Cost-effectiveness of ivosidenib versus chemotherapy for previously treated IDH1-mutant advanced intrahepatic cholangiocarcinoma in Taiwan.

BACKGROUND: International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. METHODS: A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. RESULTS: Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty. CONCLUSIONS: At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.

Cost-Effectiveness Analysis of a New Second-Line Treatment Regimen for Advanced Intrahepatic Cholangiocarcinoma: Biomarker-Driven Targeted Therapy of Pemigatinib Versus 5-FU Chemotherapy.

BACKGROUND AND OBJECTIVES: The National Comprehensive Cancer Network recommends a second-line treatment of pemigatinib for patients with intrahepatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements and modified FOLFOX (mFOLFOX) for those without FGFR2 alterations. However, these regimens are not yet covered by Taiwa's National Health Insurance. This cost-effectiveness analysis evaluated the cost-effectiveness of the pemigatinib/mFOLFOX regimen as the second-line treatment for advanced intrahepatic cholangiocarcinoma based on FGFR2 status in comparison with the regimen of fluorouracil chemotherapy and provided a cost-effectiveness analysis-based reference price for pemigatinib. METHODS: A three-state partitioned survival model with a 5-year time horizon was constructed for patients with advanced intrahepatic cholangiocarcinoma who did not respond to first-line therapy. Overall and progression-free survival functions of pemigatinib, mFOLFOX, and fluorouracil were estimated from the FIGHT-202, ABC-06, and NIFTY trials, respectively. The utility of health states and disutility of adverse events were obtained from the literature. The genetic testing fee and price of pemigatinib were set as the market price. Other costs related to advanced intrahepatic cholangiocarcinoma were calculated using National Health Insurance claims data. The willingness-to-pay threshold was three times the gross domestic product per capita in 2021 (NT$2,889,684). A 3% discount rate was applied to quality-adjusted life-years and costs. Scenario analyses included a gradual price reduction of pemigatinib, alternative survival models, application of a National Health Insurance payment conversion factor to non-medication costs, and consideration of life-years as effectiveness. A deterministic sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were performed. RESULTS: The new regimen provided an incremental 0.13 quality-adjusted life-years, with incremental costs of NT$459,697, yielding an incremental cost-effectiveness ratio of NT$3,411,098 per quality-adjusted life-year and an incremental net monetary benefit of - NT$70,268. The new regimen was found to be 53.2% cost effective in the probabilistic sensitivity analysis. The expected value of uncertainty measured by the expected value of perfect information was NT$80,695/person. In scenario analyses, the incremental net monetary benefit was positive when the price of pemigatinib was reduced by 40% or more. When applying a conversion factor to non-medical costs, the probability of the new regimen being cost effective was slightly increased from 53.2 to 56.5% compared with the base-case analysis. The utility and the cost of the new regimen were the main drivers of uncertainty. CONCLUSIONS: Although the new second-line genetic-based and biomarker-driven regimen of pemigatinib/mFOLFOX appears not cost effective for patients with advanced intrahepatic cholangiocarcinoma in the base-case analysis, our analysis suggests it is highly likely to be cost effective in the case of a 40% price reduction on pemigatinib.

Pemigatinib para colangiocarcinoma / Pemigatinib for cholangiocarcinoma

INTRODUCCIÓN: Los colangiocarcinomas abarcan todos los tumores que se originan en el epitelio de la vía biliar. Más del 90 % son adenocarcinomas y generalmente se clasifican como intrahepáticos o extrahepático. La mediana de edad en el momento del diagnóstico es de 65 años, y tasas de sobrevida relativa a los 5 años son cercanas al 10%. La resección completa con márgenes negativos es el único tratamiento potencialmente curativo para pacientes con enfermedad resecable. Sin embargo, la mayoría de los pacientes son diagnosticados con enfermedad no resecable, localmente avanzada o metastásica debido a la ausencia de síntomas hasta un momento posterior del curso de la enfermedad. Para los pacientes con estadio avanzado o irresecable y de buen estado general, el tratamiento de primera línea estándar es gemcitabina y cisplatino. En el entorno de segunda línea una vez que la enfermedad ha progresado el esquema de quimioterapia mFOLFOX (ácido folínico o leucovorina, fluorouracilo y oxaliplatino) es el régimen de tratamiento preferido. El perfil molecular de los colangiocarcinomas desempeña un papel cada vez más importante en la determinación del pronóstico y la selección de tratamientos. Recientemente se han identificado alteraciones genéticas del receptor del factor de crecimiento fibroblástico (FGFR, su sigla del inglés Fibroblast Growth Factor Receptor) en aproximadamente en un 10-16% de los colangiocarcinomas intrahepáticos y se han denominado indistintamente traslocaciones, fusiones o reordenamientos. Estas fusiones o reordenamientos rara vez se producen en los colangiocarcinomas extra-hepáticos. TECNOLOGÍA: Pemigatinib (Pemazyre®) es un inhibidor de la cinasa de FGFR1, 2 y 3 que inhibe la fosforilación y la señalización de FGFR y disminuye la viabilidad celular en las células que expresan alteraciones genéticas de FGFR, incluyendo mutaciones puntuales, amplificaciones y fusiones o reordenamientos. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de pemigatinib en el tratamiento de pacientes con colangiocarcinoma. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. En PubMed se utilizó la estrategia de búsqueda que se detalla en el Anexo I. La fecha de búsqueda de información fue hasta el 24 de octubre de 2022. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (pemigatinib [Supplementary Concept] OR pemigatinib [tiab] OR Pemazyre [tiab] OR INCB054828 [tiab]) AND (Cholangiocarcinoma [MESH] OR cholangiocarcinoma [tiab]). RECOMENDACIONES: Las guías de la Red Nacional de Centros para el Tratamiento Integral del cáncer (NCCN, su sigla del inglés National Comprehensive Cancer Network) de los Estados Unidos, menciona al pemigatinib como una de las opciones de tratamiento para el colangiocarcinoma irresecable o metastásico con fusiones o reordenamientos de FGFR2, después de la progresión de la enfermedad a una primera línea de tratamento. La Sociedad Española de Oncología Médica (SEOM) recomienda que los pacientes candidatos al tratamiento deben enrolarse en ensayos clínicos. Añade que cuando esté disponible el fármaco en el país, se debería realizar una caracterización molecular exhaustiva del tumor en aquellos pacientes con estadios avanzado; ya que ciertas alteraciones genéticas, como las mutaciones de IDH1, las fusiones de FGFR2, mutaciones del gen BRAF, la inestabilidad de los microsatélites y los reordenamientos de NTRK, entre otros, pueden beneficiarse de terapias dirigidas específicas. La valoración del beneficio clínico según la de la Sociedad Europea de Oncología Médica (ESMO, su sigla del inglés European Society for Medical Oncology) para considerar la relevancia del beneficio clínico de forma sistematizada para este fármaco en la indicación evaluada es de 3 puntos. Según esta escala las calificaciones más altas en el ámbito no curativo son 5 y 4, que indican una magnitud sustancial del beneficio clínico. En Argentina, la Asociación de Oncología Clínica (AAOC) en sus recomendaciones actuales para el tratamiento oncológico del cáncer de vía biliar no menciona su uso dentro de las opciones terapêuticas. CONCLUSIONES: La eficacia y seguridad de pemigatinib frente a otros fármacos disponibles en la indicación evaluada no pudo ser establecida debido a que no se encontraron estudios comparativos. La evidencia que sustenta la aprobación de comercialización de pemigatinib para el tratamiento de adultos con colangiocarcinoma avanzado progresados a una primera línea de tratamiento y con alteraciones moleculares en el receptor del factor de crecimiento de fibroblastos 2, se basa en un único ensayo clínico no aleatorizado en pocos participantes. Este estudio mostró que aquellos adultos que utilizaron el tratamiento tendrían una tasa de respuesta cercanas al 37% al mediano plazo. Las agencias regulatorias relevadas han autorizado su comercialización de forma acelerada, bajo la denominación de medicamento huérfano, y sujeta a un ensayo de confirmación por parte del productor de la tecnología. Una guía de la Asociación Argentina de Oncología Clínica actualizada no lo menciona dentro de las opciones actuales de tratamiento, mientras que el resto de las recomendaciones provenientes de países de altos ingresos relevados lo mencionan como una opción terapéutica. Reino Unido brinda cobertura en la indicación evaluada sujeta a un acuerdo de comercialización con un descuento en el precio de venta. Otros países, como España y Canadá, no han autorizado su cobertura debido a que consideran que la evidencia que sustenta su utilización es insuficiente y existe incertidumbre sobre su beneficio en comparación con otras alternativas terapéuticas disponibles. No se hallaron evaluaciones económicas publicadas, aunque el costo del fármaco es muy elevado.

Liver Resection for Advanced Intrahepatic Cholangiocarcinoma: A Cost-Utility Analysis.

BACKGROUND: Data on cost-effectiveness and efficacy of hepatic resection (HR) for advanced intrahepatic cholangiocarcinoma (ICC) are lacking. We sought to estimate the cost-effectiveness of upfront HR resulting in an R1 resection (strategy A) relative to initial systemic chemotherapy (sCT) followed by possible curative HR (strategy B) for patients with advanced ICC. METHODS: A Markov model was developed using data from a systematic literature review. Three base cases were considered: (1) ICC >6 cm (2) ICC with vascular invasion (3) multi-focal ICC. A Monte Carlo simulation assessed outcomes including quality-adjusted life months (QALMs) and incremental cost-effectiveness ratio (ICER). RESULTS: The net health benefit (NHB) of strategy A versus strategy B was 1.4 QALMs for ICC >6 cm and 1.3 QALMs for ICC and vascular invasion; in contrast, there was a negative NHB for HR versus sCT for multi-focal ICC (-0.3 QALMs). In single nodule ICC >6 cm, the ICER of HR versus sCT was $22,482/quality-adjusted life years (QALY) and the ICER of HR versus sCT was $20,953/QALY for ICC with vascular invasion. In multi-focal ICC, the ICER of HR compared with sCT was $83,604/QALY. Patients with a higher American Society of Anesthesiologists score (coefficient 0.94), male sex (coefficient 0.43), low quality of life after sCT (coefficient -2.57) and T3 tumors (coefficient 0.53) had a better NHB for HR relative to sCT followed by potential surgery. CONCLUSIONS: For patients with large ICC or ICC and vascular invasion, HR was more cost-effective than sCT. In contrast, HR was not associated with a positive NHB relative to sCT for patients with multi-focal ICC, and therefore these patients should be treated with sCT rather than HR.

Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy.

UNLABELLED: Overexpression of epidermal growth factor receptor (ErbB1) and/or ErbB2 has been implicated in the pathogenesis of cholangiocarcinoma, suggesting that combined ErbB1/ErbB2 targeting might serve as a target-based therapeutic strategy for this highly lethal cancer. To test this strategy, we investigated targeting with the ErbB1 inhibitor tryphostin AG1517 and the ErbB2 inhibitor tryphostin AG879, in combination and alone, as well as with the dual ErbB1/ErbB2 inhibitor lapatinib, to assess the effectiveness of simultaneous targeting of ErbB1 and ErbB2 signaling over single inhibitor treatments in suppressing cholangiocarcinoma cell growth in vitro and the therapeutic efficacy of lapatinib in vivo. Our in vitro studies were carried out using rat (BDEneu and C611B) and human (HuCCT1 and TFK1) cholangiocarcinoma cell lines. The efficacy of lapatinib to significantly suppress liver tumor growth was tested in an orthotopic, syngeneic rat model of intrahepatic cholangiocarcinoma progression. Our results demonstrated that simultaneous targeting of ErbB1 and ErbB2 signaling was significantly more effective in suppressing the in vitro growth of both rat and human cholangiocarcinoma cells than individual receptor targeting. Lapatinib was an even more potent inhibitor of cholangiocarcinoma cell growth and inducer of apoptosis than either tryphostin when tested in vitro against these respective cholangiocarcinoma cell lines, regardless of differences in their levels of ErbB1 or ErbB2 protein expression and/or mechanism of activation. Lapatinib treatment also produced a significant suppression of intrahepatic cholangiocarcinoma growth when administered early to rats, but was without effect in inhibiting liver tumor growth in rats with more advanced tumors. CONCLUSION: Our findings suggest that simultaneous targeting of ErbB1 and ErbB2 could be a potentially selective strategy for cholangiocarcinoma therapy, but is likely to be ineffective by itself against advanced cancer.

Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival.

BACKGROUND: This study reports the results of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (dex) in patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) and investigates dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of tumor vascularity as a biomarker of outcome. PATIENTS AND METHODS: Thirty-four unresectable patients (26 ICC and eight HCC) were treated with HAI FUDR/dex. Radiologic dynamic and pharmacokinetic parameters related to tumor perfusion were analyzed and correlated with response and survival. RESULTS: Partial responses were seen in 16 patients (47.1%); time to progression and response duration were 7.4 and 11.9 months, respectively. Median follow-up and median survival were 35 and 29.5 months, respectively; 2-year survival was 67%. DCE-MRI data showed that patients with pretreatment integrated area under the concentration curve of gadolinium contrast over 180 s (AUC 180) >34.2 mM.s had a longer median survival than those with AUC 180 <34 mM.s (35.1 versus 19.1 months, P = 0.002). Decreased volume transfer exchange between the vascular space and extracellular extravascular space (-DeltaK(trans)) and the corresponding rate constant (-Deltak(ep)) on the first post-treatment scan both predicted survival. CONCLUSIONS: In patients with unresectable primary liver cancer, HAI therapy can be effective and safe. Pretreatment and early post-treatment changes in tumor perfusion characteristics may predict treatment outcome.

Assessment of gefitinib- and CI-1040-mediated changes in epidermal growth factor receptor signaling in HuCCT-1 human cholangiocarcinoma by serial fine needle aspiration.

One specific limitation to the clinical development of targeted cancer therapeutics is the lack of well-validated pharmacodynamic markers. Such tools might conceivably provide a framework within which to better evaluate the selection of specific molecules as therapeutic targets. Nevertheless, the practical application of this hypothesis in clinical development remains elusive. In this study, we present a minimally invasive pharmacodynamic assay for monitoring therapy-mediated changes in the activity of target signaling pathways by using fine needle aspiration (FNA) samples and quantitative ELISA methods. To this end, we used the HuCCT-1 cholangiocarcinoma cell line treated with gefitinib (ZD1839, Iressa), a selective blocker of the epidermal growth factor receptor (EGFR), and CI-1040, a selective inhibitor of the mitogen extracellular regulated kinase [mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2]. HuCCT-1 cells were resistant to gefitinib and CI-1040 alone but susceptible to the combination of these drugs in vitro and in vivo. This effect was associated with a greater inhibition of ERK1/2 activation, a downstream mediator in the EGFR-mitogen-activated protein/ERK kinase pathway. Using this model, we sought to assess whether FNA-obtained tumor biopsies could be used to measure signaling pathway activation. Cellular extracts prepared from FNA samples yielded adequately cellular, high-quality samples to assess therapy-mediated changes in EGFR and ERK1/2 phosphorylation by Western blotting and quantitative ELISA assays. Treatment with gefitinib alone effectively inhibited EGFR activation but failed to block ERK1/2 phosphorylation and tumor growth. Blocking was achieved by the addition of CI-1040 to the treatment regimen. These results show that the combination of serial FNA sampling with highly sensitive quantitative ELISA assays permits assessment of therapy-mediated changes in signaling pathways, which correlate well with antitumor effects. This assay is simple to implement and broadly applicable to diverse tumor types in clinical studies with cancer patients and may be useful in the development of targeted anticancer agents.

PDT in clinics: indications, results, and markets.

Photodynamic therapy (PDT) is based on the selective light activation of an exogenously given drug to patients. PDT acts mainly on cell membranes either of neovascular endothelial cells or of cancer cells leading to cancer cell death. Six drugs are now marketed based on clinical assays in various indications, which showed a clear cost efficiency as compared to other classical procedures. PDT is easy to handle and can be performed in medical installations fitting the conditions of health care in developing countries. Its cost effectiveness could represent an appropriate solution to the increasing number of cancers of various origin. However despite all the clinical results now available, PDT development remains slow. The reasons for this situation include cost of development, intellectual property, and competition between pharmaceutical companies.

Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment.

BACKGROUND AND STUDY AIMS: We evaluated the therapeutic effects of percutaneous transhepatic photodynamic therapy (PDT) in patients with advanced bile duct cancer. The utility of intraductal ultrasonography (IDUS) for the assessment of responses and for regular follow up after PDT was also examined. METHODS: Percutaneous transhepatic biliary drainage (PTBD) was initiated before PDT. Following dilation and maturation of the PTBD tract, percutaneous PDT was performed. Intraluminal photoactivation was carried out using percutaneous cholangioscopy 2 days after intravenous application of a hematoporphyrin derivative. All patients were additionally provided with percutaneous bile duct drainage catheters after PDT. IDUS was conducted monthly to measure the thickness of the tumor mass before and after PDT. RESULTS: 24 patients with advanced cholangiocarcinomas (Bismuth IIIa, n = 4; IIIb, n = 10; IV, n = 10) were treated with PDT. At 3 months after PDT, the mean thickness of the tumor mass had decreased from 8.7 +/- 3.7 mm to 5.8 +/- 2.0 mm (P < 0.01). At 4 months after PDT, the thickness of the mass had increased to 7.0 +/- 3.7 mm. Quality of life indices improved dramatically and remained stable 1 month after PDT; the Karnofsky index increased from 39.1 +/- 11.36 to 58.2 +/- 22.72 points (P = 0.003). The 30-day mortality rate was 0 %, and the median survival time was 558 +/- 178.8 days (current range 62 - 810 days). CONCLUSIONS: PDT using percutaneous cholangioscopy is safe and effective for advanced hilar cholangiocarcinoma, and seems to prolong survival. IDUS is useful for evaluating changes in the thickness of the tumor mass after PDT.