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1.
J Immunother Cancer ; 8(1)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32414862

RESUMO

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with a high risk of metastasis. In 2017, avelumab (anti-programmed death-ligand 1 (PD-L1)) became the first approved treatment for patients with metastatic MCC (mMCC), based on the occurrence of durable responses in a subset of patients. Here, we report long-term efficacy and safety data and exploratory biomarker analyses in patients with mMCC treated with avelumab. METHODS: In a cohort of this single-arm, phase 2 trial (JAVELIN Merkel 200), patients with mMCC and disease progression after prior chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent review per Response Evaluation Criteria in Solid Tumors V.1.1. Other assessments included duration of response, progression-free survival, overall survival (OS), safety and biomarker analyses. RESULTS: As of 14 September 2018, 88 patients had been followed up for a median of 40.8 months (range 36.4-49.7 months). The ORR was 33.0% (95% CI 23.3% to 43.8%), including a complete response in 11.4% (10 patients), and the median duration of response was 40.5 months (95% CI 18.0 months to not estimable). As of 2 May 2019 (≥44 months of follow-up), the median OS was 12.6 months (95% CI 7.5 to 17.1 months) and the 42-month OS rate was 31% (95% CI 22% to 41%). Of long-term survivors (OS >36 months) evaluable for PD-L1 expression status (n=22), 81.8% had PD-L1+ tumors. In exploratory biomarker analyses, high tumor mutational burden (≥2 non-synonymous somatic variants per megabase) and high major histocompatibility complex class I expression (30% of tumors with highest expression) were associated with trends for improved ORR and OS. In long-term safety assessments (≥36 months of follow-up), no new or unexpected adverse events were reported, and no treatment-related deaths occurred. CONCLUSIONS: Avelumab showed continued durable responses and meaningful long-term survival outcomes in patients with mMCC, reinforcing avelumab as a standard-of-care treatment option for this disease. TRIAL REGISTRATION NUMBER: NCT02155647.

2.
Proc Natl Acad Sci U S A ; 116(47): 23662-23670, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685621

RESUMO

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαß heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Subpopulações de Linfócitos T/imunologia , Substituição de Aminoácidos , Antígenos de Neoplasias/genética , Vacinas Anticâncer/imunologia , Células Clonais , DNA de Neoplasias/genética , Células Dendríticas/imunologia , Antígenos HLA/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Melanoma/genética , Melanoma/secundário , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Neoplasias Retroperitoneais/imunologia , Neoplasias Retroperitoneais/secundário , Análise de Sequência de DNA , Especificidade do Receptor de Antígeno de Linfócitos T , Evasão Tumoral , Vacinação
3.
J Bone Miner Res ; 34(10): 1780-1788, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441962

RESUMO

Primary malignant bone tumors are rare, occur in all age groups, and include distinct entities such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Traditional treatment with some combination of chemotherapy, surgery, and radiation has reached the limit of efficacy, with substantial room for improvement in patient outcome. Furthermore, genomic characterization of these tumors reveals a paucity of actionable molecular targets. Against this backdrop, recent advances in cancer immunotherapy represent a silver lining in the treatment of primary bone cancer. Major strategies in cancer immunotherapy include stimulating naturally occurring anti-tumor T cells and adoptive transfer of tumor-specific cytotoxic T cells. Chimeric antigen receptor T cells (CAR-T cells) belong to the latter strategy and are an impressive application of both insights into T cell biology and advances in genetic engineering. In this review, we briefly describe the CAR-T approach and discuss its applications in primary bone tumors. © 2019 American Society for Bone and Mineral Research.


Assuntos
Neoplasias Ósseas/terapia , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/uso terapêutico , Neoplasias Ósseas/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/metabolismo
4.
Curr Hematol Malig Rep ; 14(4): 286-291, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31187421

RESUMO

PURPOSE OF REVIEW: Checkpoint inhibitors block co-inhibitory signals which serves to promote T cell activation/reinvigoration in the periphery and tumor microenvironment. A brief historical background as well as a summary of key observations related to the composition and prognostic value of tumor-infiltrating lymphocytes (TILs) is discussed. RECENT FINDINGS: Solid tumor patients that respond to checkpoint inhibitors have greater CD8+ T cell densities (at the tumor margin) associated with a gene inflammation signature and high tumor mutational burden. The precise specificity of effector (CD8+ T cell) TIL remains poorly defined and this deficiency represents a major challenge for the field of cancer immunology. High mutational burden cancers such as melanoma provides compelling evidence that missense mutations create neoantigens which can serve as target antigens for the immune system. Emerging evidence suggests that neoantigen-specific TILs are the major effector cells that mediate tumor regression due to checkpoint inhibition.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais , Imunomodulação/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos , Estudos Clínicos como Assunto , Humanos , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/patologia , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Resultado do Tratamento , Microambiente Tumoral
5.
Cancer Immunol Immunother ; 68(4): 609-618, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30721341

RESUMO

BACKGROUND: Response rates are primary endpoints in many oncology trials; however, correlation with overall survival (OS) is not uniform across cancer types, treatments, or lines of therapy. This study explored the association between objective response (OR) and OS in patients with chemotherapy-refractory metastatic Merkel cell carcinoma who received avelumab (anti-PD-L1). METHODS: Eighty-eight patients enrolled in JAVELIN Merkel 200 (part A; NCT02155647) received i.v. avelumab 10 mg/kg every 2 weeks until confirmed progression, unacceptable toxicity, or withdrawal. Using conditional landmark analyses, we compared OS in patients with and without confirmed OR (RECIST v1.1). We applied a Cox model that included OR as a time-varying covariate and adjusted for age, visceral disease, and number of previous therapies. RESULTS: Twenty-nine patients had confirmed OR; 20 by study week 7 and 7 more between study weeks 7 and 13. Survival probabilities 18 months after treatment initiation were 90% [95% confidence interval (CI) 65.6-97.4] in patients with OR at week 7 and 26.2% (95% CI 15.7-37.8) in patients without OR but who were alive at week 7. Median OS was not reached in patients with OR and was 8.8 months (95% CI 6.4-12.9) in patients without. Similar results were observed for the week 13 landmark. The adjusted Cox model showed OR was associated with a 95% risk reduction of death [hazard ratio 0.052 (95% CI 0.018-0.152)] compared with a nonresponse. CONCLUSIONS: Patients with OR by 7 or 13 weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Carcinoma de Célula de Merkel/metabolismo , Carcinoma de Célula de Merkel/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Modelos de Riscos Proporcionais , Resultado do Tratamento
6.
Nat Med ; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515

RESUMO

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia , Transcriptoma , Evasão Tumoral
7.
J Neurooncol ; 141(1): 95-102, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30353265

RESUMO

INTRODUCTION: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). METHODS: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). RESULTS: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. CONCLUSIONS: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.


Assuntos
Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Citotoxicidade Imunológica , Feminino , Glioblastoma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA , Linfócitos T/metabolismo , Transcriptoma , Microambiente Tumoral , Adulto Jovem
9.
Neuro Oncol ; 20(11): 1429-1438, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-29509936

RESUMO

In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T-cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Glioblastoma/imunologia , Glioblastoma/metabolismo , Humanos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética
10.
Clin Cancer Res ; 24(3): 535-540, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29158268

RESUMO

Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, an immunosuppressive microenvironment, and a partially permissive anatomic blood-brain barrier. Results from three first-in-man chimeric antigen receptor (CAR) T-cell trials targeting IL13Rα2, Her2/CMV, and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T-cell trafficking to CNS, engraftment and persistence, tumor microenvironment remodeling, and monitoring of glioma response to CAR T cells. Objective radiologic responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field. Clin Cancer Res; 24(3); 535-40. ©2017 AACR.


Assuntos
Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Estudos Clínicos como Assunto , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética
12.
Melanoma Res ; 27(6): 585-590, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29076950

RESUMO

BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.


Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Feminino , Humanos , Indóis/farmacologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/farmacologia , Vemurafenib
13.
Trends Mol Med ; 23(10): 869-871, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28867556

RESUMO

Neoantigens arising from tumor-specific genomic alterations constitute authentic non-self antigens and represent a new class of targets for cancer immunotherapy. Recent reports on various vaccine platforms targeting neoantigens suggest a basis for precision therapies customized to each patient's tumor mutational profile.


Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Imunogenicidade da Vacina , Imunoterapia , Neoplasias , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/uso terapêutico , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia
15.
JAMA Facial Plast Surg ; 19(1): 53-62, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27606893

RESUMO

Importance: Head and neck melanoma is one of the leading causes of death in the United States and is currently increasing in prevalence. While there is a tremendous amount of research published on melanoma, the actual evidence for complex clinical decision-making can be difficult to interpret and to stay up-to-date on current clinical standards. Objective: To address, in a systematic and evidence-based approach, the most common clinical controversies with regard to the workup and management of head and neck melanoma. Evidence Review: A PubMed and Medline search was performed of the entire English literature with respect to head and neck melanoma. Priority of review was given to those studies with higher-quality levels of evidence. Findings: Main topics reviewed in this article include workup for new melanoma, surgical treatment of the primary site, surgical treatment of the neck, adjuvant radiation therapy, and systemic therapy. Levels of evidence are used for each controversial clinical question to help the clinician understand the reliability of the current evidence when making complex clinical decisions for melanoma management of the head and neck. However, much of the work done in melanoma, particularly large randomized clinical trials, includes many other regions of the body. Therefore, these data must be interpreted in light of the potential differences in clinical behavior and draining lymphatics between trunk, limbs, and head and neck subsites. Conclusions and Relevance: The management of head and neck melanoma requires a multidisciplinary approach, particularly for advanced-stage disease. An in-depth knowledge of the current evidence available will help guide the surgeon in the management of this difficult disease.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Neoplasias Cutâneas/terapia , Padrão de Cuidado/normas , Progressão da Doença , Medicina Baseada em Evidências , Neoplasias de Cabeça e Pescoço/patologia , Comunicação Interdisciplinar , Colaboração Intersetorial , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia
16.
J Cancer Res Clin Oncol ; 143(3): 439-445, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27921276

RESUMO

PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.


Assuntos
Benzimidazóis/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Melanoma/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Neoplasias Uveais/tratamento farmacológico , Adulto , Idoso , Benzimidazóis/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Médicos , Qualidade de Vida , Neoplasias Uveais/epidemiologia , Neoplasias Uveais/patologia
17.
Lancet Oncol ; 17(11): 1558-1568, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27622997

RESUMO

BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Método Duplo-Cego , Humanos , Ipilimumab , Melanoma/genética , Melanoma/mortalidade , Mutação , Nivolumabe , Proteínas Proto-Oncogênicas B-raf/genética
18.
Lancet Oncol ; 17(10): 1374-1385, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27592805

RESUMO

BACKGROUND: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. METHODS: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. FINDINGS: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6-13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9-43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). INTERPRETATION: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. FUNDING: Merck KGaA, Darmstadt, Germany.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Célula de Merkel/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia
19.
Genome Med ; 8(1): 11, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26825632

RESUMO

Cancer immunotherapy has gained significant momentum from recent clinical successes of checkpoint blockade inhibition. Massively parallel sequence analysis suggests a connection between mutational load and response to this class of therapy. Methods to identify which tumor-specific mutant peptides (neoantigens) can elicit anti-tumor T cell immunity are needed to improve predictions of checkpoint therapy response and to identify targets for vaccines and adoptive T cell therapies. Here, we present a flexible, streamlined computational workflow for identification of personalized Variant Antigens by Cancer Sequencing (pVAC-Seq) that integrates tumor mutation and expression data (DNA- and RNA-Seq). pVAC-Seq is available at https://github.com/griffithlab/pVAC-Seq .


Assuntos
Antígenos de Neoplasias/genética , Biologia Computacional/métodos , Neoplasias/imunologia , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos , Simulação por Computador , Genoma Humano , Humanos , Mutação , Neoplasias/genética , Software
20.
Am J Ophthalmol Case Rep ; 2: 23-25, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29503892

RESUMO

Purpose: To report the case of an adult female who presented on different occasions with recurrent uveitis provoked by initiating therapy of two recently approved agents, dabrafenib and pembrolizumab, for treatment of metastatic melanoma. Observations: A 61 year old female presented with bilateral anterior uveitis after initiating therapy with dabrafenib for advanced metastatic melanoma. Her symptoms resolved and exam improved with oral and topical steroid therapy. Months later, she was started on pembrolizumab and transitioned off dabrafenib. Within days of starting pembrolizumab, she developed recurrent bilateral uveitis. This responded to escalating doses of topical and oral corticosteroid therapy and resolved following discontinuation of pembrolizumab. Nine months later, our patient received her third dose of pembrolizumab due to further progression of melanoma and within three days developed blurry vision, photophobia and subsequent ophthalmologic exam demonstrated bilateral panuveitis. Conclusions and importance: Dabrafenib and pembrolizumab therapy have both previously been associated with uveitis. Here, we document a case of a woman who developed acute uveitis in response to beginning therapy with dabrafenib and then later developed acute uveitis soon after initiating pembrolizumab. To our knowledge, this is the first time this uncommon side-effect has been reported in the same patient after receiving sequential targeted agents and checkpoint inhibitors.

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