RESUMEN
PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Clorhidrato de Erlotinib , Gefitinib , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Anciano , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Receptores ErbB/antagonistas & inhibidores , Gefitinib/administración & dosificación , Gefitinib/uso terapéutico , Gefitinib/farmacología , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Afatinib/administración & dosificación , Afatinib/uso terapéutico , Afatinib/farmacología , Estudios de Cohortes , Anciano de 80 o más Años , AdultoRESUMEN
Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.
Asunto(s)
Anticoagulantes , Interacciones Farmacológicas , Piridinas , Rivaroxabán , Humanos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Estudios Retrospectivos , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/farmacocinética , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anilidas/administración & dosificación , Anilidas/efectos adversos , Anilidas/farmacocinética , Hemorragia/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Trombosis/inducido químicamente , Trombosis/etiología , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Administración Oral , AncianoAsunto(s)
Agammaglobulinemia Tirosina Quinasa , Inhibidores de Proteínas Quinasas , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéuticoRESUMEN
Tyrosine kinase inhibitors (TKIs) have revolutionized Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treatment. The combination of blinatumomab and a TKI in the frontline setting has shown the safety and efficacy of the chemotherapy-free treatment approach in patients with Ph + ALL. This retrospective analysis included 19 patients with Ph + ALL and Ph-like ALL treated with the combination of blinatumomab and a TKI. Of the 14 newly diagnosed patients, the overall response, complete remission (CR), and molecular response (CMR) rates after one cycle of blinatumomab were 100% (10/10), 90% (9/10), and 57% (8/14), respectively. Of the five relapsed patients, the CR and CMR rates were 50% (2/4) and 40% (2/5). Blinatumomab in combination with TKIs is safe and effective and hence this combination therapy could be a viable therapeutic option in front-line treatment of patients with Ph + ALL.
Asunto(s)
Anticuerpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Inhibidores de Proteínas Quinasas , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Femenino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Resultado del Tratamiento , Adulto Joven , AdolescenteRESUMEN
BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.
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Neoplasias Endometriales , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Humanos , Animales , Ratones , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Neoplasias Endometriales/genética , Línea Celular Tumoral , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Secuenciación del Exoma , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Clasificación del Tumor , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Oxazepinas , Sulfonamidas , Pirazinas , Benzamidas , ImidazolesRESUMEN
Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.
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Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , 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/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Femenino , Masculino , Persona de Mediana Edad , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Terapia Molecular Dirigida/métodos , Adulto , MutaciónAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Linfocítica Crónica de Células B , Sulfonamidas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .
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Leucemia Mielomonocítica Juvenil , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Leucemia Mielomonocítica Juvenil/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Resultado del Tratamiento , Enfermedades Raras/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. α-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such α-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects.
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Doxazosina , Células Endoteliales , Hipertensión , Receptores de Factores de Crecimiento Endotelial Vascular , Animales , Perros , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Doxazosina/farmacología , Doxazosina/uso terapéutico , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteómica/métodos , Presión Sanguínea/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Lisinopril/farmacología , Lisinopril/uso terapéutico , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapéutico , Sorafenib/farmacología , Sorafenib/uso terapéuticoRESUMEN
Salivary gland carcinomas are a heterogeneous group of rare tumors. There is no established standard of care therapy for metastatic disease. We describe the case of a patient with metastatic salivary gland adenocarcinoma harboring STRN-ALK translocation, with tumor response and clinical benefit from anaplastic lymphoma kinase (ALK) inhibition. Our patient experienced clinical benefit from first and second generation ALK inhibition in a chemotherapy refractory tumor. Tumor mutation profiling can identify mutations that may render tumors sensitive to targeted therapy with tyrosine kinase inhibitors.
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Quinasa de Linfoma Anaplásico , Neoplasias de las Glándulas Salivales , Humanos , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Persona de Mediana Edad , Femenino , Proteínas de Unión a Calmodulina , Proteínas de la Membrana , Proteínas del Tejido NerviosoAsunto(s)
Sinergismo Farmacológico , Leucemia Mieloide Aguda , Mutación , Inhibidores de Proteínas Quinasas , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Quinasa Activadora de Quinasas Ciclina-Dependientes , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Bruton tyrosine kinase inhibitor (BTKi)â¯combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is the major cause of relapse and death of DLBCL. In this study, we conducted a comprehensive analysis BTKi-resistance related genes (BRRGs) and established a 10-gene (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) signature for early identifying high-risk DLBCL patients. The resistance scores based on the BRRGs signature were associated with prognosis. Furthermore, we developed a nomogram incorporating the BRRGs signature, which demonstrated excellent performance in predicting the prognosis of DLBCL patients. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Additionally, we identified TRIP13 as a key gene in our model. TRIP13 was found to be overexpressed in DLBCL and BTKi-resistant DLBCL cell lines, knocking down TRIP13 suppresses cell proliferation, promotes cell apoptosis, and enhances the apoptosis effect of BTKi on DLBCL cells by regulating the Wnt/ß-catenin pathway. In conclusion, our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL, and TRIP13 might be a potential therapeutic target for resistant DLBCL.
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Agammaglobulinemia Tirosina Quinasa , Resistencia a Antineoplásicos , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia Tirosina Quinasa/metabolismo , Pronóstico , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/efectos de los fármacos , Femenino , Masculino , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , ATPasas Asociadas con Actividades Celulares DiversasRESUMEN
BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.
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Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas , Humanos , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/efectos adversos , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Adulto , Anciano , Resultado del Tratamiento , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Puntaje de Propensión , Supervivencia sin Progresión , Adulto JovenRESUMEN
Introduction: Bruton's tyrosine kinase (BTK) and interleukin (IL)-2 Inducible T-cell Kinase (ITK) inhibitors have anti-inflammatory properties. We investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK/ITK inhibitor, in a mouse model of Graves' orbitopathy (GO). Methods: Genetic immunization was performed through intramuscular administration of the recombinant plasmid, pCMV6-hTSHR cDNA, to 8-week-old female BALB/c mice. Serum levels of T3, T4, and thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs) were quantified using enzyme-linked immunosorbent assay. Histopathological changes in orbital tissues were examined using immunohistochemistry (IHC) staining for TSHR and various inflammatory markers. Following successful genetic immunization, ibrutinib was orally administered daily for 2 weeks in the GO model mice. After treatment, the mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissues were evaluated using real-time PCR and Western blotting. Results: In total, 20 mice were sacrificed to confirm successful genetic immunization. The GO mouse group exhibited significantly increased serum T3, T4, and TRAb levels. IHC revealed increased expression of TSHR, IL-1ß, IL-6, transforming growth factor-ß1, interferon-γ, CD40, CD4, BTK, and ITK in the GO mouse model. The orbital inflammation was significantly attenuated in ibrutinib-treated mice. The mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissue were lower in ibrutinib-treated GO mouse group compared to the phosphate-buffered saline-treated GO mouse group. Conclusion: The GO mouse model demonstrated enhanced BTK and ITK expression. Ibrutinib, a BTK/ITK inhibitor, suppressed the inflammatory cytokine production. These findings highlight the potential involvement of BTK/ITK in the inflammatory pathogenesis of GO, suggesting its role as a novel therapeutic target.
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Adenina , Agammaglobulinemia Tirosina Quinasa , Modelos Animales de Enfermedad , Oftalmopatía de Graves , Inflamación , Ratones Endogámicos BALB C , Piperidinas , Pirimidinas , Animales , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/patología , Adenina/análogos & derivados , Piperidinas/uso terapéutico , Ratones , Femenino , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Pirazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Receptores de Tirotropina/metabolismo , Receptores de Tirotropina/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.
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Glioma , Inhibidores de Proteínas Quinasas , Pirazoles , Pirimidinas , Receptor trkB , Humanos , Femenino , Lactante , Pirazoles/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Receptor trkB/genética , Receptor trkB/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Fusión Oncogénica/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Clasificación del Tumor , Resultado del Tratamiento , Glicoproteínas de Membrana/genéticaRESUMEN
To observe the efficacy of topical antipruritic spray (TAS) in the treatment of epidermal growth factor receptor (EGFR) tyrosine kinase-related rashes, and to evaluate its efficacy and safety. 120 malignant tumor patients with confirmed pathological diagnosis and rash after EGFR application were selected and randomly divided into an experimental group of 60 cases and a control group of 60 cases. The 2 groups were intervened with self-made antipruritic spray and erythromycin ointment for 14 consecutive days. To observe the changes in rash, itching degree, and quality of life index of skin diseases in both groups of patients before and after treatment. The decrease in the number of itching cases in the experimental group reached 53.84%, and after 7 weeks of intervention, the total effective rate of rash treatment in this group of patients (91.67%) was significantly better than that in the control group (36.67%); The symptoms of the dermatology life quality index (DLQI) scale in the experimental group patient table after intervention showed significant changes compared to before intervention. After statistical testing, there was a significant difference between the groups and outside the group (Râ <â 0.05). And the comprehensive effect of the experimental patients with external spray after 14 weeks of intervention reached 93.16%. The self-made antipruritic spray has significant effect on improving EGFR rash and itching, and there is no obvious adverse reaction.
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Receptores ErbB , Calidad de Vida , Humanos , Masculino , Femenino , Persona de Mediana Edad , Receptores ErbB/antagonistas & inhibidores , Anciano , Adulto , Antipruriginosos/administración & dosificación , Antipruriginosos/uso terapéutico , Prurito/tratamiento farmacológico , Prurito/etiología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Eritromicina/administración & dosificación , Eritromicina/uso terapéutico , Dermatitis/tratamiento farmacológico , Dermatitis/etiología , Administración Tópica , Administración CutáneaRESUMEN
BACKGROUND: To date, no meta-analysis has been conducted to compare the effectiveness and safety of adjuvant tyrosine kinase inhibitors (TKIs) and adjuvant immunotherapies (IMTs) in renal cell carcinoma (RCC) patients using reconstructed individual patient data (IPD). This study aims to fill that gap by assessing the efficacy and safety profiles of these treatments in such patients. METHODS: This study employed a systematic approach for identifying relevant literature from the PubMed and EMBASE databases. We included articles published in English from the inception of these databases until November 11, 2023, focusing specifically on appropriate phase III randomized controlled trials (RCTs). To reconstruct survival curves, we utilized a semiautomated tool, WebPlotDigitizer, in conjunction with a novel shiny application integrated with R software. For adverse events (AEs), the summary measures were incidences, expressed as a 95% confidence interval (CI), calculated using a random-effects model with a logit transformation. RESULTS: The analysis included 8 RCTs with a total of 9119 patients. Compared to adjuvant TKIs, adjuvant IMTs showed a similar disease-free survival (DFS) (hazard ratio [HR] 1.03, 95% CI [0.98-1.09], Pâ =â .281). However, the overall survival (OS) rates between the 2 groups couldn't be directly compared due to unmatched control groups in the IMT and TKI studies. Against placebo, adjuvant IMTs demonstrated superior DFS (HR 0.82, 95% CI [0.71-0.94], Pâ =â .004) but comparable OS (HR 0.79, 95% CI [0.59-1.06], Pâ =â .120). Against placebo, adjuvant TKIs showed superior DFS (HR 0.85, 95% CI [0.79-0.92], Pâ <â .0001) and marginally better OS (HR 0.89, 95% CI [0.80-0.996], Pâ =â .042). Regarding severe AEs and discontinuation rates due to AEs, adjuvant IMTs had a significantly lower incidence of severe AEs (25% [320/1282] vs 59% [2192/3716], odds ratio [OR] 0.23, 95% CI [0.20-0.27], Pâ <â .0001) and a markedly better discontinuation rate (39% [499/1282] vs 52% [2068/4018], OR 0.60, 95% CI [0.53-0.68], Pâ <â .0001) compared to TKIs. CONCLUSION: This paper presents a thorough analysis of DFS, OS, and treatment-related AEs across various groups in RCC patients, offering a valuable resource for clinicians in everyday practice. Our findings indicate that while adjuvant IMTs and adjuvant TKIs demonstrate similar DFS, IMTs are notably superior in terms of safety and compliance.
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Carcinoma de Células Renales , Inhibidores de Puntos de Control Inmunológico , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Supervivencia sin EnfermedadRESUMEN
Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration: This trial is registered as ISRCTN06473203. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.
Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients' disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient's quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible.
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Carcinoma de Células Renales , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Años de Vida Ajustados por Calidad de Vida , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Reino Unido , Privación de Tratamiento , Sunitinib/uso terapéutico , Evaluación de la Tecnología Biomédica , Adulto , Antineoplásicos/uso terapéuticoRESUMEN
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for the management of EGFR-mutated non-small cell lung cancer. Recent results from the HARMONi-A trial lead to considering ivonescimab-a first-in-class, bispecific antibody targeting PD-1 and VEGF-plus chemotherapy as a new second-line option following third-generation TKIs.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Bruton's tyrosine kinase (BTK) inhibitors are important therapeutic advances with promising efficacy outcomes in the treatment of patients with chronic lymphocytic leukemia and other B-cell lymphoma subtypes. However, the utility of BTK inhibitors can be limited by adverse events such as infections. In this systematic review and meta-analysis, we aim to determine the risk of various infections associated with BTK inhibitor monotherapy in B-cell lymphoma patients. A comprehensive search was conducted in MEDLINE/PubMed, Embase, and Web of Science databases from their inception until October 2023. ClinicalTrials.gov, bibliographies, and relevant conference abstracts were also searched for additional records. Randomized controlled trials that included any B-cell lymphoma patients treated with BTK inhibitor monotherapy and reported infection were included. Meta-analysis was performed to calculate risk ratio (RR) using a random-effects model in R Statistical Software, version 4.3.2. Of 3292 studies retrieved, we included 12 studies in this systematic review and meta-analysis. The median age of patients across the study arms ranged between 64 and 73 years. The overall pooled RR for any grade upper respiratory tract infections (URTI) associated with BTK inhibitor treatment was 1.55 (95% Confidence Interval (CI) 1.22-1.97). The RR of grade ≥3 URTI was reported in 14 out of 1046 patients, yielding an RR of 1.46 (95% CI 0.61-3.54), which was not statistically significant. The pooled RR of any grade pneumonia was 1.20 (95% CI 0.68-2.10) and grade ≥3 pneumonia was 1.12 (95% CI 0.67-1.85), both of which were not statistically significant. Patients with B-cell lymphoma who are undergoing BTK inhibitor monotherapy face an elevated risk of developing URTI. Clinicians prescribing BTK inhibitors should be aware of the potential infectious events that may occur. Close monitoring and the implementation of effective prophylactic measures are essential for managing these patients.