Metastatic Intrahepatic Cholangiocarcinoma Research Articles

Pharmacological Profile of Novel Anti-cancer Drugs Approved by USFDA in 2022: A Review.

For any drug molecule, it is mandatory to pass the drug approval process of the concerned regulatory authority, before being marketed. The Food and Drug Administration (FDA), throughout the year, approves several new drugs for safety and efficacy. In addition to new drug approvals, FDA also works on improving access to generic drugs, aimed to lower the cost of drugs for patients and improve access to treatments. In the year 2022 twelve new drug therapies were approved for managing varying cancers. This manuscript is focused to describe the pharmacological aspects including therapeutic uses, mechanisms of actions, pharmacokinetics, adverse effects, doses, indication for special cases, contraindications, etc., of novel FDA-approved anticancer drug therapies in the year 2022. FDA has approved about 29% (11 out of 37) novel drug therapies for varying types of cancers such as lung cancer, breast cancer, prostate cancer, melanoma, leukemia, etc. The Center for Drug Evaluation and Research CDER has reported that 90% of these anticancer drugs (e.g. Adagrasib, Futibatinib, Mirvetuximabsoravtansinegynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Olutasidenib, Pacritinib, Tebentafusp-tebn, Teclistamab-cqyv, and Tremelimumab-actl) as orphan drugs and recommended to treat rare or uncommon cancers such as non-small cell lung cancer, metastatic intrahepatic cholangio-carcinoma, epithelial ovarian cancer, follicular lymphoma, metastatic melanoma, metastatic uveal melanoma, etc. CDER has identified six anticancer drugs (e.g. Lutetium (177Lu)vipivotidetetraxetan, Mirvetuximabsoravtansine- gynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Tebentafusp-tebn, Teclistamab-cqyv) as first-in-class drugs i.e. drugs having different mechanisms of action from the already existing ones. The newly approved anticancer drugs shall provide more efficient treatment options for cancer patients. Three FDA-approved anticancer drugs in the year 2023 are also briefly described in the manuscript. This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality.

The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

Establishment and external validation of prognosis prediction nomogram for patients with distant metastatic intrahepatic cholangiocarcinoma: based on a large population

BackgroundMost patients with intrahepatic cholangiocarcinoma (ICC) have developed distant metastasis at the time of diagnosis, while there is rear related nomogram to predict the prognosis.MethodsClinical data of patients pathologically diagnosed of ICC with distant metastasis were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database during 2005 to 2019. Finally, patients diagnosed as ICC in the Second Affiliated Hospital of Nanchang University from 2014 to 2019 were collected for external verification. All data were divided into training cohort and validation cohort in a ratio of 7:3. The nomogram was established based on independent prognostic factors using Cox univariate and multivariate analyses. The area under the receiver operating characteristic (ROC) curves (AUC), the calibration curve and the decision curve analysis (DCA) were used to determine the prediction accuracy of the nomogram.ResultsThis study finally included 572 ICC with distant metastasis patients, another 32 patients collected by the author’s hospital were used as external verification. Results showed that age, surgery, radiotherapy and chemotherapy were independent prognostic factors, and nomogram was established. The AUC of predicting 3, 6, 9-month overall survival were 0.866, 0.841 and 0.786. The ROC curves and calibration curves showed that the nomogram had good predictive accuracy, and DCA showed that the nomogram had good clinical applicability.ConclusionsThe nomogram has good accuracy in predicting prognosis of DM-ICC patients, which would be of good significance to improve the prognosis of these patients.

Futibatinib: A Potent and Irreversible Inhibitor of Fibroblast Growth Factor Receptors for Treatment of the Bile Duct Cancer.

Cholangiocarcinoma is a rare type of cancer. Futibatinib is an irreversible, potent, selective inhibitor of fibroblast growth factor receptors (FGFR 1-4). On September 30, 2022, the US FDA first approved futibatinib to treat adult patients with bile duct cancer whose disease is unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2</i>) gene mutations or other classes of rearrangements. The approval of this medicine was based on phase 3 clinical trial results including an overall response rate (ORR) of 42% and a duration of response (DoR) of 9.7 months. This short perspective summarizes Futibatinib's synthesis, physicochemical properties, dosage, route of administration, mechanism of action, binding mode, pharmacodynamics, pharmacokinetics, drug interactions, adverse events, and possible mechanism of resistance.

Clinical management of intrahepatic cholangiocarcinoma: surgical approaches and systemic therapies.

Intrahepatic cholangiocarcinoma (ICCA) is a rare and aggressive malignant tumor that arises from the biliary tracts in the liver. Upfront surgery with adjuvant capecitabine in patients with resectable disease is often the standard treatment. Unfortunately, only 20% of patients present with resectable disease and many individuals will develop recurrence or metastatic disease after curative-intent resection. Patients with advanced or metastatic ICCA often require multidisciplinary care with a combination of cytotoxic chemotherapy, targeted therapy, and/or locoregional therapies. Gemcitabine plus cisplatin is currently first line therapy for advanced or metastatic ICCA. In recent years, efforts have been focused to develop more effective targeted therapy, most commonly with FGFR and IDH inhibitors for ICCA. Despite these efforts, ICCA still carries a poor prognosis. We herein review the current clinical management of ICCA focusing on surgical technique and systemic therapies.

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.

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.

IL-8 is a novel prometastatic chemokine in intrahepatic cholangiocarcinoma that induces CXCR2-PI3K/AKT signaling upon CD97 activation

Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive malignant tumor arising within the liver, with a 5-year survival rate of only 20–40% after surgery. The role of interleukin-8 (IL-8) in ICC progression remains elusive. A transcriptomic approach based on IL-8 stimulation first revealed significant upregulation of the prometastatic gene CD97 and key epithelial–mesenchymal transition (EMT) factors E-cadherin and vimentin. Immunohistochemistry of 125 ICC tissues confirmed the positive correlation between IL-8 and CD97. Multivariable Cox regression indicated that they are both independent predictors of ICC prognosis. Mechanistically, IL-8 treatment induced CD97 expression at 50 and 100 ng/ml in QBC-939 and QBE cells, respectively. Moreover, the induction of cell migration and invasion upon IL-8 treatment was attenuated by CD97 RNA interference, and the expression of EMT-associated genes was dramatically inhibited. To determine whether CXCR1 or CXCR2 are downstream effectors of IL-8, siCXCR2 was applied and shown to significantly attenuate the oncogenic effects of IL-8 by inhibiting the phosphorylation of PI3K/AKT. Finally, the induction of CD97 expression by the PI3K pathway was verified by treatment with the inhibitor LY294002. In vivo, the significant tumor growth and lung metastasis effects induced by intraperitoneal injection of IL-8 were greatly inhibited by silencing CD97 in nude mice. Collectively, the study presents a novel mechanism of the IL-8-CXCR2-PI3K/AKT axis in regulating CD97 expression, which leads to ICC metastasis mainly through EMT. The study may provide alternatives for targeting the tumor microenvironment in metastatic ICC.

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.

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.

Futibatinib (Lytgobi®)

Futibatinib (Lytgobi®)

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

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

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 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 &amp;gt; 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.

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.

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.

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).

Surgical management of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICCA) is a rare tumor with a poor prognosis that arises from the intrahepatic biliary tract. Patients who present with locally advanced or metastatic ICCA are generally treated with first-line gemcitabine/cisplatin and/or liver-directed therapy with the hope of downstaging/downsizing the disease. Patients who present with resectable ICCA may be treated with upfront surgery and postoperative adjuvant capecitabine. Staging laparoscopy should be considered to evaluate for occult metastatic disease and laparoscopic ultrasound can be used to better evaluate the liver parenchyma. Resection with the goal of achieving an R0 margin, along with lymphadenectomy to adequately stage patients, should be the standard operative approach. Unfortunately, the surgical technique cannot overcome poor tumor biology, and ICCA has a high incidence of recurrence, with many patients developing metastatic disease. Targeted therapy with IDH and FGFR inhibitors has had promising results in early clinical trials. Future endeavors should strive to identify more effective systemic and targeted therapies, which will hopefully improve survival for patients with ICCA.

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.

Preservation of liver function with local radiation therapy in patients with metastatic intrahepatic cholangiocarcinoma with extrahepatic disease.

4080 Background: Tumor related liver failure (TRLF) is the most common cause of death in patients with metastatic intrahepatic cholangiocarcinoma (mICC) accounting for up to 72% deaths in patients treated with systemic therapy alone. We present our institutional experience of treating mICC patients with local liver-directed radiation therapy (RT). Methods: ICC patients with extrahepatic metastatic disease who received radiation therapy at our center with a biologically equivalent dose (BED) of at least 50 Gy from January 1, 2011 to March 31, 2021 were included in our study. Patient, tumor and treatment characteristics as well as the survival outcomes were recorded. TRLF was considered the cause of death if the patient died due to liver failure; and freedom from TRLF (FFTRLF) at 1 year and 2 years after RT was calculated. Results: Sixty-seven patients were included in the study. The median age was 63 years (range 29-83 years) and median RT dose was 60 Gy (range, 40-100 Gy). 73.1% patients received a BED &gt; 80.5 Gy. All except 1 patient were treated with upfront induction chemotherapy, followed by RT to the primary lesion in liver with (71.6%) or without (28.4%) concurrent chemotherapy. The most common induction chemotherapy regimen used was gemcitabine and cisplatin (65.7%) followed by gemcitabine, cisplatin and paclitaxel (22.4%), while the most common concurrent systemic therapy was capecitabine. Out of 43 patients with satellitosis, 29 were treated with RT to the dominant liver lesion while 14 received RT to the primary as well as one or more satellites. Overall, 15 patients (22.4%) had local progression of the radiated lesion, 42 patients (62.7%) progressed elsewhere in liver, and 52 patients (77.6%) had a distant progression. TRLF was the cause of death in 28.4% of patients. Median OS from diagnosis was 25 months while median OS after RT was 11.9 months. The 1- and 2-year rates of FFTRLF were 73.1% and 58.2% respectively, which were significantly higher than 1- and 2-year OS after RT (47.1% and 24.7% respectively, p &lt; 0.005). Univariate analysis did not identify significant association of FFTRLF or OS with age, sex, performance status, size of liver lesions, T or N stage, satellitosis, vascular thrombosis, TRLF, timing of metastasis, site of metastasis, RT technique and dose and chemotherapy. Conclusions: Liver directed radiation therapy in patients with mICC with extrahepatic disease appears to have favorable rates of TRLF and survival times, compared to historical data. Future prospective studies are warranted to define the survival benefit in these patients attributable to radiation therapy.