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BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.
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Carcinoma de Células Renais , Neoplasias Renais , Estados Unidos , Adulto , Humanos , Everolimo/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Sirolimo/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgiaRESUMO
With the expansion in cross-sectional imaging over the past few decades, there has been an increase in the number of incidentally detected renal masses and an increase in the incidence of renal cell carcinomas (RCCs). The complete characterization of an indeterminate renal mass on CT or MR images is challenging, and the authors provide a critical review of the best imaging methods and essential, important, and optional reporting elements used to describe the indeterminate renal mass. While surgical staging remains the standard of care for RCC, the role of renal mass CT or MRI in staging RCC is reviewed, specifically with reference to areas that may be overlooked at imaging such as detection of invasion through the renal capsule or perirenal (Gerota) fascia. Treatment options for localized RCC are expanding, and a multidisciplinary group of experts presents an overview of the role of advanced medical imaging in surgery, percutaneous ablation, transarterial embolization, active surveillance, and stereotactic body radiation therapy. Finally, the arsenal of treatments for advanced renal cancer continues to grow to improve response to therapy while limiting treatment side effects. Imaging findings are important in deciding the best treatment options and to monitor response to therapy. However, evaluating response has increased in complexity. The unique imaging findings associated with antiangiogenic targeted therapy and immunotherapy are discussed. An invited commentary by Remer is available online. Online supplemental material is available for this article. ©RSNA, 2021.
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Carcinoma de Células Renais , Embolização Terapêutica , Neoplasias Renais , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/terapia , Humanos , Rim , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/terapia , Imageamento por Ressonância MagnéticaRESUMO
Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.
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Antígenos de Neoplasias/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Neoplasias Cutâneas/terapia , Subpopulações de Linfócitos T/transplante , Adulto , Idoso , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/secundário , Subpopulações de Linfócitos T/imunologia , Transplante AutólogoRESUMO
The authors would like to make the following corrections to the published article.
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High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors. The PROCLAIMSM registry was established to collect and analyze data for patients treated with HD IL-2 in the current era. This analysis includes 170 patients with mM and 192 patients with mRCC treated between 2005 and 2012 with survival data current as of July 27, 2015. For patients with mM, complete response (CR) was observed in 5 %, partial response (PR) in 10 %, stable disease (SD) in 22 %, and 63 % had progressive disease (PD). The median overall survival (mOS) for these patients was 19.6 months, with a median follow-up of 43.1 months. The mOS was not reached for patients achieving CR or PR, and was 33.4 months for patients with SD. For patients with mRCC, 6 % achieved CR, 9 % had PR, 22 % had SD, and 62 % had PD. The mOS was 41 months, with a median follow-up of 46.6 months. The mOS for patients who had CR and PR was not reached and was 49.6 months for patients with SD. There were no treatment-related deaths among 362 patients. The duration of mOS for patients with mM and mRCC is longer than historically reported. These data support a continued role for IL-2 in the treatment of eligible patients with mM or mRCC and warrant further evaluation of HD IL-2 in combination or sequence with other therapeutic agents.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/farmacologia , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology. METHODS: Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms. KEY FINDINGS AND LIMITATIONS: Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC PATIENT SUMMARY: We assessed treatment with everolimus in comparison to placebo after complete surgical removal of clear-cell kidney cancer at very high risk of recurrence. We found that survival outcomes were better for patients treated with everolimus, although these patients had a higher rate of side effects.
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BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Vacinas Anticâncer/uso terapêutico , Melanoma/terapia , Anticorpos Monoclonais/efeitos adversos , Antígeno CTLA-4 , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Ipilimumab , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Src kinases are activated in melanoma, and inhibition of Src kinase activity has pre-clinical anti-tumor effects. Targeting this pathway could therefore have therapeutic activity in patients with metastatic melanoma. PATIENTS AND METHODS: We conducted a multi-center, open-label study of the Src kinase inhibitor saracatanib (AZD0530) in patients with metastatic melanoma. Twenty-three patients received saracatanib at a dose of 175 mg daily. The primary objectives were to determine whether this agent had clinical activity in patients with advanced melanoma and whether it increased progression free survival. Functional effects on circulating T cells were also assessed. RESULTS: Twenty-three patients received oral saracatanib on a continuous daily dosing regimen. There were no objective clinical responses. Saracatanib was generally well tolerated with few grade 3-4 adverse events. T cell function was inhibited in most patients, based on decreased superantigen-induced IL-2 production in post- versus pre-treatment samples. CONCLUSIONS: Saracatanib has minimal clinical activity as a single agent in an unselected population of patients with advanced melanoma, as evidenced by a lack of objective responses in this study. Reduced T cell cytokine production in most treated patients suggests potential immune suppressive activity by this agent.
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Antineoplásicos/uso terapêutico , Benzodioxóis/uso terapêutico , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Feminino , Humanos , Interleucina-2/imunologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Neoplasias Encefálicas/secundário , Feminino , Humanos , Ipilimumab , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.
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T cells that are gene-modified with tumor-specific T cell receptors are a promising treatment for metastatic melanoma patients. In a clinical trial, we treated seven metastatic melanoma patients with autologous T cells transduced to express a tyrosinase-reactive T cell receptor (TCR) (TIL 1383I) and a truncated CD34 molecule as a selection marker. We followed transgene expression in the TCR-transduced T cells after infusion and observed that both lentiviral- and retroviral-transduced T cells lost transgene expression over time, so that by 4 weeks post-transfer, few T cells expressed either lentiviral or retroviral transgenes. Transgene expression was reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines. TCR-transduced T cell lentiviral and retroviral transgene expression was also downregulated in vitro when T cells were cultured without cytokines. Transduced T cells cultured with interleukin (IL)-15 maintained transgene expression. Culturing gene-modified T cells in the presence of histone deacetylase (HDAC) inhibitors maintained transgene expression and functional TCR-transduced T cell responses to tumor. These results implicate epigenetic processes in the loss of transgene expression in lentiviral- and retroviral-transduced T cells.
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BACKGROUND: Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. METHODS: Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. FINDINGS: In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. INTERPRETATION: The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quinazolinas/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma de Células Escamosas/mortalidade , Receptores ErbB/análise , Cloridrato de Erlotinib , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Quinazolinas/efeitos adversos , Análise de Regressão , Fator de Crescimento Transformador alfa/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análiseRESUMO
Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Imidazóis/efeitos adversos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumour of the skin. While localised disease carries an overall favourable prognosis, metastatic disease is associated with poor clincal outcomes. Most cases of metastatic MCC are managed with systemic chemotherapy or immunotherapy, though 5-year survival for these patients remains a dismal 17%. Here, we present the case of a 79-year-old man with MCC of the right ear with metastases to regional lymph nodes, ipsilateral parotid gland and thoracic spine. He was treated with a combination of first-line radiotherapy and concurrent immune checkpoint inhibition (avelumab), which led to complete clinical regression of disease with minimal adverse effects. This observation suggests that combined radio-immunotherapy warrants larger-scale investigation for use in patients with unresectable MCC.
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Carcinoma de Célula de Merkel/diagnóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Carcinoma de Célula de Merkel/secundário , Carcinoma de Célula de Merkel/terapia , Terapia Combinada , Orelha Externa , Humanos , Imunoterapia , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/terapia , Vértebras TorácicasRESUMO
BACKGROUND: Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored. METHODS: Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIMSM database. Patient characteristics, toxicity and efficacy were analyzed. RESULTS: A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy. CONCLUSION: In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Interleucina-2/efeitos adversos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Adulto JovemRESUMO
BACKGROUND: Advanced renal cell cancer (RCC) continues to have a poor overall prognosis despite new FDA-approved therapies. Although taxane-based therapies are generally ineffective in RCC, research into the role of the von Hippel-Lindau protein has shown an association with microtubule dynamics. Mitotic kinesins are a class of molecular motors that also interact with microtubules and are required for proper mitotic function. SB-715992 is a new agent that inhibits the function of a mitotic kinesin known as kinesin spindle protein and leads to cell death. PATIENTS AND METHODS: Twenty patients with previously treated advanced RCC were enrolled on this phase II trial of SB-715992, with response rate as a primary endpoint. RESULTS: No patients responded with complete or partial remission. Six patients had stable disease, and 1 patient continues on therapy after 12 cycles. Common toxicities included anemia (80%), elevated creatinine (70%), lymphopenia (45%), fatigue (50%), hyperglycemia (50%), and dyspnea (45%). Reported grade 3/4 toxicities included dyspnea, fatigue, neutropenia with skin infection, dizziness, hyperuricemia, and hypertension. CONCLUSION: This dose and schedule of SB-715992 does not appear to have a significant cytotoxic effect for patients with previously treated advanced RCC.
Assuntos
Benzamidas/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Quinazolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Chicago , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Segurança , UniversidadesRESUMO
PURPOSE: BAY 50-4798 is an analogue of interleukin-2 that selectively activates T cells over natural killer cells. This phase I study was designed to determine the maximum tolerated dose (MTD) and safety of BAY 50-4798, screen for tumor response, and assess pharmacokinetics. EXPERIMENTAL DESIGN: Forty-five patients with metastatic melanoma or renal cancer were enrolled, 31 on escalating doses to determine the MTD, with 20 renal cell carcinoma patients treated at MTD to detect antitumor activity. BAY 50-4798 was delivered i.v. every 8 h, days 1 to 5 and 15 to 19, and could be repeated after 9 weeks if tumor was stable or responding. RESULTS: The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 microg/kg, and the MTD was defined as 10.4 microg/kg based on toxicities similar to those of aldesleukin. Two patients achieved partial responses, one with melanoma and one with renal cell carcinoma. Among all 45 patients, 53% and 9% experienced a grade 3 and 4 toxicity, respectively. Among the patients treated at the MTD of 10.4 microg/kg, 71% and 10% experienced a grade 3 and 4 toxicity, respectively. Pharmacokinetics showed dose-dependent peak concentrations (C(max)) and area under the curve with a half-life of approximately 2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells. CONCLUSIONS: The antitumor activity of BAY 50-4798 in malignancies that respond to high-dose interleukin-2 was low. BAY 50-4798 might provide advantages over aldesleukin in antigen-specific immunotherapies.
Assuntos
Antineoplásicos/farmacologia , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-2/uso terapêutico , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: The treatment options for metastatic malignant melanoma have drastically changed recently,including the increased use of immunotherapeutic agents that offer significant responses. Accordingly, it hasbecome common for sequential administration of such agents. Despite this, no guidelines exist on propersequencing or potential unique toxicities associated with such sequencing. CASE PRESENTATION: We describe here the first incidence, to our knowledge, of clinically significant rhabdomyolysis associated with high-dose interleukin-2 after prior treatment with ipilimumab, genetically engineered T-cell therapy and subsequent single agent pembrolizumab in a patient with BRAF wild type metastatic malignant melanoma. CONCLUSION: Further studies into the biology of sequential immunotherapy in the treatment of cancer are warranted.