 expression. Eventually, the diagnosis was changed to primary mediastinal B-cell lymphoma and DA-EPOCH was selected as the therapy. Conclusions: RNA-seq is emerging as an objective tool to evaluate key diagnostic and targetable events in multiple cancer types. The use of RNA-seq can also add value as an objective measurement to confirm critical IHC findings, potentially changing clinical care.

Tumor agnostic efficacy and safety of erdafitinib (erda) in patients (pts) with advanced solid tumors with prespecified FGFR alterations (FGFRalt): RAGNAR primary analysis.

3121 Background: FGFRalt are present across malignancies at various frequencies and may act as oncogenic drivers across tissue histology. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor with activity and safety in pts with prespecified FGFR-altered locally advanced or metastatic urothelial carcinoma (UC) and cholangiocarcinoma . RAGNAR (NCT04083976) is an ongoing phase 2 open-label, single-arm tumor agnostic trial of erda in pretreated adult and pediatric pts with FGFRalt advanced solid tumors. Interim results showed erda clinical benefit, with an objective response rate (ORR) of 29.2%. Here we report results of the primary analysis. Methods: Pts aged ≥12 y with advanced or metastatic (non-UC) tumors of any histology with predefined FGFR1-4alt (mutations/fusions per local/central test), disease progression on ≥1 prior line of systemic therapy (tx), and no alternative standard tx received oral erda until disease progression or intolerable toxicity. The primary end point was ORR by independent review committee (IRC). Secondary end points included duration of response (DOR), disease control rate (DCR [CR + PR + SD]), clinical benefit rate (CBR [CR + PR + SD &gt;4 mo]), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff, 217 pts were treated, median age was 57.0 y (range, 12-79), median prior systemic tx was 2 (46%; ≥3 lines of tx) with an ORR to last line prior to study entry of 10.1%. ORR to erda tx by IRC was 29.5% (95% CI, 23.5-36.0) with 6 CRs (2.8%) and 58 PRs (26.7%) in 16 distinct tumor types, including advanced CNS, thoracic, gastrointestinal, gynecologic, and rare tumors. ORR was comparable across FGFR1-3 mutations (25.3% [95% CI, 16.0-36.7]) and fusions (32.6% [95% CI, 25.1-40.9]). Median DOR, PFS, and OS were 6.9 mo (95% CI, 4.4-7.1), 4.2 mo (95% CI, 4.1-5.5), and 10.7 mo (95% CI, 8.7-12.1), respectively; DCR was 73.7% and CBR was 45.6%. 99.5% of pts experienced TEAEs, including 70.0% with grade ≥3. Treatment-related serious AEs occurred in 8.3% of pts with no treatment-related deaths. Conclusions: Primary analysis results from RAGNAR, the largest tumor agnostic trial of targeted tx to date, confirm efficacy of erda in heavily pretreated pts with FGFRalt advanced solid tumors. Erda activity was observed in adults and adolescents across tumor types, and across FGFR1-3 gene mutations and fusions. Erda tolerability was consistent with its known safety profile. Clinical trial information: NCT04083976 . [Table: see text]

Cavernous sinus syndrome as the first presenting sign of metastatic cholangiocarcinoma

Cholangiocarcinoma is poorly treatable and highly lethal adenocarcinoma of the hepatobiliary system. The incidence of brain metastases was 0.15%, 0.47% and 1.4% in three large case series. Cavernous sinus syndrome (CSS) refers to any disease involving the cavernous sinus. It is characterized by ophthalmoplegia, proptosis, chemosis, but also trigeminal sensory loss and Horner’s syndrome. We report the case of a 56-year-old Caucasian woman evaluated due to partial Horner syndrome, periorbital and retroorbital unilateral moderate-to-severe headache involving the left frontal and temporal areas of about 2 weeks duration.

Metastatic intrahepatic cholangiocarcinoma: a “made to measure” treatment?

Metastatic intrahepatic cholangiocarcinoma: a “made to measure” treatment?

Future liver remnant augmentation preceding ex vivo hepatectomy with IVC replacement: a strategy to achieve R0 margins.

Ex vivo hepatectomy with autotransplantation (EHAT) provides opportunity for R0 resection. As EHAT outcomes after future liver remnant (FLR) augmentation techniques are not well documented, we examine results of EHAT after augmentation for malignant tumors. Retrospective analysis of six cases of EHAT was performed. Of these, four occurred after preoperative FLR augmentation between 2018 and 2022. Six patients were offered EHAT of 26 potential candidates. Indications for resection were involvement of hepatic vein outflow and inferior vena cava (IVC) with metastatic colorectal carcinoma (n = 3), cholangiocarcinoma (n = 2), or leiomyosarcoma (n = 1). Five patients were treated with neoadjuvant chemotherapy and four had preoperative liver augmentation. One hundred percent of cases achieved R0 resection. Of the augmented cases, three patients are alive after median follow-up of 28 months. Postoperative mortality due to liver failure was 25% (n = 1). For select patients with locally advanced tumors involving all hepatic veins and the IVC for whom conventional resection is not an option, EHAT provides opportunity for R0 resection. In addition, in patients with inadequate FLR volume, further operative candidacy with acceptable results can be achieved by combined liver augmentation techniques. To better characterize outcomes in this small subset, a registry is needed.