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The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy. Citar atuação do Cabozatinib ( oral, potent inhibitor of MET and VEGFR2)
RCC: molecular pathogenesis In RCC, as in other cancers, dysregulation of normal signalling pathways occurs, leading to tumour initiation and progression, inhibition of apoptosis, and tumour angiogenesis. There are five distinct histological subtypes of RCC, which are classified according to their cell type of origin 1,2 clear-cell carcinoma arises in the proximal tubules, accounts for 75–85% of all RCCs and is associated with a mutation in the von Hippel–Lindau (VHL) gene papillary carcinoma (chromophilic carcinoma) arises in the proximal tubules, accounts for 12–14% of all RCCs and is associated with a mutation in the c-MET gene (type I) or fumarate hydratase (FH) gene (type II) chromophobic, oncocytic and collecting duct carcinomas are associated with mutations in the Birt–Hogg–Dubé (BHD) gene these arise in the collecting ducts and are less common. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335:865–75. Linehan WM, Vasselli J, Srinivasan R, et al. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res 2004;10:6282S – 9S. Low Fuhrman grade and good prognosis are associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumours are associated with a lack of E-cadherin and lower frequency of VHL staining Shows aberrant nuclear localisation of E-cadherin in clear cell RCC harbouring VHL mutations and suggests potential prognostic value of VHL and E-cadherin in clear cell RCC .
LIN- Limite inferior normal Desenvolvido no MSKCC 1990s MSKCC (2002/2004) 251 Pacientes submetidos a estudos clínicos de imunoterapia ou quimioterapia (1975-2002); todas histologias. Atualizado em 2004 para estabelecer critérios prognósticos para desenho de estudos clínicos com drogas alvo. CCF (2005) Validação e Extensão de estudo. 353 pacientes previamente não tratados para CCR metastáticos que participaram de estudos clínicos entre 1987 e 2002; todas histologias.
afety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Gore ME , Szczylik C , Porta C, Bracarda S, Bjarnason GA, Oudard S, Hariharan S, Lee SH, Haanen J, Castellano D, Vrdoljak E, Schöffski P, Mainwaring P, Nieto A, Yuan J, Bukowski R. Source Royal Marsden Hospital NHS Trust, London, UK. firstname.lastname@example.org Abstract BACKGROUND: Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. METHODS: Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897. FINDINGS: As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1-25). Reasons for discontinuation included lack of efficacy (n=1168 [27%]) and adverse events (n=362 [8%]). The most common treatment-related adverse events were diarrhoea (n=1936 [44%]) and fatigue (n=1606 [37%]). The most common grade 3-4 adverse events were fatigue (n=344 [8%]) and thrombocytopenia (n=338 [8%]) with incidences of grade 3-4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]) and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival was 18.4 months (17.4-19.2). INTERPRETATION: In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials.
Pazopanibe inibe mais quinases, com concentração menor de droga, o que talvez explique do pto de vista farmacológico, uma eventual diferente perfil de toxicidade.
Desfecho primário PFS Desfechos secundários Sobrevida global Taxa de resposta objetiva confirmada Duração de resposta Segurança e tolerabilidade
Dados primeiramente apresentados na ASCO 2002
Lancet. 2011 Dec 3;378(9807):1931-9 The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. The AXIS 1032 phase III trial marks the first head-to-head comparison of active targeted therapies in advanced RCC. Objetivo primario: SLP e objetivos secundarios
Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma.
A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib
. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm.
Background: Tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors, showed activity and tolerability in a Phase II trial ( JCO 2011;29[18S]:4550). Methods: Patients (pts) with clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, RECIST-defined measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib (T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib (S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment naïve or received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. The primary endpoint was progression-free survival (PFS) per blinded, independent radiological review. 500 pts were to be enrolled to observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 months (m) with 5% type I error (2-sided). Results: A total of 517 pts were randomized to T (n=260) or S (n=257). Demographics were well balanced between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p=0.035). Median PFS was 11.9 m for T vs 9.1 m for S (HR=0.797, 95% CI 0.639–0.993; p=0.042). In the treatment-naïve stratum (70% of pts enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 0.756, 95% CI 0.580–0.985; p=0.037). In all pts, objective response rate (ORR) for T was 33% vs 23% for S (p=0.014). The most common adverse event (AE; all grades/≥grade 3) for T was hypertension (T: 46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. Overall survival data are not mature. Conclusions: Tivozanib demonstrated significant improvement in PFS and ORR compared with sorafenib as initial targeted treatment for advanced RCC. The safety profile of tivozanib is favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, and hand-foot syndrome.
Background: Increasingly pt reported outcomes are being added to traditional efficacy outcomes to understand the clinical relevance of toxicity differences between therapies. This study investigated if tolerability differences were significant enough to lead a patient to prefer continuing their treatment with Paz or Sun. Methods: Pts with mRCC were randomized 1:1 to receive as first line treatment blinded 800mg Paz for 10 weeks followed by a 2-week washout and then 50mg Sun for 10 weeks (4/2 weeks schedule) or vice versa. Pts were stratified based on ECOG performance status (0 vs 1) and number of metastatic sites (0/1 vs 2+). The primary endpoint, patient preference assessed at 22 weeks, was compared using Prescott’s test (α=0.10). At least 102 of 160 planned pts were required to complete the preference questionnaire to provide 80% power to detect a preference for one drug over another of 50% vs 30% with 20% expressing no preference. Other endpoints included physician preference, safety, QoL, pharmacokinetics and biomarkers. Results: Of 168 randomized pts, 126 completed the preference questionnaire. In the protocol-driven primary analysis (n=114), Paz was preferred by 70% of pts, Sun by 22% and 8% had no preference. After adjusting for a modest sequence effect, the difference in preference was 49% [90% CI 37.0 – 61.5% p <0.001] in favor of Paz. All pre-planned sensitivity analyses conducted were statistically significant in favor of Paz, including one which imputed Sun for all unavailable pt preference data. The most common reasons for Paz preference were better QoL and less fatigue. 60% of physicians preferred Paz vs 21% for Sun vs 19% no preference. Adverse events (AE) were in line with known profiles for both drugs. Pts on Paz had fewer dose reductions (13% vs 20%) and interruptions (6% vs 12%) vs Sun, mostly due to AE. There was less fatigue on Paz as assessed by FACIT-Fatigue; treatment difference of 2.49, p=0.002. Investigator assessed response (RECIST 1.1) was 22% with Paz vs 24% with Sun, p=0.87. Conclusions: This innovative trial design clearly demonstrates the better tolerability of Paz compared to Sun.
Avanços sem precedente na literatura ocorreram no tratamento do mRCC de 2004-2012 Necessidade urgente do desenvolvimento de biomarcadores para melhor refinar as diversas estratégias de tto.
21 carcinoma de cels. renais metastático (cc rm)
Carcinoma de Cels. Renais Metastático (CCRm) Qual a melhor sequência? Igor Morbeck, MD, MSc Oncologista Clinico - Onco-Vida – BrasíliaProf. Medicina Interna – Univ. Católica de Brasília
Inibição de VEGF é importante em CCR 6000 Normal Câncer Renal DoençaExpressão nos níveis de VEGF 5000 Cânceres invasivos 4000 3000 Câncer de mama Câncer de próstata 2000 1000 0 Tipo de Câncer RINI, BI. et al. Clin Cancer Res, 13:1098–106, 2005. 3
Experiê ncia do Mundo Real: Sunitinibe EAPSunitibe demonstrou eficácia em sub-populações de interesse Gore ME et al. Lancet Oncol. 2009;10:757-763.
EFFECT Trial: Estudo Fase II de Sunitinibe Contínuo Versus Intermitente
EFFECT Trial: Estudo Fase II de Sunitinibe Continuo Versus Intermitente Motzer RJ et al. J Clin Oncol. 2012 Mar 19. [Epub ahead of print].
Pazopanibe é um inibidor de multiquinases mais seletivo comparado com sunitinibe Pazopanibe Sunitinibe SorafenibeQuinases inibidascom IC50 <1 μM 32 54 25 Além de VEGFR, PDGFR e c-Kit, sunitinibe inibe 49 quinases adicionais em potência de 10X mais do que a inibição de VEGFR-2 Por outro lado, pazopanibe e sorafenibe inibem 7 e 10 quinases adicionais, respectivamente 1. KUMAR, R. et al. Br J Cancer, 101:1717–23, 2009. 14
Pazopanibe em mRCC: Sobrevida Livre de Progressão
Sobrevida livre de progressão na subpopulação virgem de tratamento 1.0 PFS mediana (meses) Placebo 2.8 Porporção de ausência de progressão pazopanibe 11.1 0.8 Hazard ratio (95% IC) 0.40 (0.27, 0.60) p valor (1-sided) <0.0001 60% 0.6 de redução do risco de progressão ou morte com 0.4 pazopanibe comparado ao placebo 0.2 pazopanibe Placebo 0.0 0 5 10 15 20 Número em risco, n Tempo (meses) pazopanibe 155 84 39 11 1 Placebo 78 22 7 2 171. STERNBERG, CN. et al. J Clin Oncol, 28(6): 1061-8, 2010.
Podem os pacts serem re-tratados com TKI apó s tto. com inibidor da mTor?• Aná retrospectiva de eficá de um lise cia agente anti-angiogenico apos progressão com Everolimus (n=39).• 14 pcts receberam um outro TKI apos a progressã o.
Novos Padrõ no Tto. do CCR esNational Comprehensive Cancer Network Kidney Cancer v2 2011.
Novos Padrõ no Tto. do CCR esNational Comprehensive Cancer Network Kidney Cancer v2 2012.
Carcinoma de Cels.Renais Metastático (CCRm) ASCO 2012
ASCO 2012 • Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Resultsfrom a phase III randomized, open-label, multicenter trial. Investigador Principal: Robert Motzer - MSKCC• N= 517. SLP 12,7 m (T) vs 9,1 m (S) p=0.037• RG= 33% (T) vs 23% (S) p=0.014.• Baixa Incidência de Fadiga, diarré ia e M ielosupressão. J Clin Oncol 30, 2012 (suppl; abstr 4501)
ASCO 2012• Patient preference between Pazopanib (Paz) and Sunitinib (Sun): Results of a randomized double- blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. Autor Principal: Bernard Escudier- IGR • N= 168. 126 pts completaram o questionário. • Conclusão: 70% dos pacts preferiram Pazopanibe 60% dos mé dicos preferiram Pazopanibe Pazopanibe: < reduç ão de dose (13 vs 20%) < interrupç ão de tto (6% vs 12%) J Clin Oncol 30, 2012 (suppl; abstr CRA4502)
Carcinoma de Cels. Renais Metastático (CCRm)Estudos em Andamento
Estudos em Andamento com Drogas-alvo combinado: Segunda linha.
Quais as perguntas do Momento?1- Quando iniciar o tratamento no paciente de risco menor ?2- Qual a melhor sequência na progressão?3- Qual a melhor associação de drogas ?4- Até quando tratar com drogas antiangiogênicas ?5- Existe papel para tratamento adjuvante ?6- Existe papel para tratamento neo-adjuvante ?7- E a Interleucina-2 em altas doses ?8 - Papel dos Biomarcadores?9- Histologia nao cels. Claras?