2 Carcinoma de Cels. Renais Metastático (CCRm) Qual a melhor sequência de tratamento?Igor Morbeck, MD, MScOncologista Clinico - Onco-Vida – BrasíliaProf. Medicina Interna – Univ. Católica de Brasília
3 Declaração de Conflito de Interesses: De acordo com a Resolução 1595/2000 do Conselho Federal de Medicina e RDC 102/2000 da ANVISA, declaro que:1. Participo de estudos clínicos patrocinados pelas empresas: GSK, Sanofi-Aventis, ImClone.2. Atuo como speaker de eventos das empresas: Pfizer, Sanofi-Aventis, GSK, Novartis, Bayer e BMS.3. Participo como membro do advisory board das empresas: Pfizer, GSK, Sanofi-Aventis.4. Não possuo ações de quaisquer destas companhias farmacêuticas.
4 Tomada de Decisões em Oncologia ObjetivaNivel de Evidencia (1-4)GuidelinesAcesso aos TratamentosSubjetivaMedicoInterpretacao de dadosExperienciaPacienteQVEscolhaHistorico PessoalComo fazer decisoes de tratamento para cada paciente?Change circle to patient silhouette
5 High-dose interleukin-21 As opcoes de tto no CCRm foram revolucionadas em um curto periodo de tempoBevacizumab + IFN-α5Sorafenib2Pazopanib7Temsirolimus4High-dose interleukin-21Axitinib8Sunitinib3Everolimus6IFN-αFyfe G, et al. J Clin Oncol 1995;13:Escudier B, et al. N Engl J Med 2007;356:Motzer RJ, et al. N Engl J Med 2007;356:Hudes G, et al. N Engl J Med 2007;356:5. Escudier B, et al. Lancet 2007;370:6. Motzer RJ, et al. Lancet 2008;372:7. Sternberg CN, et al. J Clin Oncol 2010;28:8. Rini BI, et al. Lancet 2011;378:
6 The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy. Citar atuação do Cabozatinib (oral, potent inhibitor of MET and VEGFR2)
7 Carcinoma de Células Renais (CCR) Patogênese Molecular: “Doenças Diferentes” ClarasPapilíferoDuctoColetorCromófoboTipo TumoralOncocitomaHistologiaIncidência %75–8512–144–62–41RCC: molecular pathogenesisIn 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 origin1,2clear-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) genepapillary 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) genethese arise in the collecting ducts and are less common.Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med ;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 withpositive VHL and E-cadherin immunoreactivity, whereas poorprognosis and high-grade tumours are associated with a lackof E-cadherin and lower frequency of VHL staining Shows aberrant nuclear localisation of E-cadherin in clear cellRCC harbouring VHL mutations and suggests potentialprognostic value of VHL and E-cadherin in clear cell RCC .Mutaçao GenéticaVHLc-METFHC-Kit e BHDBHDBHDPadrão Crescim.Acinar/ sarcomatóidePapilar/ sarcomatóideSólido/tubular sarcomatóideNinhosTumoraisPapilar sarcomatóideBHD = Birt–Hogg–Dubé FH = fumarato hidrataseVHL = Von Hippel–LindauMotzer RJ, et al. N Engl J Med 1996;335:865–75 Linehan WM, et al. Clin Care Res 2004;10:6282S–9S
8 Carcinoma de Células Renais Critérios Prognósticos de Motzer LIN- Limite inferior normalDesenvolvido no MSKCC 1990sMSKCC (2002/2004)251 Pacientes submetidos a estudos clínicos de imunoterapia ou quimioterapia ( ); 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.Motzer RJ e cols J Clin Oncol 20:289, 2002
9 Pacientes com CCRm são Heterogêneos Doença Metastática sem Tto. PrévioPredizer Risco de Recorrência?Escolha da Terapia Apropriada?Evitar Toxicidade?ASCO 2011 Education Session
12 Experiência do Mundo Real: Sunitinibe EAP 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.SourceRoyal Marsden Hospital NHS Trust, London, UK.AbstractBACKGROUND: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, NCTFINDINGS:As of December, 2007, 4564 patients were enrolled in 52 countries 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 ) and overall survival was 18.4 months ( ).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.Sunitibe demonstrou eficácia em sub-populações de interesseGore ME et al. Lancet Oncol. 2009;10:
13 EFFECT Trial: Estudo Fase II de Sunitinibe Contínuo Versus Intermitente
14 EFFECT Trial: Estudo Fase II de Sunitinibe Continuo Versus Intermitente Motzer RJ et al. J Clin Oncol Mar 19. [Epub ahead of print].
15 Pazopanibe é um inibidor de multiquinases mais seletivo comparado com sunitinibe 32Sunitinibe54Sorafenibe25Quinases inibidas com IC50 <1 μMAlém de VEGFR, PDGFR e c-Kit, sunitinibe inibe 49 quinases adicionais em potência de 10X mais do que a inibição de VEGFR-2Por outro lado, pazopanibe e sorafenibe inibem 7 e 10 quinases adicionais, respectivamente1. KUMAR, R. et al. Br J Cancer, 101:1717–23, 2009.
16 Pazopanibe em mRCC: Estudo Fase III Desfecho primárioPFSDesfechos secundáriosSobrevida globalTaxa de resposta objetiva confirmadaDuração de respostaSegurança e tolerabilidade
17 Pazopanibe em mRCC: Sobrevida Livre de Progressão
18 Sobrevida livre de progressão na subpopulação virgem de tratamento 1.0PFS mediana (meses)Placebo2.8pazopanibe11.10.8Hazard ratio (95% IC)0.40 (0.27, 0.60)p valor (1-sided)<0.00010.6Porporção de ausência de progressão0.40.2pazopanibePlacebo0.05101520Número em risco, npazopanibePlaceboTempo (meses)1557884223971121STERNBERG, CN. et al. J Clin Oncol, 28(6): , 2010.
19 Novos Padrões no Tto. do CCR National Comprehensive Cancer Network Kidney Cancer v2/2012
20 Carcinoma de Cels. Renais Metastático (CCRm) ASCO/ESMO 2012
21 Investigador Principal: Robert Motzer - MSKCC ASCO 2012Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial.Investigador Principal: Robert Motzer - MSKCCBackground: 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.N= 517. SLP 12,7 m (T) vs 9,1 m (S) p=0.037RG= 33% (T) vs 23% (S) p=0.014.Baixa Incidência de Fadiga, diarréia e Mielosupressão.J Clin Oncol 30, 2012 (suppl; abstr 4501)
22 Autor Principal: Bernard Escudier- IGR ASCO 2012Patient 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, NCTAutor Principal: Bernard Escudier- IGRN= pts completaram o questionário.Conclusão: 70% dos pacts preferiram Pazopanibe60% dos médicos preferiram PazopanibePazopanibe: < redução de dose (13 vs 20%)< interrupção de tto (6% vs 12%)< FadigaBackground: 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= 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.J Clin Oncol 30, 2012 (suppl; abstr CRA4502)
23 800 mg qd continuous dosing Randomized, Open Label, Phase III Trial of Pazopanib versus Sunitinib in First-line Treatment of Patients with Metastatic Renal Cell Carcinoma (mRCC): Results of the COMPARZ TrialPazopanib800 mg qd continuous dosingDose reductions to600 mg or 400 mgAdvanced/metastatic RCCClear-cell histologyNo prior systemic therapyMeasurable disease (RECIST 1.0)KPS ≥ 70Adequate organ functionKey Eligibility CriteriaRandomized 1:1Pazopanib and sunitinib are oral multi-kinase angiogenesis inhibitors that each showed progression-free survival (PFS) benefit for mRCC patients in phase III trials1Indirect comparison analysis of pazopanib versus sunitinib revealed2:Comparable PFSDifferentiated safety profile for certain AEsLower incidence including fatigue, hand-foot syndrome, stomatitis with pazopanibLower incidence for liver function test abnormalities with sunitinibThe phase III COMPARZ trial VEG (NCT ) was designed to provide a direct comparison of the efficacy, safety, and tolerability for pazopanib and sunitinibSunitinib50 mg qd4 wk on/2 wk offDose reductions to37.5 mg or 25 mgStratification FactorsKPS 70/80 vs 90/100Prior nephrectomyBaseline LDH >1.5 vs ≤1.5×ULN
24 Primary Endpoint: Progression-free Survival (independent review) % progression-free at week 36(95% CI)% progression-free at week 48Pazopanib55748.4 (43.6, 53.1)39.6 (34.9, 44.3)Sunitinib55352.1 (47.3, 56.6)43.3 (38.5, 48.0)HR (95% CI ) = (0.898,1.220)PazopanibSunitinib
25 Primary Endpoint: Progression-free Survival (investigator) Median PFS (95% CI)Pazopanib55710.5 mo (8.3, 11.1)Sunitinib55310.2 mo (8.3, 11.1)HR (95% CI ) = (0.863,1.154).PazopanibSunitinib
26 Interim Analysis of Overall Survival Median OS (95% CI)Pazopanib55728.4 mos (26.2, 35.6)Sunitinib55329.3 mos (25.3, 32.5)HR (95% CI ) = (0.762,1.082)P-value = 0.275PazopanibSunitinib2626
27 Relative Risk in Adverse Events AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1Hair color changeWeight decreasedSerum ALT increasedAlopeciaUpper abdominal painSerum AST increasedFatigueRashPain in extremityConstipationTaste AlterationLDH increasedSerum creatinine increasedPeripheral edemaHand-foot syndromeDyspepsiaPyrexiaLeukopeniaHypothyroidismEpistaxisSerum TSH increasedMucositisNeutropeniaAnemiaThrombocytopeniaFavors pazopanibFavors sunitinib
28 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?Avanços sem precedente na literatura ocorreram no tratamento do mRCC deNecessidade urgente do desenvolvimento de biomarcadores para melhor refinar as diversas estratégias de tto.