RESUMEN
Metastatic urothelial carcinoma (muC) has historically had few effective therapeutic options. Recently, immune checkpoint inhibitors (ICIs), were introduced as therapeutic options for cisplatin-ineligible patients, however, direct head-to-head trials comparing these treatments are lacking. To address this gap, this study employs a Bayesian framework to indirectly compare the performance of ICIs as first-line agents for muC. A systematic review was performed to identify randomized controlled trials evaluating different ICI for mUC. Data was inputted into Review Manager 5.4 for pairwise meta-analysis. Data was then used to build a network in R Studio. These networks were used to model 200,000 Markov Chains via MonteCarlo sampling. The results are expressed as hazard ratios (HR) with 95% credible intervals (CrI). Six studies with 5,449 patients were included, 3,255 received ICI monotherapy or combination. Moreover, a total of 3,006 had PD-L1 positive tumors and 2,362 were PD-L1 negative. Median overall survival (OS) ranged from 12.1 to 31.5 months across the studies, with the combination of enfortumab vedotin and pembrolizumab demonstrating the most substantial reduction in the risk of death (HR 0.47 [95% CrI: 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI: 0.56, 0.86]). The limitations of this network meta-analysis include variability in study follow-up duration, lack of standardized methods for assessing PD-L1 positivity, and potential bias introduced by control arms with poorer survival outcomes across included trials. The enfortumab vedotin/pembrolizumab combination significantly improved survival and response rates. Avelumab showed notable single-agent activity. These findings provide a valuable framework to guide clinical decision-making and highlight priority areas for future research, including biomarker refinement and novel combination strategies to enhance antitumor immunity in this challenging malignancy.
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Teorema de Bayes , Carcinoma de Células Transicionales , Inhibidores de Puntos de Control Inmunológico , Metaanálisis en Red , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: This study aimed to evaluate the utility of RECIST criteria-based objective response rate (ORR) as a potential surrogate endpoint for long-term overall survival (OS) in patients with metastatic urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs). METHODS: The primary endpoint was overall ORR and OS, duration of treatment (DoR) with ICIs. ORR was analyzed using Fisher's exact test. Median follow-up and OS were estimated by using the Kaplan-Meier method. RESULTS: The median follow-up was 58 (1.15-71) months. Progression developed in 94 (47%) patients during the first 3 months of ICIs therapy. The treatment response to ICIs included complete response (CR), partial response (PR) and stable disease in 10% (n = 20), 23% (n = 46), and 20% (n = 41) of patients, respectively. The responder and nonresponder groups differed in terms of certain baseline characteristics, such as Bellmunt risk factors, and neutrophil-to-lymphocyte ratio (NLR). The 5-year OS rates for patients with CR and PR were 73% and 23%, respectively. The median DoR for CR, PR, and SD were 51.8 months (44.5-59.1), 20.7 months (16.7-24.6), and 8.8 months (5.5-12.1), respectively. Overall, 16(80%) patients with CR and 14(30%) patients with PR had an ongoing response at the time of the analysis. In the univariate analysis, NLR > 3, liver metastases, ECOG PS ≥ 1, and hemoglobin levels < 10 mg/dl, as well as the PR and CR, were all significantly associated with OS. In multivariate analysis, presence of liver metastases (HR 2.3; 95% CI, 1.3-4.2; P < .004) was found to be an independent determinant of short OS, while PR (HR 0.3; 95% CI, 0.15-0.5; P < .001) and CR (HR 0.06; 95% CI, 0.014-0.27; P < .001) were associated with improved OS. CONCLUSIONS: In conclusion, this 5-year analysis of real-world data in the setting of metastatic urothelial cancer indicated a significant correlation between ORR, especially CR, and OS in patients who received ICIs. Therefore, identifying a potential surrogate marker for survival in patients treated with ICIs would represent an important advance in the early identification of patients' response or resistance to ICIs.
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Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del Tratamiento , Estudios Retrospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/inmunología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/secundario , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología , Neoplasias Urológicas/inmunología , Estudios de Seguimiento , Tasa de Supervivencia , Estimación de Kaplan-MeierRESUMEN
OBJECTIVE: To test the association between number as well as locations of organ-specific metastatic sites and overall survival (OS) in systhemic-therapy exposed metastatic urothelial carcinoma of urinary bladder (mUCUB) patients. METHODS: Within Surveillance, Epidemiology and End Results database (2010-2020), all systhemic therapy-exposed mUCUB patients were identified. Kaplan-Meier and multivariable Cox regression (CRM) models first addressed OS in patients according to number of metastatic organ-locations: solitary versus 2 versus 3 or more. Subsequently, separate analyses stratified according to location type were completed in patients with solitary metastatic organ-location as well as in patients with 2 metastatic organ-locations. RESULTS: Of 1,310 mUCUB, 1,069 (82%) harbored solitary metastatic organ-location versus 193 (15%) harbored 2 separate metastatic organ-locations versus 48 (3%) harbored 3 or more metastatic organ-locations. Median OS decreased with increasing number of metastatic organ-locations (solitary vs. 2 vs. 3 or more, P < .0001). In multivariable CRM, relative to solitary metastatic organ-location, 2 (HR: 1.57, 95 Confidence interval [CI], 1.33-1.85) as well as 3 or more (HR: 1.69, 95% CI, 1.23-2.31) metastatic organ-locations independently predicted higher overall mortality (OM) (P = .001). In patients with solitary metastatic organ-location, brain metastases independently predicted higher OM (HR 1.67; 95% CI, 1.05-2.67; P = .03) than other locations. In patients with 2 metastatic organ-locations, no differences in OM were recorded according to organ type location. CONCLUSION: In systemic therapy exposed mUCUB, number of metastatic organ-locations (solitary vs. 2 vs. 3 or more), independently predicted increasingly worse prognosis. In patients with solitary metastatic organ-location, brain purported worse prognosis than others.
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Carcinoma de Células Transicionales , Programa de VERF , Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Femenino , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Anciano , Persona de Mediana Edad , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/secundario , Pronóstico , Tasa de Supervivencia , Estudios Retrospectivos , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: To evaluate the organ-specific therapeutic effect of enfortumab vedotin (EV) after chemotherapy and immunotherapy failed for advanced urothelial carcinoma. MATERIALS METHODS: At 6 institutions between December 2021 and July 2023, we retrospectively analyzed patients with metastatic upper and lower urinary tract cancer who received EV monotherapy after platinum-based chemotherapy and immune checkpoint blockade therapy. Objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: This study analyzed 58 patients with 210 tumor lesions, of which 24% were females and 48% had upper urinary tract cancer. The ORR and disease control rate were 53.5% and 74.1%. Moreover, we found 15 target lesions in the primary site, 7 in local recurrence, 93 in the lymph nodes, 46 in the lung, 29 in the liver, and 20 in the bone, with OSRRs of 40%, 71.4%, 61.1%, 70.6%, 90.9%, and 18.2%, respectively. Over time from baseline, the reduction rate (median) in tumor burden was 50% or more in the lymph node, lung, and liver metastases. CONCLUSION: The organ-specific tumor response to EV in patients with metastatic urothelial carcinoma was almost favorable. The antitumor activity of EV monotherapy may be less in bone metastasis than in other organ sites. Conversely, EV showed remarkably high efficacy against liver metastasis.
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Anticuerpos Monoclonales , Humanos , Femenino , Masculino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anciano de 80 o más Años , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Resultado del Tratamiento , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Adulto , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Metástasis de la Neoplasia , Antineoplásicos Inmunológicos/uso terapéuticoAsunto(s)
Acrodermatitis , Humanos , Acrodermatitis/tratamiento farmacológico , Acrodermatitis/patología , Masculino , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidoresRESUMEN
BACKGROUND: Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab. METHODS: A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rate on ICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup. RESULTS: ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from - 29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT. CONCLUSIONS: Our study provides real-world evidence regarding difference of oncological efficacy between maintenance avelumab and subsequent pembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT.
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Anticuerpos Monoclonales Humanizados , Inhibidores de Puntos de Control Inmunológico , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Anciano , Persona de Mediana Edad , Japón , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Supervivencia sin Progresión , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Estudios Retrospectivos , Adulto , Pueblos del Este de AsiaRESUMEN
BACKGROUND: This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. METHODS: This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. RESULTS: During the median follow-up period of 7.3 months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2 g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42 mg/L was a significant prognostic factor for OS (p = 0.001). CONCLUSION: The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.
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Anticuerpos Monoclonales Humanizados , Humanos , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Adulto , Biomarcadores de Tumor , Antineoplásicos Inmunológicos/uso terapéutico , Supervivencia sin Progresión , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/mortalidad , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/inmunología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , NeutrófilosRESUMEN
BACKGROUND: The PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib. PATIENTS AND METHODS: This was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders. RESULTS: 22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders. CONCLUSIONS: Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.
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Protocolos de Quimioterapia Combinada Antineoplásica , Paclitaxel , Humanos , Masculino , Femenino , Anciano , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Anciano de 80 o más Años , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Mutación , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Adulto , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/secundario , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Inhibidores mTOR/administración & dosificación , Inhibidores mTOR/uso terapéutico , Resultado del Tratamiento , Supervivencia sin Progresión , Esquema de Medicación , Adenina/análogos & derivados , Benzoxazoles , Serina-Treonina Quinasas TORRESUMEN
BACKGROUND/AIM: The number of available treatment options for urothelial carcinoma has increased recently. Upper tract urothelial carcinoma (UTUC) is relatively rare compared with bladder cancer. There are few reports on the efficacy of immune checkpoint inhibitors (ICIs) for metastatic UTUC, and ICIs may occasionally show less efficacy and cause severe side effects. Therefore, it is important to predict the treatment response and change the treatment strategy as appropriate. We investigated the prognostic factors for treatment response in patients with metastatic UTUC treated with pembrolizumab at our hospital. PATIENTS AND METHODS: Patients who received pembrolizumab for UTUC between January 2018 and June 2023 were analyzed. Patients who presented with bladder cancer complications at initial diagnosis were excluded. The primary endpoints assessed were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted using laboratory values obtained before and after pembrolizumab administration. The relationship between cancer and inflammation is important. Therefore, we analyzed this relationship using prognostic factors for urothelial carcinoma as previously reported. Specifically, pretreatment C-reactive protein (CRP) level, neutrophil-to-lymphocyte ratio (NLR), and NLR/albumin values were examined. RESULTS: Forty-seven patients were analyzed. The median PFS was 66 days (24-107 days), and the median OS was 164 days (13-314 days). A CRP level <1 before the first cycle was a useful factor in the multivariate analysis for both OS and PFS [OS: p=0.004, hazard ratio (HR)=3.244, 95% confidence interval (CI)=1.464-7.104; PFS: p=0.003, HR=2.998, 95%CI=1.444-6.225]. CONCLUSION: CRP level is a prognostic factor for pembrolizumab treatment response in patients with UTUC.
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Anticuerpos Monoclonales Humanizados , Proteína C-Reactiva , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Masculino , Proteína C-Reactiva/metabolismo , Anciano , Pronóstico , Persona de Mediana Edad , Anciano de 80 o más Años , Biomarcadores de Tumor , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/patología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Metástasis de la NeoplasiaAsunto(s)
Carcinoma de Células Transicionales , Calidad de Vida , Neoplasias de la Vejiga Urinaria , Humanos , Arabia Saudita/epidemiología , Carcinoma de Células Transicionales/terapia , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/patología , República de Corea/epidemiología , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/psicología , Taiwán/epidemiología , Turquía/epidemiología , Neoplasias Urológicas/terapia , Neoplasias Urológicas/patologíaAsunto(s)
Carcinoma de Células Renales , Inmunoterapia , Neoplasias Renales , Sodio , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Inmunoterapia/métodos , Sodio/sangre , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/inmunología , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/patología , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
INTRODUCTION: Concomitant medications can affect the efficacy of immune checkpoint inhibitors. The association between histamine-2 receptor antagonists (H2RAs), major antacids similar to proton pump inhibitors (PPIs), and the efficacy of pembrolizumab for metastatic urothelial carcinoma (mUC) treatment has been poorly evaluated. We evaluated the impact of PPIs and H2RAs on oncological outcomes in mUC patients treated with pembrolizumab. PATIENTS AND METHODS: This retrospective multicenter study included patients with mUC treated with pembrolizumab. Patients prescribed PPIs or H2RAs within 30 days before and after the initial administration were extracted. The overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rates (ORR) were assessed. Kaplan-Meier survival curve analysis and multivariable Cox proportional hazard models were employed to assess the association between PPIs or H2RAs and survival outcomes. RESULTS: Overall, 404 patients were eligible for this study; 121 patients (29.9%) used PPIs, and 34 (8.4%) used H2RAs. Kaplan-Meier analysis showed significantly worse OS, CSS, and PFS in patients using PPIs compared to no PPIs (P = .010, .018, and .012, respectively). In multivariable analyses, the use of PPIs was a significant prognostic factor for worse OS (HR = 1.42, 95% CI 1.08-1.87, P = .011), CSS (HR = 1.45, 95% CI 1.09-1.93, P = .011), and PFS (HR = 1.35, 95% CI 1.05-1.73, P = .020). PPIs were not associated with ORRs. The use of H2RAs was not associated with survival or ORRs. CONCLUSION: PPIs were significantly associated with worse survival of patients with mUC treated with pembrolizumab, and H2RAs could be an alternative during administration. Both the oncological and gastrointestinal implications should be carefully considered when switching these antacids.
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Antiácidos , Anticuerpos Monoclonales Humanizados , Antagonistas de los Receptores H2 de la Histamina , Humanos , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Antiácidos/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Anciano de 80 o más Años , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología , Antineoplásicos Inmunológicos/uso terapéutico , Estimación de Kaplan-Meier , Resultado del Tratamiento , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/secundario , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , PronósticoRESUMEN
BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).
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Carcinoma de Células Transicionales , Neoplasias Renales , Nefroureterectomía , Neoplasias Ureterales , Humanos , Femenino , Masculino , Anciano , Neoplasias Ureterales/cirugía , Neoplasias Ureterales/mortalidad , Neoplasias Ureterales/patología , Neoplasias Ureterales/terapia , Carcinoma de Células Transicionales/cirugía , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/secundario , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Neoplasias Renales/mortalidad , Neoplasias Renales/terapia , Tasa de Supervivencia , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Combinada , Estadificación de Neoplasias , Anciano de 80 o más AñosRESUMEN
Importance: Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective: To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants: In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions: All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures: The primary end point was objective response rate. Results: The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance: In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration: ClinicalTrials.gov Identifier: NCT03219775.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Ipilimumab , Nivolumab , Humanos , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Ipilimumab/uso terapéutico , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Masculino , Anciano , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Adulto , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/inmunología , Metástasis de la Neoplasia , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/inmunología , Inmunoterapia/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
OBJECTIVES: To evaluate demographic and clinical characteristics, treatment patterns, and quality of life in patients with locally advanced or metastatic urothelial carcinoma in Asia. METHODS: Data were drawn from the Adelphi Real World Metastatic Urothelial Carcinoma Disease Specific Programme™, a cross-sectional survey of medical oncologists/urologists and their adult patients in Saudi Arabia, South Korea, Taiwan, and Turkey. Exploratory patient-reported outcomes included the EQ-5D visual analog scale, European Organisation for Research and Treatment of Cancer Quality of Life of Patient Questionnaire global health, and Brief Pain Inventory. Analyses were descriptive. RESULTS: Overall, 175 physicians reported data for 988 patients. Mean (standard deviation) patient age was 66.3 (10.8) years, 77% were men, and 82% had bladder tumors at diagnosis. Of patients receiving first- (n = 988), second- (n = 290), and third-line (n = 87) treatments, 81%, 35%, and 59% received chemotherapy, respectively, and 17%, 63%, and 34% received programmed cell death protein 1/ligand 1 inhibitors, respectively. Patient-reported (n = 319) mean (standard deviation) EQ-5D visual analog scale score was 51.8 (15.6), European Organisation for Research and Treatment of Cancer Quality of Life of Patient Questionnaire global health status score was 44.6 (19.9), and Brief Pain Inventory score was 6.5 (1.9; n = 315). CONCLUSION: The most common first- and second-line treatments for locally advanced or metastatic urothelial carcinoma were chemotherapy and programmed cell death protein 1/ligand inhibitors, respectively. At third line, 10% of patients received best supportive care alone, underscoring an unmet need for effective third-line treatment options. Patients in all regions reported quality-of-life impairment.
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Carcinoma de Células Transicionales , Calidad de Vida , Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Transversales , Taiwán/epidemiología , Carcinoma de Células Transicionales/terapia , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/patología , Arabia Saudita/epidemiología , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/psicología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Turquía/epidemiología , República de Corea/epidemiología , Medición de Resultados Informados por el Paciente , Pautas de la Práctica en Medicina/estadística & datos numéricosRESUMEN
There is no clear standard-of-care treatment for patients with metastatic urothelial carcinoma following progression on enfortumab vedotin and pembrolizumab, although multiple regimens are available, including platinum-based chemotherapy, sacituzumab govitecan, and erdafitinib for selected patients. Clinical trials will be important in informing decisions on the best treatment.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Carcinoma de Células Transicionales , Progresión de la Enfermedad , Neoplasias de la Vejiga Urinaria , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patologíaRESUMEN
OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.
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Inmunoconjugados , Humanos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , China , Persona de Mediana Edad , Anciano de 80 o más Años , Receptor ErbB-2/metabolismo , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Supervivencia sin Progresión , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Resultado del Tratamiento , AdultoRESUMEN
BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CIï¼38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CIï¼70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CIï¼5.4-NE) and 14.9 months (95%CIï¼11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Inmunoconjugados , Receptor ErbB-2 , Humanos , Femenino , Masculino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Anciano , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Adulto , Anciano de 80 o más Años , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundarioRESUMEN
OBJECTIVES: The development of reliable biomarkers for the prediction of immune checkpoint inhibition (ICI) response in patients with metastatic renal cell carcinoma (mRCC) and urothelial carcinoma (mUC) remains an unresolved challenge. Conventional ICI biomarkers typically focus on tumor-related factors such as PD-L1 expression. However, a comprehensive evaluation of the predictive value of serum electrolyte levels, a so far widely unexplored area, is still pending. METHODS: We conducted a post-hoc analysis of baseline sodium, potassium, chloride, magnesium and calcium levels in two independent phase 3 clinical trials: IMvigor211 for mUC comparing atezolizumab to chemotherapy, and IMmotion151 for mRCC comparing atezolizumab+bevacizumab to sunitinib. This analysis aimed to evaluate the prognostic and predictive value of these electrolyte levels in these clinical settings. A total of 1787 patients (IMvigor211 n = 901; IMmotion151 n = 886) were analyzed. RESULTS: We found a linear correlation of baseline serum sodium and chloride with prognosis across both trials, which was not found for potassium, magnesium and calcium. In multivariate analysis, the prognostic capacity of sodium was limited to patients receiving ICI as compared to the control group. Interestingly, in both studies, the chance of achieving an objective response was highest in the patient subgroup with high baseline serum sodium levels of > 140 mmol/L (IMmotion151: Complete response in 17.9% versus 2.0% in patients with mRCC with baseline sodium < 135 mmol/L). Serum sodium outperformed tumor PD-L1 expression as a predictor for immunotherapy efficacy. CONCLUSIONS: Patients exhibiting elevated serum sodium levels derive the greatest benefit from immunotherapy, suggesting that baseline serum concentration could serve as a valuable and cost-effective predictive biomarker for immunotherapy across entities.
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Carcinoma de Células Renales , Neoplasias Renales , Sodio , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/sangre , Neoplasias Renales/patología , Neoplasias Renales/inmunología , Masculino , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/patología , Femenino , Sodio/sangre , Anciano , Persona de Mediana Edad , Inmunoterapia/métodos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab/uso terapéutico , Biomarcadores de Tumor/sangre , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sunitinib/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/sangre , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/inmunologíaRESUMEN
Aim: This study assessed real-world treatment in patients with metastatic urothelial carcinoma (mUC) in Germany. Materials & methods: Patients diagnosed with mUC from 2015 to 2019 were identified in two claims databases: AOK PLUS and GWQ. Results: 3226 patients with mUC were analyzed; 1286 (39.9%) received systemic treatment within 12 months of diagnosis (platinum-based chemotherapy: 64.2%). Factors associated with receiving treatment were: younger age, male sex, less comorbidity and recent diagnosis. In AOK PLUS and GWQ populations, unadjusted median overall survival (interquartile range) from diagnosis in treated patients was 13.7 (6.8-32.9) and 13.8 (7.1-41.7) months, and in untreated patients was 3.0 (1.2-10.8) and 3.6 (1.2-18.8) months, respectively. Conclusion: A significant proportion of patients with mUC in Germany receive no systemic treatment.
What is this article about? This article reports the results from a study in Germany between 2015 and 2019 that investigated how advanced bladder cancer that has spread to other organs was treated and how long people lived after diagnosis. The study looked at systemic therapies, which means treatments that affect the entire body.What were the results? Only 40% of people diagnosed with advanced bladder cancer received systemic treatment within the first 12 months. Of those who did receive systemic treatment, the majority received combination therapy that included a chemotherapy drug containing platinum (64%). Systemic treatment was more likely to be given to people who were younger, less sick, male, or more recently diagnosed. After 12 months, 56% of treated people were still alive, compared with 26% of people without treatment. On average, people who received systemic treatment lived for about 14 months, while people without systemic treatment lived for only 3 to 4 months.What do the results of the study mean? Many people with advanced bladder cancer in Germany do not receive systemic treatment. People who receive treatment are likely to live longer than those who do not receive treatment.