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2.
ESMO Open ; 5(6): e000798, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33188050

RESUMO

On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value<0.0001). The median OS was not reached for the nivolumab + ipilimumab group and was 25.95 months for the sunitinib group. The OS rates were 89.5% and 86.2% at 6 months, and 80.1% and 72.1% at 12 months in the nivolumab +ipilimumab and the sunitinib groups, respectively. K-M curves separated after approximately 3 months, favouring nivolumab + ipilimumab. This was not mirrored in the favourable-risk patients where no statistically significant difference was observed between nivolumab + ipilimumab and sunitinib in favourable-risk patients (HR 1.45 (descriptive 99.8% CI 0.51 to 4.12), p =0.2715).


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Imunoterapia , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
J Glob Oncol ; 4: 1-11, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30521412

RESUMO

Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/farmacologia , Criança , Humanos , Adulto Jovem
4.
Eur J Cancer ; 49(7): 1654-61, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23481513

RESUMO

The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).


Assuntos
Aprovação de Drogas/organização & administração , Avaliação de Medicamentos , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Sulfonamidas/uso terapêutico , Ensaios Clínicos Fase III como Assunto , União Europeia , Humanos , Melanoma/genética , Melanoma/patologia , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Sobrevida , Resultado do Tratamento , Vemurafenib
5.
Pigment Cell Melanoma Res ; 23(1): 112-20, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20002887

RESUMO

We recently demonstrated that expression of (V600E)Braf in mature mouse melanocytes induces melanoma. Here, we show that expression of (V600E)Braf using the tyrosinase promoter leads to an unexpected embryonic lethality, with the animals dying before, at, or shortly after birth. The mice suffer from a range of developmental defects in the skin, the brain, the eyes and the heart, tissues that are normally colonized by melanocytes. We show that the (V600E)Braf expressing cells are potential melanocytic precursors that are fully transformed, suggesting that (V600E)Braf stimulates proliferation and blocks differentiation of these cells. Our data suggests that the presence of these cells in the organs that are normally occupied by melanocytes leads to severe developmental disruption, resulting in catastrophic defects and leading to death of the individual.


Assuntos
Transformação Celular Neoplásica/genética , Anormalidades Congênitas/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Letais/genética , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Diferenciação Celular/genética , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Anormalidades Congênitas/metabolismo , Desenvolvimento Embrionário/genética , Técnicas de Introdução de Genes , Integrases/genética , Melanócitos/metabolismo , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Transgênicos , Monofenol Mono-Oxigenase/genética , Regiões Promotoras Genéticas/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Células-Tronco/metabolismo
6.
Cancer Cell ; 15(4): 294-303, 2009 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-19345328

RESUMO

We show here that inducible expression of Braf(V600E) off the endogenous Braf gene in mouse melanocytes stimulates skin hyperpigmentation and the appearance of nevi harboring senescent melanocytes. Additionally, approximately 70% of Braf(V600E) mice develop melanomas that reproduce many of the cardinal histological and molecular features of human melanoma and whose cells can colonize the lungs of nude mice. We show that the tumor suppressor p16(INK4a) is not required to induce melanocyte senescence and that its loss is not required for tumor progression, although it does regulate tumor penetrance and latency. Thus, we have developed a mouse model of melanoma driven by Braf(V600E) expressed at physiological levels that reflects the genetics and pathology of the human disease.


Assuntos
Senescência Celular , Melanócitos/citologia , Melanócitos/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/fisiologia , Animais , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Nus , Camundongos Transgênicos , Nevo/genética , Nevo/metabolismo , Nevo/patologia
7.
J Immunol ; 179(1): 400-8, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17579061

RESUMO

CTLA-4 can negatively regulate cytokine production and proliferation, increase motility, and override the TCR-induced stop-signal needed for stable T cell-APC conjugation. Despite this, little is known regarding whether CTLA-4 can alter T cell morphology and the nature of the signaling events that could account for this event. In this study, we demonstrate that anti-CTLA-4 and CD3/CTLA-4 induce rapid T cell polarization (i.e., within 15-30 min) with increases in lamellipodia, filopodia, and uropod formation. This was observed with anti-CTLA-4 and CD80-Ig ligation of CTLA-4, but not with anti-CD3 alone, or anti-CD3/CD28 coligation. Polarization required PI3K, the guanine nucleotide exchange factor Vav1, the GTP-binding protein Cdc42, as well as myosin L chain kinase. By contrast, a key downstream target of PI3K, protein kinase B, as well as Rho kinase and RhoA, were not needed. Our results demonstrate that CTLA-4 is a potent activator T cell polarization needed for motility, and this process involves specific set of signaling proteins that might contribute to coreceptor regulation of T cell function.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação/metabolismo , Movimento Celular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Quinase de Cadeia Leve de Miosina/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-vav/fisiologia , Linfócitos T/citologia , Proteína cdc42 de Ligação ao GTP/fisiologia , Animais , Antígenos CD/imunologia , Antígenos CD/fisiologia , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/fisiologia , Complexo CD3/imunologia , Antígeno CTLA-4 , Células Cultivadas , Humanos , Soros Imunes/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pseudópodes/imunologia , Linfócitos T/enzimologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/enzimologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Regulação para Cima/imunologia , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP/metabolismo
8.
Cancer Res ; 65(23): 10686-91, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16322212

RESUMO

Hsp90 is a ubiquitously expressed molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins. The benzoquinone ansamysin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer drug that disrupts Hsp90 binding to its clients, causing their degradation through the ubiquitin-dependent proteasomal pathway. The protein kinase B-RAF is mutated in approximately 7% of human cancers. The most common mutation (approximately 90%) is (V600E)B-RAF, which has constitutively elevated kinase activity, stimulates cancer cell proliferation, and promotes survival. Here, we show that (V600E)B-RAF is an Hsp90 client protein that requires Hsp90 for its folding and stability. (V600E)BRAF is more sensitive to degradation by 17-AAG treatment than (WT)B-RAF and we show that the majority of the other mutant forms of B-RAF are also sensitive to 17-AAG-mediated proteasomal degradation. Our data show that B-RAF is an important target for 17-AAG in human cancer.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Rifabutina/análogos & derivados , Animais , Benzoquinonas , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Lactamas Macrocíclicas , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Rifabutina/farmacologia
9.
Proc Natl Acad Sci U S A ; 102(36): 12861-6, 2005 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-16126897

RESUMO

Although cytotoxic T lymphocyte antigen-4 (CTLA-4) negatively regulates T cell activation, the full range of functions mediated by this coreceptor has yet to be established. In this study, we report the surprising finding that CTLA-4 engagement by soluble antibody or CD80 potently up-regulates lymphocyte function-associated antigen 1 (LFA-1) adhesion to intercellular adhesion molecule-1 (ICAM-1) and receptor clustering concurrent with IL-2 inhibition. This effect was also observed with CTLA-4 ligation and not with other coreceptors. T cell antigen receptor (TcR)-induced lymphocyte function-associated antigen 1 function was also dependent on CTLA-4 expression as observed with reduced adhesion/clustering on CTLA-4(-/-) primary T cells. CTLA-4 up-regulated adhesion was mediated by regulator for cell adhesion and polarization type 1 (Rap-1) as shown by anti-CTLA-4-induced Rap-1 activation as well as Rap-1-N17 blockade and Rap-1-V12 mimicry of adhesion/clustering. Our findings identify a potent role for CTLA-4 in directing integrin adhesion and provide an alternate mechanism to account for aspects of CTLA-4 function in T cell immunity.


Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Regulação para Cima , Animais , Anticorpos/imunologia , Antígenos CD , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antígeno B7-1/imunologia , Antígeno B7-1/metabolismo , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígeno CTLA-4 , Adesão Celular , Linhagem Celular , Integrinas/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Solubilidade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Aderências Teciduais , Proteínas rap1 de Ligação ao GTP/genética , Proteínas rap1 de Ligação ao GTP/metabolismo
10.
Cancer Metastasis Rev ; 24(1): 165-83, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15785879

RESUMO

Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. If detected early, it is easily treated by surgical excision. However, once melanoma metastasises it is notoriously resistant to existing therapies and for many patients the outlook is dismal. Thus a full description of melanoma etiology and a full understanding of the genetic lesions that underlie this disease is required to allow us to develop new and effective therapeutic strategies for its treatment. RAF proteins are a family of serine/threonine-specific protein kinases that form part of a signalling module that regulates cell proliferation, differentiation and survival. In mammals there are three isoforms, A-RAF, B-RAF and C-RAF, and recently it was shown that the B-RAF isoform is mutated in a high proportion of melanomas. In light of these exciting findings, we review what we have learned about B-RAF and its role in cutaneous melanoma.


Assuntos
Melanoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Animais , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Melanoma/etiologia , Melanoma/patologia , Melanoma/terapia , Proteínas Proto-Oncogênicas B-raf/genética , Fatores de Risco
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