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BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Nefrectomía , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Quimioterapia Adyuvante/efectos adversos , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Análisis de Intención de Tratar , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Recurrencia , Análisis de SupervivenciaRESUMEN
Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
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Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Quinolinas/farmacología , Quinolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-3/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mutación Missense , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/efectos adversos , Receptor ErbB-2/química , Receptor ErbB-2/genética , Receptor ErbB-3/química , Receptor ErbB-3/genética , Resultado del TratamientoRESUMEN
INTRODUCTION: This study investigates how quantitative texture analysis can be used to non-invasively identify novel radiogenomic correlations with clear cell renal cell carcinoma (ccRCC) biomarkers. METHODS: The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma open-source database was used to identify 190 sets of patient genomic data that had corresponding multiphase contrast-enhanced CT images in The Cancer Imaging Archive. 2,824 radiomic features spanning fifteen texture families were extracted from CT images using a custom-built MATLAB software package. Robust radiomic features with strong inter-scanner reproducibility were selected. Random forest, AdaBoost, and elastic net machine learning (ML) algorithms evaluated the ability of the selected radiomic features to predict the presence of 12 clinically relevant molecular biomarkers identified from the literature. ML analysis was repeated with cases stratified by stage (I/II vs. III/IV) and grade (1/2 vs. 3/4). 10-fold cross validation was used to evaluate model performance. RESULTS: Before stratification by tumor grade and stage, radiomics predicted the presence of several biomarkers with weak discrimination (AUC 0.60-0.68). Once stratified, radiomics predicted KDM5C, SETD2, PBRM1, and mTOR mutation status with acceptable to excellent predictive discrimination (AUC ranges from 0.70 to 0.86). CONCLUSIONS: Radiomic texture analysis can potentially identify a variety of clinically relevant biomarkers in patients with ccRCC and may have a prognostic implication.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/genética , Neoplasias Renales/patología , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/métodos , Aprendizaje Automático , Estudios RetrospectivosRESUMEN
BACKGROUND: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated. METHODS: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2. RESULTS: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC. CONCLUSIONS: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02599324.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Piperidinas , Adenina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. FINDINGS: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab. INTERPRETATION: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy. FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.
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Carcinoma de Células Renales , Hipertensión , Neoplasias Renales , Adulto , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/cirugía , Método Doble Ciego , Estudios de Seguimiento , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/etiología , Neoplasias Renales/cirugía , Nefrectomía/efectos adversosRESUMEN
PURPOSE: There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer. MATERIALS AND METHODS: Evolution of modern bladder cancer management and its impact on outcomes was analyzed using a longitudinal cohort of 3,347 patients who underwent RC at an academic center between 1971 and 2018. Outcomes included recurrence-free survival (RFS) and overall survival (OS). Associations were assessed using univariable and multivariable models. RESULTS: In all, 70.9% of cases underwent open RC in the last decade, although trend for robot-assisted RC rose since 2009. While lymphadenectomy template remained consistent, nodal submission changed to anatomical packets in 2002 with increase in yield (p <0.001). Neoadjuvant chemotherapy (NAC) use increased with time with concomitant decrease in adjuvant chemotherapy; this was notable in the last decade (p <0.001) and coincided with improved pT0N0M0 rate (p=0.013). Median 5-year RFS and OS probabilities were 65% and 55%, respectively. Advanced stage, NAC, delay to RC, lymphovascular invasion and positive margins were associated with worse RFS (all, multivariable p <0.001). RFS remained stable over time (p=0.73) but OS improved (5-year probability, 1990-1999 51%, 2010-2018 62%; p=0.019). Among patients with extravesical and/or node-positive disease, those who received NAC had worse outcomes than those who directly underwent RC (p ≤0.001). CONCLUSIONS: Despite perioperative and surgical advances, and improved pT0N0M0 rates, there has been no overall change in RFS trend following RC, although OS rates have improved. While patients who are downstaged with NAC derive great benefit, our real-world experience highlights the importance of preemptively identifying NAC nonresponders who may have worse post-RC outcomes.
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Carcinoma de Células Transicionales/terapia , Cistectomía/tendencias , Recurrencia Local de Neoplasia/epidemiología , Procedimientos Quirúrgicos Robotizados/tendencias , Neoplasias de la Vejiga Urinaria/terapia , Centros Médicos Académicos/estadística & datos numéricos , Centros Médicos Académicos/tendencias , Anciano , California/epidemiología , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Quimioterapia Adyuvante/estadística & datos numéricos , Quimioterapia Adyuvante/tendencias , Cistectomía/métodos , Cistectomía/estadística & datos numéricos , Supervivencia sin Enfermedad , Femenino , Humanos , Escisión del Ganglio Linfático/estadística & datos numéricos , Escisión del Ganglio Linfático/tendencias , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/estadística & datos numéricos , Terapia Neoadyuvante/tendencias , Recurrencia Local de Neoplasia/prevención & control , Estudios Prospectivos , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/estadística & datos numéricos , Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
PURPOSE OF REVIEW: The field of liquid biopsies is constantly evolving through novel technologies. This review outlines current data on liquid biopsies and application to clinical management of metastatic prostate cancer. RECENT FINDINGS: To date, there are three platforms with FDA approval for use in the setting of metastatic prostate cancer and others which have been clinically validated. There is substantial evidence supporting the use of circulating tumor cell (CTC) enumeration to guide prognosis in metastatic castration-resistant prostate cancer (mCRPC). Additional evidence supports targeted sequencing of CTC and cell-free DNA (cfDNA) to guide androgren-directed therapy, identify candidates for treatment with PARP inhibitors, and monitor development of resistance. As a real-time and minimally invasive approach, utilization of liquid biopsies has the potential to drastically impact the treatment of metastatic prostate cancer and improve overall survival. With further clinical validation, additional liquid biopsy is likely to enter standard clinical practice.
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Células Neoplásicas Circulantes , Neoplasias de la Próstata Resistentes a la Castración , Biomarcadores de Tumor/genética , Humanos , Biopsia Líquida , Masculino , Células Neoplásicas Circulantes/patología , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
BACKGROUND: Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. METHODS: EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. FINDINGS: Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. INTERPRETATION: Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. FUNDING: Astellas Pharma Global Development and Seagen.
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Antígeno B7-H1/genética , Carcinoma/tratamiento farmacológico , Moléculas de Adhesión Celular/genética , Receptor de Muerte Celular Programada 1/genética , Neoplasias Urológicas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma/genética , Carcinoma/patología , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias Urológicas/genética , Neoplasias Urológicas/patología , Urotelio/efectos de los fármacos , Urotelio/patologíaRESUMEN
Background CD-30 is highly expressed in some patients with non-seminomatous germ-cell tumors. Brentuximab vedotin is an antibody-drug conjugate directed to CD-30. We report a phase 2 trial of brentuximab vedotin in patients with chemo-refractory GCT. Patients and methods This is a single arm, two cohort phase 2 trial investigating brentuximab vedotin 1.8 mg/kg IV every 3 weeks until disease progression or intolerable toxicities in patients with relapsed GCT who have no curative options. Patients with mGCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (high-dose or standard-dose chemotherapy) were eligible. CD30 expression was assessed and two cohorts defined: CD30 positive and CD30 negative/unknown. Results 18 patients were enrolled. Median age 34.7 (range, 23-56). All patients had non-seminoma. Median AFP 4.9 (range, 1-219,345) and hCG 282 (range, 0.6-172,064). Five patients had late relapse (> 2 years). Median number of previous chemotherapy regimens was 3 (range, 2-7). Ten patients received prior high-dose chemotherapy. Seven patients had positive CD30 staining. There were two grade 3 treatment-related adverse events. No partial or complete responses were observed. 6 patients achieved radiographic stable disease (range, 9-14.9 weeks), 5 had elevated AFP or hCG at trial entry and all 5 had transient > 50% decline in baseline AFP/hCG: 4 had CD30 -ve and 2 had CD30 + ve staining; 10 patients had progression of disease as their best response; 2 were not evaluable for response. Conclusion Brentuximab vedotin does not appear to have clinically meaningful single-agent activity in patients with refractory GCT.
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Antineoplásicos Inmunológicos/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Antígeno Ki-1/efectos de los fármacos , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Testiculares/tratamiento farmacológico , Adulto , Antineoplásicos Inmunológicos/farmacología , Brentuximab Vedotina/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patologíaRESUMEN
BACKGROUND: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models including modulation of apoptosis in bladder cancer cell lines. We evaluated the efficacy and toxicity of the HDACi vorinostat in patients with mUC failing first-line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease. METHODS: Vorinostat was given orally 200 mg twice daily continuously until progression or unacceptable toxicity. The primary end point was RECIST response rate (RR); a RR > 20% was deemed interesting in a 2-stage design requiring one response in the first 12 patients to proceed to 2nd stage for a total of 37 subjects. CT or MRI scan imaging occurred every 6 weeks. RESULTS: Fourteen patients were accrued characterized by: median age 66 years (43-84); Caucasian (79%); males (86%); and Karnofsky performance status ≥90 (50%). Accrual was terminated in the first stage as no responses were observed. Best response was stable disease (3 patients). Progression was observed in 8 patients. Two patients came off therapy prior to re-imaging and a 3rd patient died while on treatment and was not assessed for response. Median number of cycles was 2 (range 1-11). Median disease-free survival and overall survival times were 1.1 (0.8, 2.1) & 3.2 (2.1, 14.5) months, respectively. Toxicities were predominantly cytopenias and thrombocytopenic bleeding. Two pts. had grade 5 toxicity unlikely related to treatment. Two pts. had grade 4 and 6 had grade 3 toxicities observed. Two patients with stable disease remained on therapy for 6+ cycles. CONCLUSIONS: Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Vorinostat/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Femenino , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Resultado del Tratamiento , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología , Urotelio/patología , Vorinostat/efectos adversosRESUMEN
BACKGROUND: Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings. METHODS: Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin-fixed, paraffin-embedded tissues. Blood was collected for cell-free DNA analysis using a 600-gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response [PR] plus complete response [CR]) and disease control rate (DCR; CR plus PR plus stable disease [SD]) were characterized. RESULTS: A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%). CONCLUSIONS: Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3-restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.
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Ácidos Nucleicos Libres de Células/análisis , Mutación , Compuestos de Fenilurea/uso terapéutico , Pirimidinas/uso terapéutico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
BACKGROUND: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. METHODS: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. RESULTS: The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). CONCLUSIONS: Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Docetaxel , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Paclitaxel/uso terapéutico , Compuestos de Platino/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Análisis de Supervivencia , Taxoides/uso terapéutico , Neoplasias Urológicas/patología , Urotelio , Vinblastina/análogos & derivados , Vinblastina/uso terapéuticoRESUMEN
CDX-014 is an antibody-drug conjugate directed against TIM-1, a surface marker highly expressed in renal cell carcinoma (RCC) and ovarian carcinoma. This phase I, first-in-human trial was conducted to evaluate the safety and preliminary activity of CDX-014 in patients with advanced refractory RCC, following a dose-escalation and dose expansion design. CDX-014 was administered intravenously at doses ranging from 0.15 to 2.0 mg/kg every 2 or 3 weeks until progression or unacceptable toxicity. Sixteen patients received at least one dose of CDX-014. The maximum tolerated dose was not identified. Most frequent adverse grade 1 or 2 adverse events included nausea (38%), fatigue, alopecia, elevation of AST and decreased appetite (25% each). Adverse events of grade 3 or more included hyperglycemia (19%), urosepsis (6%), and one multi-organ failure (6%) responsible for one treatment-related death. Two patients discontinued therapy for adverse events including fatigue grade 2 and urosepsis grade 4. CDX-014 showed antitumor activity with one prolonged partial response and a clinical benefit rate (objective response or stable disease >6 months) of 31%. The two patients that exhibited the most marked tumor shrinkage had high TIM-1 expression on tumor tissue. Overall, CDX-014 exhibited a manageable toxicity profile and early signs of activity, supporting further evaluation of antibody-drug conjugates in patients with advanced RCC and potentially other TIM-1 expressing cancers. Trial registration https://clinicaltrials.gov/ct2/show/NCT02837991 NCT02837991; July 20, 2016.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Receptor Celular 1 del Virus de la Hepatitis A/antagonistas & inhibidores , Inmunoconjugados/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Femenino , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacocinética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Several studies have investigated the relationship between experience measured by caseload and oncological outcomes, economics, and access to care for prostate cancer care. Oncological outcomes have been limited to biochemical failure after radical prostatectomy. Questions remain regarding the more definitive measures of outcomes and their relationship with caseload. METHODS: The National Cancer Database was used to investigate the outcomes of radical prostatectomy in the United States. With overall survival (OS) as the primary outcome, the relationship between the facility annual caseload (FAC) for all prostate cancer encounters and the facility annual surgical caseload (FASC) for those requiring radical prostatectomy was examined with a Cox proportional hazards model. Four volume groups were defined by caseload: <50th percentile (volume group 1 [VG1]), 50th to 74th percentiles (volume group 2 [VG2]), 75th to 89th percentiles (volume group 3 [VG3]), and ≥90th percentile (volume group 4 [VG4]). By FAC/FASC, 11%/8%, 17%/18%, 25%/26%, and 47%/49% of patients were treated in VG1 through VG4, respectively. RESULTS: Between 2004 and 2014, 488,389 patients underwent radical prostatectomy. At a median follow-up of 60.75 months, the median OS was not reached. There was a significant OS benefit as the caseload increased. For FAC, the adjusted OS difference between VG1 and VG4 at 90th percentile survivorship reached 13.2 months (hazard ratio [HR], 1.30; 95% CI, 1.23-1.36; P < .0001). For FASC, this was 11.3 months (HR, 1.25; 95% CI, 1.192-1.321; P < .0001). CONCLUSIONS: There is a statistically significant OS advantage from performing radical prostatectomy at a facility with a high annual caseload. Caseload measured by all prostate cancer encounters is a better predictor of favorable outcomes than the number of surgeries performed at a facility. LAY SUMMARY: An in-depth analysis of 488,389 cases of radical prostatectomy performed in more than 1000 facilities over a 10-year period showed better survival when surgery was performed in facilities with more experience and greater caseload. A survival difference of up to 13 months was observed when comparing patients treated at less experienced versus more experienced centers. Experience across all stages of prostate cancer was a stronger predictor of survival outcome than just the number of surgeries performed.
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Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Próstata/cirugía , Prostatectomía/métodos , Neoplasias de la Próstata/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Modelos de Riesgos Proporcionales , Próstata/patología , Neoplasias de la Próstata/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.
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Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Extractos de Tejidos/uso terapéutico , Anciano , Humanos , Masculino , Metástasis de la Neoplasia , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/patología , Sistema de Registros , Extractos de Tejidos/farmacologíaRESUMEN
BACKGROUND: After radical prostatectomy (RP) for prostate cancer (PC), p53 alterations predict biochemical relapse (BCR), however, recent evidence suggests that metastatic relapse (MR) not BCR is a surrogate for PC specific mortality (PCSM). This updated analysis of a previously published study investigated the association between p53 aberrations, MR and PCSM in men with localised PC. METHODS: Two hundred and seventy-one men with localised PC treated with RP were included. RP specimens stained for p53 by immunohistochemistry were scored as (a) percentage of p53-positive tumour nuclei; and (b) clustering, where ≥12 p53-positive cells within a ×200 power field was deemed 'cluster positive'. Associations between p53 status and clinical outcomes (BCR, MR and PCSM) were evaluated. RESULTS: Increasing percentage of p53-positive nuclei was significantly associated with shorter time to BCR, MR and PCSM (All p < 0.001). Half of the patients were p53 cluster positive. p53 cluster positivity was significantly associated with poorer outcomes at all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p < 0.001; MR: HR 4.1, 95% CI 2.02-8.14, p < 0.001; PCSM: HR 12.2, 95% CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables. CONCLUSIONS: p53 aberrations in radical prostatectomy tissue predict clinically relevant endpoints of MR and PCSM.
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Núcleo Celular/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Neoplasias de la Próstata/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Anciano , Genes p53 , Humanos , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Pronóstico , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Estudios Retrospectivos , Factores de TiempoRESUMEN
Background Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Gosipol/análogos & derivados , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Femenino , Gosipol/efectos adversos , Gosipol/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-2 , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
The SIU (Société Internationale d'Urologie)-ICUD (International Consultation on Urologic Diseases) working group on systemic therapy for metastatic bladder cancer has summarized the most recent findings on the aforementioned topic and came to conclusions and recommendations according to the evidence published. In Europe and the United States, treatment for metastatic UC has changed a great deal recently, mainly involving a move from chemotherapy to immune checkpoint blockers. This is particularly true in platinum-refractory disease, where supportive randomized data exist. Five checkpoint blockers have been approved in this setting by the FDA: avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab. Nivolumab, pembrolizumab, and atezolizumab have been approved in Europe.
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Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma de Células Transicionales/secundario , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Doxorrubicina/uso terapéutico , Humanos , Neoplasias Hepáticas/secundario , Metotrexato/uso terapéutico , Nivolumab/uso terapéutico , Paclitaxel/administración & dosificación , Neoplasias de la Vejiga Urinaria/patología , Vinblastina/uso terapéutico , GemcitabinaRESUMEN
BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.