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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificaciónAsunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
PURPOSE: This study analyzes the effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration (nAMD) in real clinical practice. MATERIAL AND METHODS: The study included patients with nAMD who received brolucizumab treatment and evaluated the changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), macular volume, as well as the number of injections and adverse events. RESULT: The group of previously treated patients included 28 subjects (28 eyes) that were switched to brolucizumab with a loading phase. By 12 months, BCVA changed from 0.43±0.29 to 0.33±0.27 LogMAR (p=0.11), CRT decreased from 281.5±58.2 to 239.9±45.6 µm (p=0.02). The group of previously untreated patients included 29 subjects (29 eyes). By 12 months, BCVA changed from 0.47±0.32 to 0.40±0.30 LogMAR (p=0.09), CRT decreased from 333.2±77.3 to 226.2±49.6 µm (p<0.001). Patients received 6.3±0.7 injections. In this group, baseline choroidal thickness showed a statistically significant correlation with final visual acuity (r=0.54; p<0.05) and CRT (r= -0.5; p<0.05). The group of previously treated patients switched without a loading phase included 18 patients (18 eyes). By 6 months, BCVA changed from 0.42±0.2 to 0.37±0.26 LogMAR (p=0.42). CRT remained stable at 285.6±56.9 µm (p=0.97). No adverse events related to intraocular inflammation were reported during the course of 385 injections. CONCLUSION: Brolucizumab therapy helps achieve significant anatomical and functional improvements in real clinical practice both in patients switched from previous treatments and in treatment-naïve patients. Greater baseline choroidal thickness may be associated with better anatomical and functional outcomes with brolucizumab treatment.
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Inhibidores de la Angiogénesis , Anticuerpos Monoclonales Humanizados , Inyecciones Intravítreas , Agudeza Visual , Humanos , Masculino , Femenino , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado del Tratamiento , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Tomografía de Coherencia Óptica/métodos , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/diagnóstico , Degeneración Macular/fisiopatología , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatologíaRESUMEN
BACKGROUND: Equivalent efficacy and comparable pharmacokinetic, immunogenicity, and safety profiles of the biosimilar BAT1806/BIIB800 and reference tocilizumab (TCZ) in participants with moderate-to-severe rheumatoid arthritis (RA) have been reported up to week 24 (treatment period [TP] 1) of the phase 3 study. Here we present results for TP2 (study weeks 24-48). METHODS: In this phase 3, multicenter, multiregional, double-blind, active-controlled, equivalence study, participants with active RA despite methotrexate were randomized (1:1:2) to intravenous administration of 8 mg/kg TCZ every 4 weeks to week 48 (TCZ group), or TCZ to week 24 followed by BAT1806/BIIB800 to week 48 (TCZ to BAT1806/BIIB800 group), or BAT1806/BIIB800 to week 48 (BAT1806/BIIB800 group). Efficacy in TP2 was evaluated using American College of Rheumatology (ACR) response criteria (ACR20/50/70) and change from baseline in Disease Activity Score on 28 joints (DAS28). Pharmacokinetics (trough levels), safety, and immunogenicity were also evaluated. RESULTS: Of 621 randomized participants, 577 (92.9%) completed TP1 and entered TP2 (TCZ: N = 145 [93.5%]; TCZ to BAT1806/BIIB800: N = 142 [92.2%]; BAT1806/BIIB800: N = 290 [92.9%]). Proportions of ACR20 responders were similar between treatment groups throughout TP2 (87.8%, 90.3%, and 90.4%, respectively, at week 48), as were proportions of ACR50 and ACR70 responders, and reduction in DAS28. Drug trough levels and antidrug antibody incidences were comparable between the treatment groups. Adverse events were balanced across the treatment groups and no fatal events were reported. CONCLUSION: In TP2, efficacy, safety, immunogenicity, and pharmacokinetic profiles were comparable between the TCZ, TCZ to BAT1806/BIIB800, and BAT1806/BIIB800 groups. TRIAL REGISTRATION: NCT03830203 and EudraCT 2018-002202-31.
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Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Reumatoide , Biosimilares Farmacéuticos , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Metotrexato/uso terapéutico , Metotrexato/farmacocinética , Metotrexato/administración & dosificación , Femenino , Método Doble Ciego , Persona de Mediana Edad , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/uso terapéutico , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapéutico , Antirreumáticos/administración & dosificación , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado del Tratamiento , Anciano , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) is a new avenue for treating migraine. The efficacy and safety of intravenous Lu AG09222, a humanized monoclonal antibody directed against the PACAP ligand, for migraine prevention are unclear. METHODS: In a phase 2, double-blind, randomized, placebo-controlled trial, we enrolled adult participants (18 to 65 years of age) with migraine for whom two to four previous preventive treatments had failed to provide a benefit. The trial included a 4-week treatment period and an 8-week follow-up period. Participants were randomly assigned in a 2:1:2 ratio to receive a single-dose baseline infusion of 750 mg of Lu AG09222, 100 mg of Lu AG09222, or placebo. The primary end point was the mean change from baseline in the number of migraine days per month, during weeks 1 through 4, in the Lu AG09222 750-mg group as compared with the placebo group. RESULTS: Of 237 participants enrolled, 97 received 750 mg of Lu AG09222, 46 received 100 mg of Lu AG09222, and 94 received placebo. The mean number of baseline migraine days per month was 16.7 in the overall population, and the mean change from baseline over weeks 1 through 4 was -6.2 days in the Lu AG09222 750-mg group, as compared with -4.2 days in the placebo group (difference, -2.0 days; 95% confidence interval, -3.8 to -0.3; P = 0.02). Adverse events with a higher incidence in the Lu AG09222 750-mg group than in the placebo group during the 12-week observation period included coronavirus disease 2019 (7% vs. 3%), nasopharyngitis (7% vs. 4%), and fatigue (5% vs. 1%). CONCLUSIONS: In a phase 2 trial, a single intravenous infusion of 750 mg of Lu AG09222 showed superiority over placebo in reducing migraine frequency over the subsequent 4 weeks. (Funded by H. Lundbeck; HOPE ClinicalTrials.gov number, NCT05133323.).
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Anticuerpos Monoclonales Humanizados , Trastornos Migrañosos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Método Doble Ciego , Infusiones Intravenosas , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/antagonistas & inhibidores , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Brote de los SíntomasAsunto(s)
Antígeno de Maduración de Linfocitos B , Inmunosupresores , Lupus Eritematoso Sistémico , Inducción de Remisión , Adulto , Femenino , Humanos , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Antígeno de Maduración de Linfocitos B/inmunología , Resistencia a Medicamentos , Inmunosupresores/administración & dosificación , Inyecciones Subcutáneas , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Inducción de Remisión/métodosAsunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Talidomida/análogos & derivados , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacosRESUMEN
PURPOSE: Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a condition associated with high mortality, necessitating prompt recognition and treatment initiation. This study aimed to assess the impact of implementing a clinical care pathway algorithm on reducing the time to treatment for ICI-P. METHODS: Patients with lung cancer and suspected ICI-P were enrolled, and a multimodal intervention promoting algorithm use was implemented in two phases. Pre- and post-intervention analyses were conducted to evaluate the primary outcome of time from ICI-P diagnosis to treatment initiation. RESULTS: Of the 82 patients admitted with suspected ICI-P, 73.17% were confirmed to have ICI-P, predominantly associated with non-small cell lung cancer (91.67%) and stage IV disease (95%). Pembrolizumab was the most commonly used immune checkpoint inhibitor (55%). The mean times to treatment were 2.37 days in the pre-intervention phase, 3.07 days (p = 0.46), and 1.27 days (p = 0.40) in the post-intervention phases 1 and 2, respectively. Utilization of the immunotoxicity order set significantly increased from 0 to 27.27% (p = 0.04) after phase 2. While there were no significant changes in ICU admissions or inpatient mortality, outpatient pulmonology follow-ups increased statistically significantly, demonstrating enhanced continuity of care. The overall mortality for patients with ICI-P was 22%, underscoring the urgency of optimizing management strategies. Notably, all patients discharged on high-dose corticosteroids received appropriate gastrointestinal prophylaxis and prophylaxis against Pneumocystis jirovecii pneumonia infections at the end of phase 2. CONCLUSION: Implementing a clinical care pathway algorithm for managing severe ICI-P in hospitalized lung cancer patients standardizes practices, reducing variability in management.
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Algoritmos , Vías Clínicas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Neumonía , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Femenino , Anciano , Persona de Mediana Edad , Neumonía/etiología , Anciano de 80 o más Años , Hospitalización/estadística & datos numéricos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacologíaRESUMEN
Given the early use of triplet and quadruplet regimens, most patients with multiple myeloma (MM) will be exposed and/or refractory to PIs, IMiDs, and anti-CD38 mAbs after first- or second-line treatment. Effective treatment for this group of triple class exposed/refractory (TCE/R) patients is crucial. Here we present a post-hoc subgroup analysis of TCE/R patients treated on the ALGONQUIN study of belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd) for relapsed MM. Of the 99 patients treated on the ALGONQUIN study, 69 were TCE and 56 were TCR and were included in this analysis. Patients had a median of three prior lines of therapy. The ORR was 86.4% in TCE patients and 84.9% in TCR patients, with ≥ very good partial response rates of 64% and 68% respectively. The median progression free survival was 18.3 months in TCE patients and 19.6 months in TCR patients, with overall survival not yet reached and 34.4 months, respectively for TCE and TCR patients. No new safety signals were identified. The most common Grade ≥ 3 AEs were keratopathy (48%), decreased visual acuity (42%), neutropenia (36%), thrombocytopenia (27%), and infection (25%). In this subgroup analysis of the ALGONQUIN study, patients with TCE/TCR disease treated with belamaf-Pd achieved high clinical response rates with durable remissions, comparable to other novel therapeutics in this space.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Talidomida/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Compuestos de Boro/uso terapéutico , Compuestos de Boro/administración & dosificación , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resistencia a AntineoplásicosRESUMEN
Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7-78.9%) and the DCR was 76% (95% CI: 54.9-90.6%). The mPFS was 6.0 months (95% CI: 5.4-9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Indoles , Neoplasias Pulmonares , Quinolinas , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Anciano , Indoles/administración & dosificación , Indoles/uso terapéutico , Indoles/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Estadificación de Neoplasias , AlbúminasRESUMEN
We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.
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Anticuerpos Monoclonales Humanizados , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Modelos Biológicos , Trasplante Homólogo , Humanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Enfermedad Injerto contra Huésped/prevención & control , Masculino , Femenino , Persona de Mediana Edad , Adulto Joven , Anciano , Adolescente , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). METHODS: Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1-3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. RESULTS: The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. CONCLUSIONS: Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Fluorouracilo , Humanos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Fluorouracilo/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Masculino , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Persona de Mediana Edad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Anciano , Antígeno B7-H1 , Resultado del Tratamiento , Estadificación de Neoplasias , Progresión de la EnfermedadRESUMEN
This study reports a significant clinical outcome following the use of bronchoscopic interventional therapy combined with pembrolizumab for treating pulmonary large cell neuroendocrine carcinoma (LCNEC), showcasing a novel approach in managing this aggressive cancer.
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Anticuerpos Monoclonales Humanizados , Broncoscopía , Carcinoma Neuroendocrino , Neoplasias Pulmonares , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/terapia , Broncoscopía/métodos , Masculino , Resultado del Tratamiento , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/patología , Carcinoma de Células Grandes/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Persona de Mediana Edad , Terapia Combinada/métodos , Tomografía Computarizada por Rayos X/métodos , AncianoRESUMEN
Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18-70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1-5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81-99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Nervioso Central , Metotrexato , Rituximab , Temozolomida , Humanos , Masculino , Femenino , Persona de Mediana Edad , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Rituximab/administración & dosificación , Temozolomida/administración & dosificación , Temozolomida/farmacología , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Adulto , Linfoma/tratamiento farmacológico , Linfoma/genética , Linfoma/inmunologíaRESUMEN
Psossibility and appropriate timing of discontinuation of dupilumab for atopic dermatitis (AD) remain unclear. We explored the possibility of patients, who could maintain remission with topical therapy alone after withdrawing dupilumab in the real world. Furthermore, we identified their characteristics. All adult AD patients who initiated dupilumab from June 2018 to July 2022 and were treated with dupilumab for more than 3 months at our hospital were included in this study. The observation period was from June 2018 to July 2023. In 138 patients, 58 (42.0%) discontinued dupilumab at least once. Among them, 18 (13.0%) discontinued dupilumab but reinitiated dupilumab later due to exacerbation. Only seven patients (5.1%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM, VAS of pruritus, serum levels of TARC and LDH, and neutrophil counts at baseline, and those of longer duration of dupilumab until its discontinuation (24.0 ± 13.3 vs. 12.8 ± 7.3 months) and lower EASI and affected BSA at the discontinuation of dupilumab. In 118 patients treated with dupilumab for at least 1 year, 38 patients (32.2%) discontinued at least once. Only four patients (3.4%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM at baseline and lower EASI at the discontinuation of dupilumab. In conclusion, maintaining remission after withdrawing dupilumab is challenging. Discontinuation of dupilumab may be considered in patients with low baseline POEM, after more than 2 years of dupilumab treatment, with a substantial decrease in EASI.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Femenino , Masculino , Persona de Mediana Edad , Inducción de Remisión , Japón , Estudios Retrospectivos , Privación de Tratamiento , Prurito/tratamiento farmacológico , Administración Cutánea , Adulto Joven , Administración Tópica , Índice de Severidad de la Enfermedad , Pueblos del Este de AsiaRESUMEN
Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association with treatment response. Sixty-two HER2+ BC patients were recruited. Pre-treatment samples were obtained before the start of treatment, while post-treatment samples were obtained after completing therapy and before surgery and were analyzed by flow cytometry. The pathologic complete response (pCR) rate achieved was 82.3%. The expression of the NKp30, PD-1, and TIM-3 receptors was reduced in the Natural Killer (NK)-CD56dim subset of patients who did not achieve pCR. Following therapy, many changes were found in leukocytes, including alterations in T cell lymphocyte proportions. Also, the percentage of NK cells decreased, and several phenotypic changes were observed in this population. After treatment, IFN-γ production by NK cells against HER2+-cells with or without trastuzumab was significantly reduced. HER2-targeted therapy plus chemotherapy demonstrated high efficacy in most patients, reducing the statistical power for finding immunological markers. However, NK subset phenotypes correlated better with response groups, and numerous changes in the percentage of leukocytes and T and NK cells, as well as changes in the functionality of NK cells, were observed in most patients after treatment, encouraging further research into these immune populations.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Células Asesinas Naturales , Terapia Neoadyuvante , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Femenino , Terapia Neoadyuvante/métodos , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , AncianoRESUMEN
BACKGROUND: Nirsevimab is an extended half-life monoclonal antibody (mAb) licensed for the prevention of respiratory syncytial virus (RSV)-associated lower respiratory tract disease in neonates, infants and medically vulnerable children. We characterized RSV isolates recovered from participants enrolled in MEDLEY: a randomized, palivizumab-controlled phase 2/3 trial of nirsevimab in infants born preterm and/or with congenital heart disease or chronic lung disease of prematurity. METHODS: Participants were assessed in two RSV seasons (Season 1 and 2). Season 1 participants were randomized (2:1) to receive a single dose of nirsevimab (50 mg if weight <5 kg or 100 mg if weight ≥5 kg in Season 1; 200 mg in Season 2) followed by four monthly doses of placebo, or five once-monthly doses of palivizumab (15 mg/kg weight per dose). Season 2 participants continued nirsevimab and placebo (nirsevimab/nirsevimab) or were re-randomized (1:1) to switch to nirsevimab (palivizumab/nirsevimab) or continue palivizumab (palivizumab/palivizumab). Cases of RSV infection were identified by central testing of nasal swabs from participants seeking medical attention for respiratory illnesses. Nirsevimab and palivizumab binding site substitutions were assessed via microneutralization assay. RESULTS: Twenty-five cases of confirmed RSV infection were observed during the trial and sequenced: 12 in nirsevimab recipients and 10 in palivizumab recipients during Season 1, and 1 case in each Season 2 group. Molecular sequencing of RSV A (n = 14) isolates detected no nirsevimab binding site substitutions, and 3 palivizumab neutralization-resistant substitutions (Lys272Met, Lys272Thr, Ser275Leu). The nirsevimab binding site Ile206Met:Gln209Arg and Ile206Met:Gln209Arg:Ser211Asn substitutions were the only anti-RSV mAb binding site substitutions detected among RSV B isolates (n = 11). Nirsevimab neutralized all nirsevimab and palivizumab binding site substitutions in RSV A and B isolates recovered from MEDLEY participants. CONCLUSION: No binding site substitution detected during MEDLEY affected RSV susceptibility to nirsevimab neutralization.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Antivirales , Palivizumab , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Palivizumab/uso terapéutico , Palivizumab/administración & dosificación , Infecciones por Virus Sincitial Respiratorio/prevención & control , Lactante , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Método Doble Ciego , Masculino , Virus Sincitial Respiratorio Humano/inmunología , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Virus Sincitial Respiratorio Humano/genética , Femenino , Recién Nacido , Anticuerpos Antivirales/inmunología , Preescolar , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangreRESUMEN
An 84-year-old woman underwent laparoscopic partial hepatectomy for a single 3.0-cm-diameter nodule of hepatocellular carcinoma at segment 5. Although the postoperative condition was uneventful, multiple recurrences were observed six months after hepatic resection. Transcatheter arterial chemoembolization (TACE) was the second-line therapy. However, she was later diagnosed as TACE refractory due to residual tumor and presence of portal vein tumor thrombus. Third-line therapy was the combination of atezolizumab and bevacizumab, which was discontinued after 22 courses due to disease progression. Two months after the conclusion of chemotherapy, sudden onset of purpura was observed around her eyes and on her lower legs. Laboratory tests revealed severe thrombocytopenia, and she was diagnosed with secondary immune thrombocytopenic purpura. Steroids and immunoglobulin therapy were then administered. Although the immature platelet fraction increased after treatment, the platelet count did not. The patient died of intracranial hemorrhage 10 days after initiation of steroid and immunoglobulin therapy.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Bevacizumab , Carcinoma Hepatocelular , Neoplasias Hepáticas , Púrpura Trombocitopénica Idiopática , Humanos , Femenino , Neoplasias Hepáticas/tratamiento farmacológico , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Resultado Fatal , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/diagnóstico por imagen , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear. METHODS: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate. RESULTS: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab. CONCLUSIONS: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Quimioradioterapia Adyuvante , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Anciano , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Recurrencia Local de Neoplasia/terapia , Terapia Neoadyuvante/métodos , Quimioradioterapia Adyuvante/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , EsofagectomíaRESUMEN
RATIONALE: Cytokine release syndrome (CRS) is a common adverse event of chimeric antigen receptor T (CAR-T) cell therapy. CRS is generally a systemic inflammatory reaction, but in rare cases, it can occur in specific body areas and is referred to as "local CRS (L-CRS)." A case of laryngeal edema due to L-CRS that required tracheal intubation because of the lack of response to tocilizumab (TCZ) and dexamethasone (DEX) is reported. PATIENT CONCERNS: A 67-year-old woman with relapsed transformed follicular lymphoma was treated with CAR-T cell therapy. Although she had been given TCZ and DEX for CRS, neck swelling appeared on day 4 after infusion. DIAGNOSES: Laryngoscopy showed severe laryngeal edema, which was presumed to be due to L-CRS, since there were no other apparent triggers based on history, physical examination, and computed tomography. INTERVENTIONS: Tracheal intubation was performed because of the risk of upper airway obstruction. Ultimately, 4 doses of tocilizumab (8 mg/kg) and 6 doses of dexamethasone (10 mg/body) were required to improve the L-CRS. OUTCOMES: On day 7, laryngeal edema improved, and the patient could be extubated. LESSONS: The lessons from this case are, first, that CAR-T cell therapy may induce laryngeal edema in L-CRS. Second, TCZ alone may be ineffective in cervical L-CRS. Third, TCZ, as well as DEX, may be inadequate. In such cases, we should recognize L-CRS and manage it early because it may eventually progress to laryngeal edema that requires securing the airway.