RESUMEN
Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation.
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Acetatos , Antivirales , Infecciones por Citomegalovirus , Trasplante de Órganos , Quinazolinas , Ribonucleósidos , Humanos , Infecciones por Citomegalovirus/tratamiento farmacológico , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacología , Ribonucleósidos/uso terapéutico , Ribonucleósidos/efectos adversos , Ribonucleósidos/farmacología , Trasplante de Órganos/efectos adversos , Acetatos/uso terapéutico , Acetatos/efectos adversos , Acetatos/farmacología , Quinazolinas/uso terapéutico , Quinazolinas/farmacología , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Citomegalovirus/efectos de los fármacos , Diclororribofuranosil Benzoimidazol/análogos & derivadosRESUMEN
BACKGROUND: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. METHODS: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. RESULTS: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. CONCLUSIONS: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Irinotecán , Quinazolinas , Tiofenos , Humanos , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Anciano , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Tiofenos/uso terapéutico , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Estudios Prospectivos , Adulto , Supervivencia sin Progresión , Adulto JovenRESUMEN
The neuroprotective activity of tryptanthrin and its oxime was compared in male Wistar rats with a model of intraluminal occlusion of the middle cerebral artery. Neurobehavioral tests were performed 4, 24, and 48 h after focal cerebral infarction (FCI) using a modified neurological severity score (mNSS); additionally, the horizontal stability test, the plantar sensitivity test of the fore and hind limbs, holding on the tilted cage top test, and negative geotaxis test were performed. The size of FCI and the severity of brain tissue swelling were examined on day 2 after occlusion. Tryptanthrin and its oxime were administered at a dose of 10 mg/kg intraperitoneally during FCI, then daily for 2 days. In the control group, the mean score of neurological deficit remained at a high level for 2 days. FCI size was 43.8±3.4% of hemisphere area, and the hemisphere volume increased by 18.5±2.0% due to brain tissue swelling and edema. Administration of tryptanthrin and its oxime significantly decreased neurological deficits at all control points and reduced FCI size (by 24.2 and 30.4%, respectively) and brain tissue swelling of the affected hemisphere (by 64.9 and 62.7%, respectively). Therefore, the neuroprotective effect of tryptanthrine and its oxime in the acute period of FCI is largely determined by their anti-inflammatory activity.
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Infarto de la Arteria Cerebral Media , Fármacos Neuroprotectores , Oximas , Quinazolinas , Ratas Wistar , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Masculino , Ratas , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Oximas/farmacología , Oximas/uso terapéutico , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/patología , Modelos Animales de Enfermedad , Encéfalo/efectos de los fármacos , Encéfalo/patologíaRESUMEN
OBJECTIVE: Icotinib has been approved for adjuvant treatment of stage II-IIIA non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations in China, yet the long-term costs and outcomes of this strategy are unknown. Thus, we examined the cost effectiveness of adjuvant icotinib, compared with adjuvant chemotherapy, for the treatment of resected stage II-IIIA EGFR-mutated NSCLC. DESIGN: We performed a cost-effectiveness analysis from the perspective of the Chinese healthcare system, comparing 2-year adjuvant icotinib with four cycles of adjuvant chemotherapy. Costs and quality-adjusted life years (QALYs) were estimated using a Markov model. Model inputs were obtained from local data and literature. The influence of model parameters and assumptions was explored in sensitivity analyses. All costs are expressed in 2022 US dollars, and costs and QALYs were discounted at a rate of 5% per year. The willingness-to-pay (WTP) threshold was set at three times the per capita gross domestic product. SETTING: The Chinese healthcare system perspective. PARTICIPANTS: A hypothetical Chinese cohort of patients with resected stage II-IIIA EGFR-mutated NSCLC. INTERVENTIONS: Icotinib versus chemotherapy. PRIMARY OUTCOME MEASURE: Costs, QALYs, incremental cost-effectiveness ratio. RESULTS: The incremental cost per QALY gained with the use of 2-year icotinib, from the Chinese healthcare system perspective, was $3440.66 compared with adjuvant chemotherapy. At a WTP threshold of $40 500, adjuvant icotinib was the optimal treatment in over 99% of replications. The interpretation of the results was insensitive to model and input assumptions. CONCLUSIONS: Compared with adjuvant chemotherapy, adjuvant icotinib may be a cost-effective treatment for resected stage II-IIIA EGFR-mutated NSCLC as the WTP threshold is set at $40 500 per QALY.
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Carcinoma de Pulmón de Células no Pequeñas , Análisis Costo-Beneficio , Éteres Corona , Receptores ErbB , Neoplasias Pulmonares , Mutación , Años de Vida Ajustados por Calidad de Vida , Quinazolinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/economía , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/economía , Neoplasias Pulmonares/patología , Éteres Corona/uso terapéutico , Éteres Corona/economía , Quimioterapia Adyuvante/economía , Receptores ErbB/genética , Quinazolinas/uso terapéutico , Quinazolinas/economía , China , Estadificación de Neoplasias , Cadenas de Markov , Antineoplásicos/uso terapéutico , Antineoplásicos/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Femenino , MasculinoRESUMEN
Cytomegalovirus (CMV) infection is the main opportunistic infection observed after kidney transplantation. Despite the use of prevention strategies, CMV disease still occurs, especially in high-risk patients (donor seropositive/recipient seronegative). Patients may develop complicated CMV, i.e. recurrent, refractory or resistant CMV infection. CMV prevention relies on either universal prophylaxis or preemptive therapy. In high-risk patients, universal prophylaxis is usually preferred. Currently, valganciclovir is used in this setting. However, valganciclovir can be responsible for severe leucopenia and neutropenia. A novel anti-viral drug, letermovir, has been recently compared to valganciclovir. It was as efficient as valganciclovir to prevent CMV disease and induced less hematological side-effects. It is still not available in France in this indication. Recent studies suggest that immune monitoring by ELISPOT or Quantiferon can be useful to determine the duration of prophylaxis. Other studies suggest that prophylaxis may be skipped in CMV-seropositive kidney-transplant patients given mTOR inhibitors. Refractory CMV is defined by the lack of decrease of CMV DNAemia of at least 1 log10 at 2 weeks after effective treatment. In case of refractory CMV infection, drug resistant mutations should be looked for. Currently, maribavir is the gold standard therapy for refractory/resistant CMV. At 8 weeks therapy and 8 weeks later, it has been shown to be significantly more effective than other anti-viral drugs, i.e. high dose of ganciclovir, foscarnet or cidofovir. However, a high rate of relapse was observed after ceasing therapy. Hence, other therapeutic strategies should be evaluated in order to improve the sustained virological rate.
L'infection à cytomégalovirus (CMV) est la principale infection opportuniste après transplantation rénale. Malgré les stratégies préventives, il persiste des maladies à CMV, notamment chez les patients à haut risque (donneur séropositif/receveur séronégatif). Certains patients présentent des formes complexes avec des récurrences et des infections réfractaires et/ou résistantes aux antiviraux. La prévention de l'infection à CMV repose soit sur une prophylaxie universelle, soit sur une stratégie préemptive. Chez les patients à haut risque, la stratégie prophylactique est le plus souvent utilisée. Elle repose sur l'utilisation du valganciclovir, qui peut être responsable de leucopénies et de neutropénies sévères. Un nouvel antiviral, le létermovir, qui n'est pas encore disponible sur le marché en France dans cette indication, a montré une efficacité similaire au valganciclovir avec peu d'effets secondaires hématologiques. Des études récentes suggèrent l'intérêt de l'immuno-surveillance par ELISPOT ou Quantiféron pour guider la durée de la prophylaxie. D'autres études suggèrent également la possibilité de se passer d'un traitement prophylactique anti-CMV chez des transplantés rénaux CMV-séropositifs recevant des inhibiteurs de la mTOR. Le CMV réfractaire est défini par une absence de baisse de la charge virale d'au moins 1 log10 après deux semaines de traitement efficace. En cas d'absence de baisse de la charge virale, une recherche de mutations de résistance aux antiviraux doit être effectuée. Actuellement, le maribavir constitue le traitement de référence pour les formes réfractaires et résistantes. La clairance virale à la fin du traitement, ou huit semaines plus tard, est significativement supérieure à celle observée avec les autres antiviraux tels que le ganciclovir donné à forte dose, le foscarnet, ou le cidofovir. Cependant, le taux de rechute à l'arrêt du traitement par maribavir reste important. D'autres stratégies thérapeutiques doivent être évaluées pour améliorer ce taux de réponse virologique soutenue.
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Antivirales , Infecciones por Citomegalovirus , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Antivirales/uso terapéutico , Valganciclovir/uso terapéutico , Quinazolinas/uso terapéutico , Ganciclovir/uso terapéutico , Ribonucleósidos/uso terapéutico , Acetatos , Diclororribofuranosil Benzoimidazol/análogos & derivadosRESUMEN
AIMS: Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with metastatic colorectal cancer (CRC) who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). MATERIALS AND METHODS: A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). RESULTS: The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. CONCLUSIONS: Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.
Fruquintinib is a treatment for metastatic colorectal cancer that has progressed after or not responded to multiple guideline-recommended therapies. This budget impact analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the per plan member per month cost of covering fruquintinib was $0.07 for a United States commercial health plan and $0.17 for Medicare.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Bevacizumab , Neoplasias Colorrectales , Piridinas , Timina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Benzofuranos/uso terapéutico , Benzofuranos/economía , Estados Unidos , Bevacizumab/uso terapéutico , Bevacizumab/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Piridinas/uso terapéutico , Piridinas/economía , Trifluridina/uso terapéutico , Trifluridina/economía , Presupuestos , Quinazolinas/uso terapéutico , Quinazolinas/economía , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/economía , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/economía , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/economía , Análisis Costo-Beneficio , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/economía , Antineoplásicos/economía , Antineoplásicos/uso terapéutico , Irinotecán/uso terapéutico , Irinotecán/economía , Medicare , Fluorouracilo/uso terapéutico , Fluorouracilo/economía , Oxaliplatino/uso terapéutico , Oxaliplatino/economía , Receptores de Factores de Crecimiento Endotelial Vascular , Modelos Económicos , Combinación de Medicamentos , PirrolidinasRESUMEN
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as icotinib, osimertinib, and aumolertinib have emerged as promising treatment options for EGFR mutated Non-small cell lung cancer (NSCLC) patients. Additionally, anlotinib, an anti-angiogenic agent targeting VEGFR, FGFR, and PDGFR, has been used in combination with EGFR-TKIs in NSCLC cases. A method utilizing ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for quantifying icotinib, osimertinib, aumolertinib and anlotinib simultaneously in clinical TDM. The chromatographic separation was performed using a Kinetex C18 column (100â¯mm × 2.1â¯mm) and an elution gradient of ammonium acetate in water acidified with 0.1â¯% formic acid and in acetonitrile. The assay was validated over a linear range of 4-2000â¯ng/mL for icotinib, 2-1000â¯ng/mL for osimertinib, 1-500â¯ng/mL for aumolertinib, and 0.8-400â¯ng/mL for anlotinib, following the guidelines on bioanalytical methods by FDA. The quantification method exhibited satisfactory performance in terms of selectivity, accuracy (from 91.3â¯% to 107â¯%), precision (intra- and inter-day coeffficients of variation ranged from 0.944â¯% to 7.48â¯%), linearity, recovery (from 86.0â¯% to 91.9â¯%), matrix effect (IS-normalized matrix factors were from 96.7â¯% to 102â¯%), and stability. Overall, the method proved to be sensitive, reliable, and straightforward, enabling successful simultaneous determination of blood concentrations of icotinib, osimertinib, aumolertinib, and anlotinib in patients. The validity of the method has been confirmed across various instruments.
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Acrilamidas , Compuestos de Anilina , Éteres Corona , Monitoreo de Drogas , Indoles , Quinazolinas , Quinolinas , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Quinolinas/sangre , Quinolinas/uso terapéutico , Quinolinas/farmacocinética , Indoles/sangre , Indoles/farmacocinética , Indoles/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Acrilamidas/sangre , Compuestos de Anilina/sangre , Quinazolinas/sangre , Quinazolinas/uso terapéutico , Quinazolinas/farmacocinética , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Reproducibilidad de los Resultados , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Pirazinas/sangre , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/sangre , Cromatografía Líquida con Espectrometría de Masas , Benzamidas , PirimidinasRESUMEN
BACKGROUND AND PURPOSE: The poor delivery of drugs to infiltrating tumor cells contributes to therapeutic failure in glioblastoma. During the early phase of an anti-angiogenic treatment, a remodeling of the tumor vasculature could occur, leading to a more functional vessel network that could enhance drug delivery. However, the restructuration of blood vessels could increase the proportion of normal endothelial cells that could be a barrier for the free diffusion of drugs. The net balance, in favor or not, of a better delivery of compounds during the course of an antiangiogenic treatment remains to be established. This study explored whether cediranib and thalidomide could modulate perfusion and vessel permeability in the brain U87 tumor mouse model. METHODS: The dynamic evolution of the diffusion of agents outside the tumor core using the fluorescent dye Evans Blue in histology and Gd-DOTA using dynamic contrast-enhanced (DCE)-MRI. CD31 labelling of endothelial cells was used to measure the vascular density. RESULTS AND INTERPRETATION: Cediranib and thalidomide effectively reduced tumor size over time. The accessibility of Evans Blue outside the tumor core continuously decreased over time. The vascular density was significantly decreased after treatment while the proportion of normal vessels remained unchanged over time. In contrast to histological studies, DCE-MRI did not tackle any significant change in hemodynamic parameters, in the core or margins of the tumor, whatever the parameter used or the pharmacokinetic model used. While cediranib and thalidomide were effective in decreasing the tumor size, they were ineffective in transiently increasing the delivery of agents in the core and the margins of the tumor.
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Inhibidores de la Angiogénesis , Neoplasias Encefálicas , Glioblastoma , Quinazolinas , Talidomida , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/irrigación sanguínea , Talidomida/farmacología , Talidomida/uso terapéutico , Animales , Inhibidores de la Angiogénesis/farmacología , Ratones , Quinazolinas/farmacología , Quinazolinas/farmacocinética , Quinazolinas/uso terapéutico , Humanos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Imagen por Resonancia Magnética , Ensayos Antitumor por Modelo de Xenoinjerto , Permeabilidad Capilar/efectos de los fármacos , Ratones Desnudos , Línea Celular Tumoral , IndolesRESUMEN
BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Neoplasias Pancreáticas , Ftalazinas , Piperazinas , Quinazolinas , Humanos , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Ftalazinas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Microambiente Tumoral/inmunología , Supervivencia sin Progresión , Anciano de 80 o más Años , IndolesRESUMEN
ABSTRACT: Copanlisib, a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α and δ isoforms, previously demonstrated durable responses as monotherapy and improved progression-free survival (PFS) in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). CHRONOS-4 was a phase 3, randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of copanlisib in combination with standard immunochemotherapy in patients with relapsed iNHL. Patients (n = 524) were randomized (1:1) to copanlisib (60 mg IV) plus immunochemotherapy (rituximab and bendamustine [R-B] or placebo plus R-B). Copanlisib/placebo were administered with R-B (days 1, 8, and 15 of each 28-day cycle) for ≤6 cycles and as monotherapy from cycle 7 up to 12 months. The primary study end point was PFS. Median exposure was 8.5 months (0.2-12.9) for copanlisib plus R-B and 11.4 months (0.1-12.6) for placebo plus R-B. Median PFS was 32.9 months (95% confidence interval [CI], 24.4-38.6) for copanlisib plus R-B and 33.3 months (95% CI, 27.8-42.8) for placebo plus R-B (hazard ratio, 1.13; 95% CI, 0.88-1.44; P = .83). No differences between treatment arms were observed in overall survival (data not yet mature), objective response rate, and duration of response for the overall population or individual histology types. Overall, copanlisib plus R-B was associated with higher rates of serious treatment-emergent adverse events (TEAEs), grade 4 and 5 TEAEs, and treatment discontinuation. A number of serious TEAEs were infections. Overall, copanlisib plus R-B did not provide clinical benefit vs placebo plus R-B and was associated with worse tolerability in patients with relapsed iNHL. This trial was registered at www.ClinicalTrials.gov as #NCT02626455.
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Protocolos de Quimioterapia Combinada Antineoplásica , Pirimidinas , Rituximab , Humanos , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Adulto , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/mortalidad , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Anciano de 80 o más Años , Resultado del Tratamiento , Método Doble Ciego , RecurrenciaRESUMEN
Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis.
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Autoanticuerpos , Receptores ErbB , Interferón-alfa , Lapatinib , Nefritis Lúpica , Inhibidores de Proteínas Quinasas , Receptor ErbB-2 , Animales , Lapatinib/uso terapéutico , Lapatinib/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptores ErbB/inmunología , Femenino , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/inmunología , Humanos , Fibrosis , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Modelos Animales de Enfermedad , Quinazolinas/uso terapéutico , Quinazolinas/farmacología , Ratones Endogámicos NZBRESUMEN
OBJECTIVES: Efficacy and safety of letermovir as prophylaxis for clinically significant cytomegalovirus infections (csCVMi) was evaluated in randomised controlled trials while most of the real-world studies are single-centre experiences. METHODS: We performed a retrospective, multi-centre case-control study at six German university hospitals to evaluate clinical experiences in patients receiving CMV prophylaxis with letermovir (n = 200) compared to controls without CMV prophylaxis (n = 200) during a 48-week follow-up period after allogeneic hematopoietic cell transplantation (aHCT). RESULTS: The incidence of csCMVi after aHCT was significantly reduced in the letermovir (34%, n = 68) compared to the control group (56%, n = 112; p < 0.001). Letermovir as CMV prophylaxis (OR 0.362) was found to be the only independent variable associated with the prevention of csCMVi. Patients receiving letermovir showed significantly better survival compared to the control group (HR = 1.735, 95% CI: 1.111-2.712; p = 0.014). Of all csCMVi, 46% (n = 31) occurred after discontinuation of letermovir prophylaxis. Severe neutropenia (<500 neutrophils/µL) on the day of the stem cell infusion was the only independent variable for an increased risk of csCMVi after the end of letermovir prophylaxis. CONCLUSIONS: Our study highlights the preventive effects of letermovir on csCMVi after aHCT. A substantial proportion of patients developed a csCMVi after discontinuation of letermovir. In particular, patients with severe neutropenia require specific attention after drug discontinuation.
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Acetatos , Antivirales , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Quinazolinas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Infecciones por Citomegalovirus/prevención & control , Femenino , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Estudios Retrospectivos , Antivirales/uso terapéutico , Adulto , Acetatos/uso terapéutico , Acetatos/administración & dosificación , Estudios de Casos y Controles , Anciano , Trasplante Homólogo/efectos adversos , Adulto Joven , Citomegalovirus , Adolescente , Alemania/epidemiología , IncidenciaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Irinotecán , Quinazolinas , Sistema de Registros , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Irinotecán/administración & dosificación , Irinotecán/uso terapéutico , Estudios Prospectivos , Masculino , Femenino , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Persona de Mediana Edad , Anciano , Metástasis de la Neoplasia , Adulto , TiofenosRESUMEN
BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of fruquintinib-based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma. METHODS: Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib-based therapy were recorded and reviewed retrospectively, including progression-free survival (PFS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow-up was 10.2 months (95% CI, 6.4-11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5-13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70-12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14-0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15-0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31-10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment-emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group. CONCLUSIONS: Fruquintinib-based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.
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Benzofuranos , Neoplasias Óseas , Quinazolinas , Sarcoma , Humanos , Femenino , Sarcoma/tratamiento farmacológico , Sarcoma/mortalidad , Sarcoma/patología , Masculino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Anciano , Benzofuranos/uso terapéutico , Benzofuranos/efectos adversos , Neoplasias Óseas/secundario , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Adulto Joven , Terapia Recuperativa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Progresión , Adolescente , Resultado del TratamientoRESUMEN
Aim: The objective of this study was to compare adverse event (AE) management costs for fruquintinib, regorafenib, trifluridine/tipiracil (T/T) and trifluridine/tipiracil+bevacizumab (T/T+bev) for patients with metastatic colorectal cancer (mCRC) previously treated with at least two prior lines of therapy from the US commercial and Medicare payer perspectives. Materials & methods: A cost-consequence model was developed to calculate the per-patient and per-patient-per-month (PPPM) AE costs using rates of grade 3/4 AEs with incidence ≥5% in clinical trials, event-specific management costs and duration treatment. Anchored comparisons of AE costs were calculated using a difference-in-differences approach with best supportive care (BSC) as a common reference. AE rates and treatment duration were obtained from clinical trials: FRESCO and FRESCO-2 (fruquintinib), RECOURSE (T/T), CORRECT (regorafenib) and SUNLIGHT (T/T, T/T+bev). AE management costs for the commercial and Medicare perspectives were obtained from publicly available sources. Results: From the commercial perspective, the AE costs (presented as per-patient, PPPM) were: $4015, $1091 for fruquintinib (FRESCO); $4253, $1390 for fruquintinib (FRESCO-2); $17,110, $11,104 for T/T (RECOURSE); $9851, $4691 for T/T (SUNLIGHT); $8199, $4823 for regorafenib; and $11,620, $2324 for T/T+bev. These results were consistent in anchored comparisons: the difference-in-difference for fruquintinib based on FRESCO was -$1929 versus regorafenib and -$11,427 versus T/T; for fruquintinib based on FRESCO-2 was -$2257 versus regorafenib and -$11,756 versus T/T. Across all analyses, results were consistent from the Medicare perspective. Conclusion: Fruquintinib was associated with lower AE management costs compared with regorafenib, T/T and T/T+bev for patients with previously treated mCRC. This evidence has direct implications for treatment, formulary and pathways decision-making in this patient population.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Bevacizumab , Neoplasias Colorrectales , Compuestos de Fenilurea , Piridinas , Timina , Trifluridina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/economía , Estados Unidos , Piridinas/economía , Piridinas/uso terapéutico , Piridinas/efectos adversos , Timina/uso terapéutico , Trifluridina/uso terapéutico , Trifluridina/economía , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/economía , Bevacizumab/uso terapéutico , Bevacizumab/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/economía , Compuestos de Fenilurea/efectos adversos , Benzofuranos/economía , Benzofuranos/uso terapéutico , Benzofuranos/efectos adversos , Irinotecán/uso terapéutico , Irinotecán/economía , Combinación de Medicamentos , Pirrolidinas/uso terapéutico , Pirrolidinas/economía , Oxaliplatino/economía , Oxaliplatino/uso terapéutico , Oxaliplatino/efectos adversos , Medicare/economía , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/economía , Camptotecina/efectos adversos , Quinazolinas/economía , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Compuestos Organoplatinos/economía , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/efectos adversos , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/economía , Uracilo/efectos adversos , Fluorouracilo/uso terapéutico , Fluorouracilo/economía , Fluorouracilo/efectos adversos , Modelos Económicos , Productos Biológicos/economíaRESUMEN
BACKGROUND AND OBJECTIVE: Cytomegalovirus (CMV) is a common opportunistic infection after allogenic hematopoietic stem cell transplantation (allo-HSCT). Letermovir, an inhibitor of CMV DNA terminase, is approved for CMV prophylaxis in allo-HSCT patients. We report the final results of post-marketing surveillance of letermovir in Japan. METHODS: The case report forms were drafted in part by the Japanese Data Center for Hematopoietic Cell Transplantation using data elements in the Transplant Registry Unified Management Program and sent to individual HSCT centers to decrease the burden of reporting. Hematopoietic stem cell transplantation patients who received letermovir between May 2018 and May 2022 were registered. Data collected included physician-assessed adverse events/adverse drug reactions and clinical effectiveness (development of CMV disease, CMV antigen status, and use of preemptive therapy). RESULTS: A total of 821 HSCT patients were included in the safety analyses. Adverse drug reactions occurred in 11.33% of patients, with serious adverse drug reactions in 3.05%. The five most common adverse drug reactions were nausea (1.58%), renal impairment (1.46%), and acute graft versus host disease, CMV test positive, and hepatic function abnormal (0.61% each). A total of 670 patients were eligible for effectiveness analyses. Among these patients, 16.57% and 28.66% required preemptive therapy through week 14 and week 48, respectively. In addition, relatively few patients developed CMV disease throughout the follow-up period (1.34% at week 14 and 3.85% at week 48). CONCLUSIONS: This final analysis of post-marketing surveillance with up to 48 weeks follow-up period in Japan provides further evidence supporting the safety profile and effectiveness of letermovir for CMV prophylaxis in patients undergoing allo-HSCT in real-world settings.
Cytomegalovirus (CMV) infection is common after allogenic hematopoietic stem cell transplantation and causes both directly and indirectly a serious disease that frequently results in the death or severe outcomes for the affected patient. Letermovir is a drug that inhibits CMV replication and infection and can be administered to prevent CMV infection in at-risk patients undergoing allogenic hematopoietic stem cell transplantation. After it was approved in Japan, a post-marketing surveillance was started in order to confirm the safety profile and effectiveness of letermovir in clinical practice in Japan. The data collected included the adverse drug reactions during treatment and the effectiveness of letermovir. In this article, we describe the final results of this survey. The most common adverse drug reactions were nausea (1.58% of patients), renal impairment (1.46%), and acute graft versus host disease, CMV test positive, and hepatic function abnormal (0.61% each). There were few cases of myelosuppression, which is frequently seen in patients treated with ganciclovir/valganciclovir, and blood cells recovered steadily over time. Cytomegalovirus antigens were detected in 38.36% of patients through 48 weeks. Preemptive therapy was initiated to 28.66% of patients for up to 48 weeks. Cytomegalovirus disease was infrequent, occurring in 3.85% of patients. Overall, these findings are in alignment with the currently approved product label and provide further evidence supporting the consistent safety profile and effectiveness of letermovir for CMV prophylaxis in patients in Japan undergoing allogenic hematopoietic stem cell transplantation in clinical practice.
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Antivirales , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Vigilancia de Productos Comercializados , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Japón/epidemiología , Persona de Mediana Edad , Femenino , Antivirales/efectos adversos , Antivirales/uso terapéutico , Adulto , Infecciones por Citomegalovirus/prevención & control , Acetatos/uso terapéutico , Acetatos/efectos adversos , Acetatos/administración & dosificación , Anciano , Adulto Joven , Adolescente , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Niño , Trasplante Homólogo/efectos adversosRESUMEN
The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.
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Radioisótopos de Yodo , Piperidinas , Quinazolinas , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Piperidinas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Radioisótopos de Yodo/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Antineoplásicos/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control. PATIENTS AND METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant. RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months. CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Dosis Máxima Tolerada , Receptor ErbB-2 , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Receptor ErbB-2/metabolismo , Anciano , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Oxazoles/uso terapéutico , Oxazoles/farmacología , Oxazoles/administración & dosificación , Quinazolinas/uso terapéutico , Quinazolinas/farmacología , Quinazolinas/administración & dosificación , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Uracilo/análogos & derivados , Uracilo/farmacología , Uracilo/uso terapéutico , Uracilo/administración & dosificación , Ado-Trastuzumab Emtansina/uso terapéutico , Ado-Trastuzumab Emtansina/farmacología , Fulvestrant/farmacología , Fulvestrant/uso terapéutico , Fulvestrant/administración & dosificación , Trastuzumab/uso terapéutico , Trastuzumab/farmacología , Imidazoles , Oxazepinas , Anticuerpos Monoclonales HumanizadosRESUMEN
The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Unión Esofagogástrica , Paclitaxel , Neoplasias Gástricas , Humanos , Paclitaxel/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Unión Esofagogástrica/patología , Unión Esofagogástrica/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Benzofuranos/uso terapéutico , Benzofuranos/administración & dosificación , Benzofuranos/efectos adversos , Adulto , Método Doble Ciego , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Quinazolinas/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Supervivencia sin Progresión , Anciano de 80 o más AñosRESUMEN
Following the identification of specific epidermal growth factor receptor (EGFR)-activating mutations, gefitinib, one of the first-generation tyrosine kinase inhibitors (TKIs), has proven efficacious in targeting NSCLC that is driven by specific EGFR-activating mutations. However, most patients who initially respond to gefitinib, develop acquired resistance. In the current study, we devised a novel strategy to enhance the efficacy of gefitinib. We developed a simple and effective, nano-interrupter termed zeolitic imidazolate framework-8@Gefitinib@hyaluraonic nanoparticle (ZIF-8@G@HA NP). This nanoparticle was prepared by loading gefitinib onto a ZIF-8 nanoplatform followed by coating with hyaluronic acid (HA). The burst of Zn2+ release triggered by pH-sensitive degradation of ZIF-8@G@HA NPs was shown to enhance the efficacy of gefitinib in parental lung carcinoma HCC827 cells and overcame acquired gefitinib resistance in gefitinib drug resistant (GDR) HCC827 cells. We found that when treated with ZIF-8@G@HA NPs, Zn2+ acts synergistically with gefitinib via increased apoptosis in both parental and GDR HCC827 cells. Consistently, this in vitro activity was correlated with in vivo tumor growth inhibition. Interestingly, GDR cells were more sensitive to Zn2+ when compared with parental cells. We further found that ZIF-8 NPs overcame gefitinib resistance by triggering reactive oxygen species (ROS) generation and consequent cell cycle arrest at the G2/M phase, resulting in cancer cell apoptosis. Zn2+ was also found to block P-gp activity, facilitating the accumulation of gefitinib in GDR cells, thus enhancing the anti-tumor efficacy of gefitinib resulting in reversal of gefitinib resistance. Thus, this study offers a novel and promising strategy to surmount acquired gefitinib resistance via cell cycle arrest at the G2/M phase by facilitating gefitinib accumulation in GDR cells.