Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands: data from a cross-sectional multicentre study.

PURPOSE: This study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life. METHODS: A cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30. RESULTS: In total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7-214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties. CONCLUSION: Even in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.

Cost Evaluation Analysis of Genetic Testing and Tailored Adjuvant Imatinib in Patients With Resected High-Risk GI Stromal Tumors: The Brazilian Perspective.

PURPOSE: Mutations of the KIT gene are the molecular hallmark of most GI stromal tumors (GISTs). Imatinib has revolutionized GIST treatment. Adjuvant imatinib for 3 years is the standard of care for high-risk resected GIST. However, the GIST molecular biologic profile has found different responses to this approach. Despite this, genetic testing at diagnosis is not a routine and empirical adjuvant imatinib remains the rule. Barriers to genetic profiling include concerns about the cost and utility of testing. This analysis aims to determine whether targeted genetic testing reduces costs as an ancillary tool for a limited-resource scenario instead of adjuvant empirical imatinib in patients with resected high-risk GIST. METHODS: The cost evaluation analysis of molecular testing for GIST was based on the Cost of Preventing an Event (COPE), considering the Number Needed to Treat and the costs of each test compared with the cost of 3-year empirical adjuvant imatinib and real treatment costs (median number of cycles) from the public and private Brazilian Healthcare System's perspective. The analysis compared the costs of the molecular tests (broad next-generation sequencing [NGS], GS Infinity DNA/RNA assay, and targeted NGS: GS Focus GIST and the Fleury GIST Tumor DNA sequencing panel), costs of drug acquisition, considering discounts (imatinib mesylate and Glivec), and the costs of supportive care. RESULTS: In both scenarios, public and private, regardless of the use of imatinib or Glivec, tailoring adjuvant treatment reduced costs, irrespective of the number of cycles. The only exception was the combination of the broad NGS test and imatinib in the Public Healthcare System. CONCLUSION: The molecularly tailored adjuvant imatinib reduced costs considering the COPE of available NGS tests for both the public and private Brazilian health care systems.

KIT-Associated Familial GIST Syndrome: Response to Tyrosine Kinase Inhibitors and Implications for Risk Management.

Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.

Indication-Specific Generic Uptake of Imatinib Demonstrates the Impact of Skinny Labeling.

PURPOSE: Generic competition can be delayed if brand-name manufacturers obtain additional patents on supplemental uses. The US Food and Drug Administration allows generic drug manufacturers to market versions with skinny labels that exclude patent-protected indications. This study assessed whether use of generic versions of imatinib varied between indications included and excluded from the skinny labels. METHODS: In this cross-sectional study, we identified adult patients covered by commercial insurance or Medicare Advantage plans who initiated imatinib from February 2016 (first generic availability) to September 2020. Generic versions were introduced with skinny labels that included indications covering treatment of chronic myelogenous leukemia (CML) but excluded treatment of gastrointestinal stromal tumors (GISTs) because of remaining patent protections. Logistic regression was used to determine whether use of generic versus brand-name imatinib differed between patients with a diagnosis of CML or GIST, adjusting for demographics, insurance type, prior use of brand-name drugs, and calendar month. RESULTS: Among 2,000 initiators, 934 (47%) had CML and 686 (34%) had GIST. Within 3 years after generics entered the market, more than 90% of initiators in both groups used generic imatinib. Initiation of generic imatinib was slightly lower among patients with GIST than among patients with CML (85% v 88%; adjusted odds ratio 0.56; 95% CI, 0.39 to 0.80; P ≤ .001). CONCLUSION: Generic versions of imatinib were dispensed frequently for indications both included (CML) and excluded (GIST) from the skinny labeling, although patients with GIST were slightly less likely to receive a generic version. The skinny labeling pathway allowed generics to enter the market before patent protection for treating patients with GIST expired, facilitating lower drug prices.

Multimodal functional imaging for early response assessment in patients with gastrointestinal stromal tumor treated with tyrosine kinase inhibitors.

BACKGROUND: Several imaging modalities are used in the early work-up of patients with gastrointestinal stromal tumor (GIST) receiving tyrosine kinase inhibitor (TKI) treatment and there is a need to establish whether they provide similar or complimentary information. PURPOSE: To compare 18F-fluorodeoxyglucose positron emission tomography (FDG PET), computed tomography (CT) and magnetic resonance imaging (MRI) as early predictors of three-month outcomes for patients with GIST receiving TKI treatment. MATERIAL AND METHODS: Thirty-five patients with advanced GIST were prospectively included between February 2011 and June 2017. FDG PET, contrast-enhanced CT (CECT), and MRI were performed before and early after onset of TKI treatment (range 8-18 days). Early response was categorized according to mRECIST (CT), the Choi criteria (CECT), and PERCIST (FDG PET/CT). For MRI, volumetry from T2-weighted images and change in apparent diffusion coefficient (ADC) from diffusion-weighted imaging was used. The reference standard for early assessment was the three-month mRECIST evaluation based on CT. At three months, both stable disease (SD) and partial response (PR) were categorized as response. Clinical usefulness was defined as agreement between early and three-month assessment. RESULTS: At the three-month assessment, 91% (32/35) were responders, 37% (13/35) PR, 54% (19/35) SD, and 9% (3/35) had progressive disease (PD). Early assessment correctly predicted three-month response in 93% (27/29) for MRI, 80% (28/35) for PERCIST, 74% (26/35) for Choi, and 23% (8/35) for mRECIST. Six patients had non-FDG-avid tumors. For the FDG-avid tumors, PET/CT correctly predicted three-month response in 97% (28/29). CONCLUSION: MRI was superior to CECT for early assessment of TKI-treatment response in GIST. If the tumor was FDG-avid, PET and MRI were equally good. Changes in functional parameters were superior to changes in longest tumor diameter (mRECIST).

Dual-Energy CT Vital Iodine Tumor Burden for Response Assessment in Patients With Metastatic GIST Undergoing TKI Therapy: Comparison With Standard CT and FDG PET/CT Criteria.

BACKGROUND. CT-based criteria for assessing the gastrointestinal stromal tumor (GIST) response to tyrosine kinase inhibitor (TKI) therapy are limited in part because tumor attenuation is influenced by treatment-related changes including hemorrhage and calcification. The iodine concentration may be less impacted by such changes. OBJECTIVE. The purpose of this study was to determine whether the dual-energy CT (DECT) vital iodine tumor burden (TB) allows improved differentiation between treatment responders and nonresponders among patients with metastatic GIST who are undergoing TKI therapy compared with established CT and PET/CT criteria. METHODS. An anthropomorphic phantom with spherical inserts mimicking GIST lesions of varying iodine concentrations and having nonenhancing central necrotic cores underwent DECT to determine a threshold iodine concentration. Forty patients (25 women and 15 men; median age, 57 years) who were treated with TKI for metastatic GIST were retrospectively evaluated. Patients underwent baseline and follow-up DECT and FDG PET/CT. Response assessment was performed using RECIST 1.1, modified Choi (mChoi) criteria, vascular tumor burden (VTB) criteria, DECT vital iodine TB criteria, and European Organization for Research and Treatment of Cancer (EORTC) PET criteria. DECT vital iodine TB criteria used the same percentage changes as RECIST 1.1 response categories. Progression-free survival was compared between responders and nonresponders for each response criterion by use of Cox proportional hazard ratios and Harrell C-indexes (i.e., concordance indexes). RESULTS. The phantom experiment identified a threshold of 0.5 mg/mL to differentiate vital from nonvital tissue. With use of the DECT vital iodine TB, median progression-free survival was significantly different between responders and nonresponders (623 vs 104 days; p < .001).. For nonresponders versus responders, the hazard ratio for disease progression for DECT vital iodine TB was 6.9 versus 7.6 for EORTC PET criteria, 3.3 for VTB criteria, 2.3 for RECIST 1.1, and 2.1 for mChoi criteria. The C-index was 0.74 for EORTC PET criteria, 0.73 for DECT vital iodine TB criteria, 0.67 for VTB criteria, 0.61 for RECIST 1.1, and 0.58 for mChoi criteria. The C-index was significantly greater for DECT vital iodine TB criteria than for RECIST 1.1 (p = .02) and mChoi criteria (p = .002), but it was not different from that for VTB and EORTC PET criteria (p > .05). CONCLUSION. DECT vital iodine TB criteria showed performance comparable to that of EORTC PET criteria and outperformed RECIST 1.1 and mChoi criteria for response assessment of metastatic GIST treated with TKI therapy. CLINICAL IMPACT. DECT vital iodine TB could help guide early management decisions in patients receiving TKI therapy.

The EMA assessment of avapritinib in the treatment of gastrointestinal stromal tumours harbouring the PDGFRA D842V mutation.

Avapritinib is a protein kinase inhibitor designed to selectively inhibit oncogenic KIT and platelet-derived growth factor receptor alpha (PDGFRA) mutants by targeting the active conformation of the kinase. On 24 September 2020, a marketing authorisation valid through the European Union was issued for avapritinib as treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumours (GIST) harbouring the PDGFRA D842V mutation. The drug was evaluated in an open-label, phase I, first-in-human, dose-escalation, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of avapritinib in adults with unresectable or metastatic GIST. The benefit of avapritinib was observed in patients with GIST harbouring the PDGFRA D842V mutation. The overall response rate was 95% (95% confidence interval 82.3%-99.4%), with a median duration of response of 22.1 months (95% confidence interval 14.1-not estimable months). The most common adverse events were nausea, fatigue, anaemia, periorbital and face oedema, hyperbilirubinaemia, diarrhoea, vomiting, increased lacrimation, and decreased appetite. Most of the reported cognitive effects were mild memory impairment. Rarer events were cases of severe encephalopathy and intracranial or gastrointestinal bleeding. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.

Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumor: A Systematic Review.

Background: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved the clinical effectiveness of patients with locally advanced and/or metastatic gastrointestinal stromal tumors (GIST), and this systematic review was conducted aiming at the cost-effectiveness analysis of TKIs in GIST. Methods: A thorough literature search of online databases was performed, using appropriate terms such as "gastrointestinal stromal tumor or GIST," "cost-effectiveness," and "economic evaluation." Data extraction was conducted independently by two authors, and completeness of reporting and quality of the evaluation were assessed. The systematic review was conducted following the PRISMA statement. Results: Published between 2005 and 2020, 15 articles were incorporated into the systematic review. For advanced GIST, imatinib followed by sunitinib was considered cost-effective, and regorafenib was cost-effective compared with imatinib re-challenge therapy in the third-line treatment. For resectable GIST, 3-year adjuvant imatinib therapy represented a cost-effective treatment option. The precision medicine-assisted imatinib treatment was cost-effective compared with empirical treatment. Conclusion: Although identified studies varied in predicted costs and quality-adjusted life years, there was general agreement in study conclusions. More cost-effectiveness analysis should be conducted regarding more TKIs that have been approved for the treatment of GIST. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO: CRD42021225253.

Financial Implications of Avapritinib for Treatment of Unresectable Gastrointestinal Stromal Tumors in Patients With a PDGFRA Exon 18 Variant or After 3 Previous Therapies in a Hypothetical US Health Plan.

Importance: With the approval of avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 variant, including PDGFRA D842V variants, and National Comprehensive Cancer Network guideline recommendations as an option for patients with GIST after third-line treatment, it is important to estimate the potential financial implications of avapritinib on a payer's budget. Objective: To estimate the budget impact associated with the introduction of avapritinib to a formulary for metastatic or unresectable GISTs in patients with a PDGFRA exon 18 variant or after 3 or more previous treatments from the perspective of a US health plan. Design, Setting, and Participants: For this economic evaluation, a 3-year budget impact model was developed in March 2020, incorporating costs for drug acquisition, testing, monitoring, adverse events, and postprogression treatment. The model assumed that avapritinib introduction would be associated with increased PDGFRA testing rates from the current 49% to 69%. The health plan population was assumed to be mixed 69% commercial, 22% Medicare, and 9% Medicaid. Base case assumptions included a GIST incidence rate of 9.6 diagnoses per million people, a metastatic PDGFRA exon 18 mutation rate of 1.9%, and progression rate from first-line to fourth-line treatment of 17%. Exposures: The model compared scenarios with and without avapritinib in a formulary. Main Outcomes and Measures: Annual, total, and per member per month (PMPM) budget impact. Results: In a hypothetical 1-million member plan, fewer than 0.1 new patients with a PDGFRA exon 18 variant per year and 1.2 patients receiving fourth-line therapy per year were eligible for treatment. With avapritinib available, the total increase in costs in year 3 for all eligible adult patients with a PDGFRA exon 18 variant was $46 875, or $0.004 PMPM. For patients undergoing fourth-line treatment, the total increase in costs in year 3 was $69 182, or $0.006 PMPM. The combined total budget impact in year 3 was $115 604, or $0.010 PMPM, including an offset of $3607 in postprogression costs avoided or delayed. The higher rates of molecular testing resulted in a minimal incremental testing cost of $453 in year 3. Conclusions and Relevance: These results suggest that adoption of avapritinib as a treatment option would have a minimal budget impact to a hypothetical US health plan. This would be primarily attributable to the small eligible patient population and cost offsets from reduced or delayed postprogression costs.

Cost-effectiveness Analysis of Genetic Testing and Tailored First-Line Therapy for Patients With Metastatic Gastrointestinal Stromal Tumors.

Importance: Gastrointestinal stromal tumor (GIST) is frequently driven by oncogenic KIT variations. Imatinib targeting of KIT marked a new era in GIST treatment and ushered in precision oncological treatment for all solid malignant neoplasms. However, studies on the molecular biological traits of GIST have found that tumors respond differentially to imatinib dosage based on the KIT exon with variation. Despite this knowledge, few patients undergo genetic testing at diagnosis, and empirical imatinib therapy remains routine. Barriers to genetic profiling include concerns about the cost and utility of testing. Objective: To determine whether targeted gene testing (TGT) is a cost-effective diagnostic for patients with metastatic GIST from the US payer perspective. Design, Setting, and Participants: This economic evaluation developed a Markov model to compare the cost-effectiveness of TGT and tailored first-line therapy compared with empirical imatinib therapy among patients with a new diagnosis of metastatic GIST. The main health outcome, quality-adjusted life years (QALYs), and costs were obtained from the literature, and transitional probabilities were modeled from disease progression and survival estimates from randomized clinical trials of patients with metastatic GIST. Data analyses were conducted October 2019 to January 2020. Exposure: TGT and tailored first-line therapy. Main Outcomes and Measures: The primary outcome was QALYs and cost. Cost-effectiveness was defined using an incremental cost-effectiveness ratio, with an incremental cost-effectiveness ratio less than $100 000/QALY considered cost-effective. One-way and probabilistic sensitivity analyses were conducted to assess model stability. Results: Therapy directed by TGT was associated with an increase of 0.10 QALYs at a cost of $9513 compared with the empirical imatinib approach, leading to an incremental cost-effectiveness ratio of $92 100. These findings were sensitive to the costs of TGT, drugs, and health utility model inputs. Therapy directed by TGT remained cost-effective for genetic testing costs up to $3730. Probabilistic sensitivity analysis found that TGT-directed therapy was considered cost-effective 70% of the time. Conclusions and Relevance: These findings suggest that using genetic testing to match treatment of KIT variations to imatinib dosing is a cost-effective approach compared with empirical imatinib.

Prognosis assessment in metastatic gastrointestinal stromal tumors treated with tyrosine kinase inhibitors based on CT-texture analysis.

PURPOSE: Identification of prognostic CT-textural features in patients with gastrointestinal stromal tumors undergoing tyrosine kinase inhibitor (TKI) therapy. METHODS AND MATERIALS: We identified 25 GIST patients (mean age, 70.58 ± 9.7 years; range, 41.25-84.08 years; 20 males, 5 females) with a total of 123 scans, each examined with a standardized CT protocol between 1/2014-7/2018. 92 texture features, based on pyradiomics library, were extracted and correlated to response categories; evaluated with help of modified Choi criteria. All patients underwent therapy with imatinib in the first line and different tyrosine kinase inhibitors after disease progression. KIT and PDGFR-mutations were registered in all patients as well as the number of previous treatment regimens, patient's age as well as gender and the presence of contrast enhancement (vitality) in tumor. The lesion with the largest diameter was chosen and contoured using the spherical VOI tool. Inter-rater testing was performed by a second experienced radiologist. Regression and AUC analysis was performed. RESULTS: Ten variables could be confirmed to be significantly associated with disease progression. Of them, four textural parameters were significantly positively associated with disease progression and negatively with progression free survival (Glcm Id [grey-level co-occurrence matrix inverse difference], p = 0.012, HR 3.83; 95% CI 1.697-8.611, Glcm Idn [grey-level co-occurrence matrix inverse difference normalized], p = 0.045, HR 2.06, 95% CI 1.015-4.185, Glrlm [grey-level run length matrix] normalized, p = 0.005, HR 3.181; 95% CI 1.418-7.138 and Ngtdm [neighboring grey-tone difference matrix] coarseness, p < 0.001, HR 3.156, 95% CI 1.554-6.411). Single variables were shown to be significantly inferior to the combination of all variables. After 6 months, 90% of patients with 0-1 risk factors (group 1), 64.4% with 2-3 risk variables and 38.1% of patients presenting > 3 structural risk variables showed stable disease. Gclm Id, Gclm Idn and Glrlm non-uniformity were associated with the number of previous treatments, Glrlm non-uniformity also with tumor vitality (enhancement), whereas Gclm Idn and Ngtdm coarseness were associated with the number of tumor mutations. CONCLUSION: Some of the CT-textural features correlate with disease progression and the progressive free survival as well as with the number of gene mutations and the number of treatment regimens the patients were exposed to as well as with the tumor enhancement. All these features reflect tumor homogeneity.

Optimizing the dose in patients treated with imatinib as first line treatment for gastrointestinal stromal tumours: A cost-effectiveness study.

AIMS: Patients with metastatic gastrointestinal stromal tumours (GIST) are treated in first line with the oral tyrosine kinase inhibitor, imatinib, until progressive disease. With this fixed dosing regimen, only approximately 40% of patients reach adequate plasma levels within the therapeutic index. Therapeutic drug monitoring (TDM) is a solution to reach plasma levels within the therapeutic index. However, introducing TDM will also increase costs, due to prolonged imatinib use and laboratory costs. The aim of this study was to evaluate the cost-effectiveness of TDM in patients with metastatic/unresectable GIST treated with imatinib as a first line treatment, compared with fixed dosing. METHODS: A survival model was created to simulate progression, mortality and treatment costs over a 5-year time horizon, comparing fixed dosing vs TDM-guided dosing. The outcomes measured were treatments costs, life-years and quality-adjusted life-years. RESULTS: Total costs over the 5-year time horizon were estimated to be €106 994.85 and €150 477.08 for fixed dosing vs TDM-guided dosing, respectively. A quality-adjusted life year gain of 0.74 (95% confidence interval 0.66-0.90) was estimated with TDM-guided dosing compared to fixed dosing. An average incremental cost-effectiveness ratio of €58 785.70 per quality-adjusted life year gained was found, mainly caused by longer use and higher dosages of imatinib. CONCLUSION: Based on the currently available data, this analysis suggests that TDM-guided dosing may be a cost-effective intervention for patients with metastatic/unresectable GIST treated with imatinib which will be improved when imatinib losses its patency.

Caregivers of patients receiving long-term treatment with a tyrosine kinase inhibitor (TKI) for gastrointestinal stromal tumour (GIST): a cross-sectional assessment of their distress and burden.

BACKGROUND: TKIs are a long-term treatment for GIST, and may have an impact on caregivers. MATERIAL AND METHODS: For this cross-sectional study, patients and caregivers were both included when patients had been treated with TKIs for at least six months. Caregivers completed questionnaires including demographics, distress (Hospital Anxiety and Depression scale), burden (Self-Perceived Pressure from Informal Care) general health (RAND-36), comorbidity (Self-administered Comorbidity Questionnaire), social support (Social Support List - Discrepancies) and marital satisfaction (Maudsley Marital Questionnaire). Patients completed similar questionnaires, without 'burden'. We conducted analyses to explore differences between caregivers with low/moderate versus high levels of burden and low versus high levels of distress. RESULTS: Sixty-one out of seventy-one eligible couples (84%) were included in the analysis. The median age of the caregivers was 60 years; 66% were female and 78% were the patients' spouse. The median age of the patients was 66 years; 43% were female. Caregivers experienced high levels of burden and distress in 10% and 23%, respectively. Caregivers with high levels of burden perceived significantly lower mental health, less vitality, lower general health and high levels of distress. Significantly higher levels of burden were found in non-spouses, caregivers of patients with more treatment-related side-effects, caregivers who spent more hours caring, and those caring for more than one person. For distress, caregivers with high levels of distress perceived significantly more burden, lower social functioning, more role physical and emotional problems, lower mental health, less vitality and lower general health. Furthermore, high levels of distress were found in caregivers of more dependent patients and those caring for more than one person. CONCLUSIONS: Caregivers of the patients with GIST treated with TKI are managing well. There is a small, vulnerable group of caregivers with high levels of burden and/or distress, show more health-related problems, both physical and mental, and require adequate support.

Informe de evaluación científica en la evidencia disponible: tumor de estroma gastrointestinal / Scientific evaluation report on available evidence: gastrointestinal stromal tumor

INTRODUCCIÓN: Se considerarán para su evaluación aquellas solicitudes realizadas conforme al Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con sistema de protección financiera, según lo establecido en los artículos 7° y 8° de la Ley N° 20.850. Estas solicitudes no son vinculantes para el Ministerio de Salud, debiendo, sin embargo, tomar especialmente en cuenta aquellas solicitudes y opiniones que hayan sido realizadas por sus comisiones técnicas asesoras y por las asociaciones de pacientes incluidas en el Registro de Asociaciones de Pacientes que crea la Ley 20.850. De igual forma, para ser incorporadas en el proceso de evaluación científica de la evidencia, cada intervención debe cumplir con los criterios establecidos en el Artículo 6o del Reglamento mencionado, según lo indicado en el Numeral 9 del presente informe. Los tumores mesenquimatosos del tracto gastrointestinal más frecuentes son los del estroma gastrointestinal (GIST). Se localizan preferentemente en el estómago y el intestino delgado, aunque pueden desarrollarse en cualquier lugar del aparato digestivo e incluso fuera de él. Son originarios de células mesenquimales del tracto gastrointestinal que actúan como marcapasos del tubo digestivo, o de un precursor común de células a lo largo del intestino; desde el punto de vista molecular presentan mutaciones características y recurrentes en los genes KIT (75-80%), PDGFRA (5-8%). Son tumores raros, con una incidencia estimada de 1,5/100.000 habitantes /año. Existe mayor incidencia en hombres con localizaciones de estómago e intestino delgado, estimándose que la incidencia puede llegar a 2/100. TECNOLOGÍAS SANITARIA DE INTERÉS: Imatinib: Es un inhibidor selectivo de quinasa que se une a los receptores c-KIT activados y bloquea la vía de señalización celular, evitando la proliferación celular incontrolada. Sunitinib: Sunitinib cuenta con registro en el ISP e indicación para tumores del estroma gastrointestinal (GIST) en adultos después del fracaso del tratamiento con imatinib debido a resistencia o intolerancia. Regorafenib: El Regorafenib (Stivarga, Bayer) inhibe los receptores de la quinasa angiogénica, tales como el factor de crecimiento endotelial vascular y el receptor TIE2, que juegan un papel en la angiogénesis. También inhibe quinasas oncogénicas tales como RAF, RET y cKIT, previniendo así la proliferación de células cancerosas. EFICACIA DE LOS TRATAMIENTOS: La evidencia encontrada indica que: Imatinib probablemente no disminuye la mortalidad en tumores del estroma gastrointestinal operados y aumenta los efectos adversos grado 3 o 4. Sin embargo, la población del estudio reportado no es la óptima para evaluar la eficacia de la indicación analizada. Sunitinib probablemente disminuye la mortalidad en GIST avanzado que progresa tras tratamiento de primera línea con imatinib y podría no asociarse a efectos adversos severos, pero la certeza de la evidencia es baja. Regorafenib no disminuye la mortalidad y aumenta los efectos adversos grado 3 o 4. La certeza de la evidencia es moderada. ALTERNATIVAS DISPONIBLES: El tratamiento del GIST depende principalmente del tamaño del tumor, su localización, metástasis y tasa de crecimiento mitótico. Los tumores localizados pequeños y resecables son removidos quirúrgicamente y en algunos casos, se da tratamiento farmacológico posterior a la cirugía para disminuir el riesgo de recidiva. Para los tumores localizados no pequeños, por lo general se indica tratamiento farmacológico para tratar de reducir el tamaño del tumor y poder removerlo mediante cirugía. Cuando los tumores son metastásicos o no resecables, la cirugía deja de ser una opción de tratamiento y se inicia terapia farmacológica hasta progresión de la enfermedad o toxicidad. Otras opciones para el tratamiento de los cánceres que se han propagado al hígado incluyen la ablación y la embolización para tratar de destruir estos tumores. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: Imatinib: Los tumores del estroma gastrointestinal (GIST) son tumores mesenquimáticos provenientes de las células intersticiales de Cajal. Si bien se considera un cáncer raro, es el más frecuente dentro de los sarcomas de tubo digestivo y de los sarcomas de partes blandas en general. Desde el punto de vista sistémico, los GIST tienen tratamiento molecularmente dirigido, con imatinib (Inhibidor de Kit, PDGFRA y ABL), tras descubrirse el rol patogénico que juegan en la mayoría de los pacientes las mutaciones de kit y del receptor alfa del factor de crecimiento derivado de las plaquetas. No obstante, para la enfermedad localizada el tratamiento de elección es la cirugía, que puede o no verse seguida de tratamiento adyuvante con imatinib si el riesgo de recurrencia se juzga como suficientemente alto. El presente resumen compara imatinib con placebo en pacientes con GIST resecado completamente, para prevenir su recurrencia (tratamiento adyuvante, con intención curativa). Sunitinib: Los tumores del estroma gastrointestinal (GIST) son tumores mesenquimáticos provenientes de las células intersticiales de Cajal (marcapasos del intestino). Si bien se considera un cáncer raro, es el más frecuente dentro de los sarcomas de tubo digestivo y de los sarcomas de partes blandas en general. Del punto de vista sistémico, los GIST tienen tratamiento molecularmente dirigido, con imatinib (Inhibidor de tirosina kinasa de Kit, PDGFRA y ABL), tras descubrirse el rol patogénico que juegan en la mayoría de los pacientes (80%) las mutaciones de kit y del receptor alfa del factor de crecimiento derivado de las plaquetas. No obstante, para la enfermedad localizada el tratamiento de elección es la cirugía, que puede o no verse seguida de tratamiento adyuvante con imatinib si el riesgo de recurrencia se juzga como lo suficientemente alto. Regorafenib: Los tumores del estroma gastrointestinal (GIST) son tumores mesenquimáticos provenientes de las células intersticiales de Cajal (marcapasos del intestino). Si bien se considera un cáncer raro, es el más frecuente dentro de los sarcomas de tubo digestivo y de los sarcomas de partes blandas en general. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable para los fármacos sunitinib e imatinib, y no favorable para regorafenib, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Cost-Effectiveness Analysis of Regorafenib for Gastrointestinal Stromal Tumour (GIST) in Germany.

BACKGROUND: No study has compared the cost-effectiveness of active treatment options for unresectable or metastatic gastrointestinal stromal tumours in patients who progressed on or are intolerant to prior treatment with imatinib and sunitinib. The aim of this study was to estimate the cost-effectiveness of regorafenib compared to imatinib rechallenge in this setting in Germany. METHODS: Hazard ratios for progression-free (PFS) and overall survival (OS) with regorafenib versus imatinib rechallenge were estimated by indirect comparison. A state distribution model was used to simulate progression, mortality and treatment costs over a lifetime horizon. Drug acquisition costs and utilities were derived from clinical trial data and published literature; non-drug costs were not included. The outcomes measured were treatment costs, life-years (LYs) and quality-adjusted life-years (QALYs). RESULTS: The indirect comparison suggested that median PFS and OS were longer with regorafenib compared to imatinib but results were not statistically significant. Regorafenib versus imatinib rechallenge was estimated to have hazard ratios of 0.58 (95% CI 0.31-1.11) for PFS and 0.77 (95% CI 0.34-1.77) for OS, with substantial uncertainty due to the rarity of the disease and small number of patients within the trials. Regorafenib treatment per patient over a lifetime horizon provided an additional 0.61 LYs and 0.42 QALYs over imatinib rechallenge, with additional direct drug costs of €8,773. The incremental cost-effectiveness ratio was €21,127 per QALY gained. At a cost-effectiveness threshold of €50,000 per QALY, regorafenib had a 67% probability of being cost-effective. CONCLUSION: Based on the currently available clinical data, this analysis suggests that regorafenib is cost-effective compared with imatinib rechallenge in Germany.

Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors for Patients with Advanced Gastrointestinal Stromal Tumors.

INTRODUCTION: The management of advanced gastrointestinal stromal tumors (GISTs) has been modified considerably by the availability of costly tyrosine kinase inhibitors (TKIs); however, the best therapeutic sequence in terms of cost and effectiveness remains unknown. OBJECTIVE: The aim of this study was to compare four potential strategies (reflecting the potential daily practice), each including imatinib 400 mg/day, as first-line treatment: S1 (imatinib400/best supportive care [BSC]); S2 (imatinib400/imatinib800/BSC); S3 (imatinib400/sunitinib/BSC); and S4 (imatinib400/imatinib800/sunitinib/BSC). METHODS: A Markov model was developed with a hypothetical cohort of patients and a lifetime horizon. Transition probabilities were estimated from the results of clinical trials. The analysis was performed from the French payer perspective, and only direct medical costs were included. Clinical and economic parameters were discounted, and the robustness of results was assessed. RESULTS: The least costly and effective strategy was S1, at a cost of €65,744 for 32.9 life months (reference). S3 was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of €48,277/life-year saved (LYS). S2 was dominated, and S4 yielded an ICER of €363,320/LYS compared with S3. Sensitivity analyses confirmed the robustness of these results; however, when taking into account a price reduction of 80 % for imatinib, S2 and S4 become the most cost-effective strategies. CONCLUSION: Our approach is innovative to the extent that our analysis takes into account the sequential application of TKIs. The results suggest that the S1 strategy is the best cost-effective strategy, but a price reduction of imatinib impacts on the results. This approach must continue, including new drugs and their impact on the quality of life of patients with advanced GISTs.

Eficacia y seguridad del uso de regorafenib para el tratamiento de tumor estromal del tracto gastrointestinal (gist) metastásico con progresión de enfermedad luego de imatinib y sunitinib / Efficacy and safety of the use of regorafenib for the treatment of stromal tumor of the gastrointestinal (gist) metastatic tract with disease progression after imatinib and sunitinib

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad del uso de regorafenib para el tratamiento de GIST metastásico con progresión a enfermedad luego de imatinib y sunitinib. Los tumores estromales del tracto gastrointestinal (GIST, por sus siglas en inglés) son tumores mesenquimales que se encuentran en el tracto gastrointestinal, representando al tipo de tumor mesenquimal más común y el tipo de sarcoma gastrointestinal más frecuente. El estudio de Soreide et al., 2016, encontró una incidencia por cada mil habitantes que fluctúa entre 4.3 a 21.1, incluyendo Estados Unidos y países de Europa y Asia. En Perú, se encontró un estudio realizado por Manrique M.N et al., 2012 en relación a la población atendida en el Hospital Nacional Edgardo Rebagliati Martins, donde se identificaron 103 casos desde el año 2002 hasta el 2010, es de notar que el objetivo de dicho estudio no fue estimar prevalencias ni incidencias. El tratamiento estándar de primera línea para GIST metastásico o irresecable es imatinib en dosis 400 mg y se menciona la dosis de 800 mg como una alternativa adicional. Asimismo, luego de progresión a imatinib se menciona el uso de sunitinib. Sin embargo, en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N. ° 051-SDEPFyOTS-DETS-IETSI-2017 el cual tuvo como objetivo evaluar la eficacia y seguridad del uso de sunitinib para el tratamiento de GIST que ha progresado a imatinib, se decidió no aprobar el uso de sunitinib para el tratamiento de GIST metastásico que ha progresado a imatinib debido a que la razón riesgo beneficio no era clara. Por lo tanto, en la actualidad imatinib es el único tratamiento incluido dentro del Petitorio Farmacológico de EsSalud. A pesar de ello, existen pacientes que luego de haber progresado a altas dosis de imatinib, adquirieron sunitinib fuera de EsSalud, progresando también a esta alternativa. Así, existe un grupo de pacientes que en la actualidad ha progresado a ambos tratamientos, por lo que surge la necesidad de evaluar alternativas que podrían ser de beneficio para dichos pacientes. TECNOLOGIA SANITARIA DE INTERÉS: Regorafenib es un inhibidor multiquinasa de los receptores de tirosina quinasa intracelulares y de membrana, con actividad antitumoral y anti angiogénica (Thangaraju, Singh, and Chakrabarti 2015) . Este posee acción inhibitoria frente a receptores de tirosina quinasa claves en la angiogénesis, oncogénesis, el mantenimiento del microambiente tumoral, y en las vías de señalización de crecimiento y proliferación del tumor. METODOLOGIA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad del uso de regorafenib para el tratamiento de GIST metastásico con progresión de enfermedad luego de imatinib y sunitinib. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE) y National Library of Medicine (Pubmed-Medline). Adicionalmente, se realizó una búsqueda manual del listado de referencias bibliográficas de los estudios seleccionados a fin de identificar otros estudios que pudieran ser útiles para la presente evaluación. Por otro lado, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como la Cochrane Group, The National Institute for Health and Care Excellence (NICE), the Agency for Health care Research and Quality (AHRQ), The Scottish Medicines Consortium (SMC), y The Canadian Agency for Drugs and Technologies in Health (CADTH). Esta búsqueda se completó revisando publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica dentro de américa y Europa, como The National Comprehensive Cancer Network (NCCN), The American Society of Clinical Oncology (ASCO) y The European Society of Medical Oncology (ESMO). Por último, se completó la búsqueda ingresando a la página web www.clinicaltrials.gov, para así poder identificar ensayos clínicos en elaboración o que no hayan sido publicados aún, y así disminuir el riesgo de sesgo de publicación. RESULTADOS: A la fecha, la evidencia de uso de regorafenib en pacientes con GIST metastásico que han progresado a imatinib y sunitinib, recaen en los resultados del ensayo GRID, publicados por Demetri et al., 2013. Así, las cuatro guías de práctica clínica y las dos ETS incluidas basan sus recomendaciones en los resultados de este ensayo. El ensayo GRID es un ensayo de fase III, aleatorizado, y doble ciego contra placebo. Este ensayo tuvo como objetivo principal evaluar eficacia en términos de sobrevida libre de progresión, y seguridad y tolerancia del fármaco. Se observaron diferencias significativas con respecto a la sobrevida libre de progresión (HR: 0.27; IC95 %: 0.19-0.39; valor p <0.001), con una mediana de 4.8 meses (rango intercuartil (IQR) 1.4-9.2) para el grupo de regorafenib y de 0.9 meses (IQR 0.9-1.8) para el grupo placebo. Sin embargo, esta diferencia no se tradujo en una diferencia en el análisis interino de la sobrevida global (HR: 0.77; IC95 %: 0.42-1.4; valor p=0.199). Asimismo, el rango intercuartil de las medianas de sobrevida libre de progresión se cruzan entre si y no se presenta una prueba estadística de las diferencias de dichas medianas, que permita concluir que esta diferencia de 3.9 meses es estadísticamente significativa. Debido a que solo se observa diferencias en relación a la sobrevida libre de progresión, un desenlace cuya relevancia clínica no es del todo convincente; la evaluación de la calidad de vida toma mayor relevancia. Con ello, tal como se menciona en el documento de Scottish Medicines Consortium (SMC) en torno a evaluación de la calidad de vida del ensayo GRID, no se muestran diferencias entre los grupos en relación al deterioro del estado de salud, adicionalmente, en la sub-escala del cumplimiento de la función de rol (role function subscale) si se encuentra un deterioro clínico significativo en el grupo de regorafenib. Además, en relación a los eventos adversos se observa una mayor proporción de eventos en el grupo de regorafenib, donde si bien las pérdidas por eventos adversos son similares, las disminuciones de dosis son bastante más frecuentes en el grupo de regorafenib (72 %), con un 29 % de eventos adversos serios versus a 21 % de eventos adversos serios de placebo. Así, no queda claro la razón riesgo beneficio en relación al uso de regorafenib en la población de interés del presente dictamen. Es de notar que las ETSs, las cuales utilizan la misma evidencia en relación a eficacia y seguridad, consideran que, al precio ofertado, regorafenib no resulta ser una alternativa costo-efectiva, con lo cual condicionan su aprobación a un descuento confidencial ofrecido por la compañía farmacéutica que permita que regorafenib alcance la costo-efectividad dentro de sus sistemas de salud.CONCLUSIÓN: El Instituto de Evaluación de Tecnologías Sanitarias-IETSI no aprueba el uso de regorafenib para el tratamiento de GIST metastásico con progresión de enfermedad luego de imatinib y sunitinib.

Informe de evaluación científica en la evidencia disponible: tumor de estroma gastrointestinal / Scientific evaluation report on available evidence: gastrointestinal stromal tumor

INTRODUCCIÓN: Los tumores mesenquimatosos del tracto gastrointestinal más frecuentes son los del estroma gastrointestinal (GIST). Se localizan preferentemente en el estómago y el intestino delgado, aunque pueden desarrollarse en cualquier lugar del aparato digestivo e incluso fuera de él. Son originarios de células mesenquimales del tracto gastrointestinal que actúan como marcapasos del tubo digestivo, o de un precursor común de células a lo largo del intestino; desde el punto de vista molecular presentan mutaciones características y recurrentes en los genes KIT (75-80%), PDGFRA (5-8%). Son tumores raros, con una incidencia estimada de 1,5/100.000 habitantes /año. Existe mayor incidencia en hombres con localizaciones de estómago e intestino delgado, estimándose que la incidencia puede llegar a 2/100. Son tumores raros, con una incidencia estimada de 1,5/100.000 habitantes /año (3), esto incluye sólo GIST clínicamente relevantes y no incluye lesiones microscópicas. Existe mayor incidencia en hombres con localizaciones de estómago e intestino delgado, estimándose que la incidencia puede llegar a 2/100. En Chile no se cuenta con un registro específico para determinar variables epidemiológicas. Aproximadamente el 50%-70% de tumores clínicamente relevantes surgen en el estómago, 20% - 30% en el intestino delgado, 5% -15% en el intestino grueso y menos de 5% en el esófago. La edad media de presentación va entre 60 a 65 años. Sin embargo pueden afectar a cualquier edad, en los niños es muy rara (menos del 3% en menores de 21 años), aunque los GIST pediátricos pueden representar un grupo distinto por sus características clínicas y biológicas. TECNOLOGÍAS SANITARIA DE INTERÉS: Imatinib: Es un inhibidor selectivo de quinasa que se une a los receptores c-KIT activados y bloquea la vía de señalización celular, evitando la proliferación celular incontrolada. Sunitinib: Es uno de un grupo de inhibidores de tirosina quinasa estrechamente relacionados. Inhibe el factor de crecimiento del endotelio vascular (VEGF) y los receptores del factor de crecimiento derivado de plaquetas (PDGF) en células cancerosas, células endoteliales vasculares y pericitos. Esto reduce la proliferación de células tumorales y el desarrollo de vasos sanguíneos tumorales. Regorafenib: El Regorafenib (Stivarga, Bayer) inhibe los receptores de la quinasa angiogénica, tales como el factor de crecimiento endotelial vascular y el receptor TIE2, que juegan un papel en la angiogénesis. También inhibe quinasas oncogénicas tales como RAF, RET y cKIT, previniendo así la proliferación de células cancerosas. EFICACIA DE LOS TRATAMIENTOS: La evidencia encontrada indica que: Imatinib probablemente no disminuye la mortalidad en tumores del estroma gastrointestinal operados; Imatinib aumenta los efectos adversos grado 3 o 4; Sunitinib probablemente disminuye la mortalidad en GIST avanzado que progresa tras tratamiento de primera línea con imatinib; Sunitinib podría no asociarse a efectos adversos severos, pero la certeza de la evidencia es baja; Regorafenib no disminuye la mortalidad. La certeza de la evidencia es moderada; Regorafenib aumenta los efectos adversos grado 3 o 4. ALTERNATIVAS DISPONIBLES: El tratamiento del GIST depende principalmente del tamaño del tumor, su localización, metástasis y taza de crecimiento mitótico. Los tumores localizados pequeños y resecables son removidos quirúrgicamente y en algunos casos, se da tratamiento farmacológico posterior a la cirugía para disminuir el riesgo de recidiva. Para los tumores localizados no pequeños, por lo general se indica tratamiento farmacológico para tratar de reducir el tamaño del tumor y poder removerlo mediante cirugía. Cuando los tumores son metastásicos o no resecables, la cirugía deja de ser una opción de tratamiento y se inicia terapia farmacológica hasta progresión de la enfermedad o toxicidad. Otras opciones para el tratamiento de los cánceres que se han propagado al hígado incluyen la ablación y la embolización para tratar de destruir estos tumores. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: Imatinib: Los tumores del estroma gastrointestinal (GIST) son tumores mesenquimáticos provenientes de las células intersticiales de cajal (marcapasos del intestino). Si bien se considera un cáncer raro, es el más frecuente dentro de los sarcomas de tubo digestivo y de los sarcomas de partes blandas en general. Desde el punto de vista sistémico, los GIST tienen tratamiento molecularmente dirigido, con imatinib (Inhibidor de Kit, PDGFRA y ABL), tras descubrirse el rol patogénico que juegan en la mayoría de los pacientes las mutaciones de kit y del receptor alfa del factor de crecimiento derivado de las plaquetas. No obstante, para la enfermedad localizada el tratamiento de elección es la cirugía, que puede o no verse seguida de tratamiento adyuvante con imatinib si el riesgo de recurrencia se juzga como suficientemente alto. El presente resumen compara imatinib con placebo en pacientes con GIST resecado completamente, para prevenir su recurrencia (tratamiento adyuvante, con intención curativa). Sunitinib: Los tumores del estroma gastrointestinal (GIST) son tumores mesenquimáticos provenientes de las células intersticiales de cajal (marcapasos del intestino). Si bien se considera un cáncer raro, es el más frecuente dentro de los sarcomas de tubo digestivo y de los sarcomas de partes blandas en general. Del punto de vista sistémico, los GIST tienen tratamiento molecularmente dirigido, con imatinib (Inhibidor de tirosina kinasa de Kit, PDGFRA y ABL), tras descubrirse el rol patogénico que juegan en la mayoría de los pacientes (80%) las mutaciones de kit y del receptor alfa del factor de crecimiento derivado de las plaquetas. No obstante, para la enfermedad localizada el tratamiento de elección es la cirugía, que puede o no verse seguida de tratamiento adyuvante con imatinib si el riesgo de ecurrencia se juzga como lo suficientemente alto. Por otro lado, pacientes con enfermedad irresecable o metastásica se tratan con terapia sistémica. Para la primera línea el estándar es imatinib, a menos que se documenten mutaciones que confieren resistencia en su contra. Se logran buenos resultados, pero la mayoría de los pacientes desarrollan resistencia al tratamiento, en una mediana de 2 años desde su inicio. Sunitinib es otro inhibidor de tirosina kinasa que inhibe kit, FLT3, RET y VEGFR (1,2 y 3); su principal diferencia con imatinib es el efecto antiangiogénico, que podría hacerlo activo en segunda línea ya que la angiogénesis es un mecanismo de progresión bien establecido en cáncer metastásico en general. El presente resumen compara sunitinib con placebo para el tratamiento de segunda línea de pacientes con GIST avanzado, vale decir que progresaron o tuvieron efectos adversos inaceptables con la terapia de primera línea (imatinib). Regorafenib: Los tumores del estroma gastrointestinal (GIST) son tumores mesenquimáticos provenientes de las células intersticiales de cajal (marcapasos del intestino). Si bien se considera un cáncer raro, es el más frecuente dentro de los sarcomas de tubo digestivo y de los sarcomas de partes blandas en general. Desde el punto de vista sistémico, los GIST tienen tratamiento molecularmente dirigido, con imatinib (Inhibidor de Kit, PDGFRA y ABL), tras descubrirse el rol patogénico que juegan en la mayoría de los pacientes (80%) las mutaciones de kit y del receptor alfa del factor de crecimiento derivado de las plaquetas. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Informe de evaluación científica basada en la evidencia disponible: tumor de estroma gastrointestina / Scientific evaluation report based on available evidence: gastrointestinal stromal tumor

INTRODUCCIÓN: Los tumores mesenquimatosos del tracto gastrointestinal más frecuentes son los del estroma gastrointestinal (GIST). Se localizan preferentemente en el estómago y el intestino delgado, aunque pueden desarrollarse en cualquier lugar del aparato digestivo e incluso fuera de él. Son originarios de células mesenquimales del tracto gastrointestinal que actúan como marcapasos del tubo digestivo, o de un precursor común de células a lo largo del intestino; desde el punto de vista molecular presentan mutaciones características y recurrentes en los genes KIT (75-80%), PDGFRA (5-8%). Son tumores raros, con una incidencia estimada de 1,5/100.000 habitantes /año. Existe mayor incidencia en hombres con localizaciones de estómago e intestino delgado, estimándose que la incidencia puede llegar a 2/100. TECNOLOGÍAS SANITARIAS ANALIZADAS: Imatinib, Sunitinib, Regorafenib. EFICACIA DE LOS TRATAMIENTOS: La evidencia encontrada indica que: -Imatinib probablemente no disminuye la mortalidad en tumores del estroma gastrointestinal operados. -Imatinib aumenta los efectos adversos grado 3 o 4. -Sunitinib probablemente disminuye la mortalidad en GIST avanzado que progresa tras tratamiento de primera línea con imatinib. -Sunitinib podría no asociarse a efectos adversos severos, pero la certeza de la evidencia es baja. -Regorafenib no disminuye la mortalidad. La certeza de la evidencia es moderada. -Regorafenib aumenta los efectos adversos grado 3 o 4. EVALUACIÓN ECONÓMICA: Existe gran incertidumbre alrededor de los resultados de las evaluaciones económicas del tratamiento con Imatinib en 1ra línea. En general, de los estudios encontrados se puede afirmar que no fueron todos concluyentes con respecto a su perfil de costo efectividad relacionándola directamente con el precio al que se pueda obtener el medicamento. En Chile, existen varias alternativas en el mercado de Imatinib por lo que se podrían lograr mejores precios que los mencionados en los estudios encontrados. Los estudios encontrados para Sunitinib en segunda línea al compararlo con Imatinib en segunda línea concluyen que Sunitinib es más caro y de menor eficacia que Imatinib. Cuando se compara Sunitinib en 2da línea contra tratamiento habitual, los estudios no son concluyentes entre sí, llegando a recomendarlos en algunos países por su relación de costo-efectividad o como en el caso de Canadá, recomendarlo a pesar de no ser costo-efectivo por convertirse en la única alternativa disponible de tratamiento para los que no responden a imatinib. Un solo estudio evaluó la costo-efectividad de Regorafenib en tercera línea luego del fracaso a Imatinib y Sunitinib, concluyendo que se recomienda el tratamiento, siempre y cuando la costoefectividad mejore, principalmente por el costo del medicamento. El impacto presupuestario esperado para el primer año es de $ 4.496 millones para Imatinib, $ 2.256 millones para Sunitinib y $ 4.101 millones para Regorafenib. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours.

PURPOSE: Therapeutic drug monitoring (TDM) is being considered as a tool to individualise sunitinib treatment of gastrointestinal stromal tumours (GIST). Here, we used computer simulations to assess the expected impact of sunitinib TDM on the clinical outcome of patients with GIST. METHODS: Monte Carlo simulations were performed in R, based on previously published pharmacokinetic-pharmacodynamic models. Clinical trials with dose-limiting toxicity and patient dropout were simulated to establish the study size required to obtain sufficient statistical power for comparison of TDM-guided and fixed dosing. RESULTS: The simulations revealed that TDM might increase time to tumour progression by about 1-2 months (15-31 %) in eligible patients. However, the number of subjects required for a sufficient statistical power to quantify clinical benefit of TDM guided is likely to be prohibitively high (>1000). CONCLUSION: Although data from randomised clinical trials on the clinical impact of sunitinib TDM are lacking, our findings support implementation of sunitinib TDM in clinical practice. For rare cancers with well-defined exposure-response relationships, modelling and simulation might allow the optimisation of dosing strategies when clinical trials cannot be performed due to low number of patients.