Tratamento do CEC pulmão: Algum padrão? pulmão

Transcrição

1 Tratamento do CEC pulmão: Quimioterapia no câncer de Algum padrão? pulmão Gilberto de Castro Junior Instituto do Câncer do Estado de São Paulo Hospital Sírio Libanês São Paulo - BRASIL

2 Conflitos de interesse Categories Grants to participate i t in Boehringer Ingelheim, scientific meetings or advisory Novartis, Roche, Astra Zeneca, boards Lilly Investigator of sponsored clinical i l studies Lecture Honoraria Amgen, Pfizer, Boehringer Ingelheim, Novartis, Roche, Astra Zeneca, Astellas, Millenium, Lilly Roche, Astra Zeneca, Lilly

3 Sumário CEC pulmão: queda na incidência Quimioterapia citotóxica Nab-paclitaxel Moduladores da resposta imune Terapias de alvo molecular Conclusões & perspectivas

4 Lung Cancer ICESP NSCLC (n = 213) N % Histology Adenocarcinoma SCC LCC 5 2 NSCLC - NOS 17 7 Staging I II IIIA IIIB IV Caires-Lima R et al. LALCA 2012

5 Quimioterapia citotóxica em CPCNP Quimioterapia e a histologia 1725 pacientes com CPCNP avançado SOBREVIDA GLOBAL MEDIANA: 10.3 MESES. EM AMBOS OS BRAÇOS Scagliotti, J Clin Oncol 26:

6 Quimioterapia citotóxica em CPCNP CIS PEM vs. CIS GEM Não escamosos Escamosos Scagliotti, J Clin Oncol 26:

7 ECOG 4599 trial Bevacizumabe Anti VEGF N= 878 pacientes Carboplatina AUC 6 + Paclitaxel 200mg/m 2 com CPNCP R avançado + Bevacizumab 15mg/kg + Manutenção q3s. Carboplatina AUC 6 + Paclitaxel 200mg/m 2 Excluídos: Histologiaescamosa i Hemoptise Metástase SNC Diátese hemorrágica Anticoagulação Anti plaquetários

8 Nab-paclitaxel ph III nab-p/c sb-p/c RRR/HR P value Squamous cell ORR, n (%) n = (41) n = (24) < % CI (min max) Complete response, n (%) 0 1 (<1) Partial response, n (%) 94 (41) 53 (24) PFS, median months % CI (min max) OS, median months % CI (min max) max)

9 Perfil de toxicidade

10 Neuropatia

11 Salama A K, Hodi F S Clin Cancer Res 2011;17:

12 Phase 2 Trial of Ipilimumab (IPI) and Paclitaxel/Carboplatin (P/C) in First line Stage IIIb/IV Non small Cell Lung Cancer (NSCLC) Thomas Lynch, 1 Joel Neal, 2 Igor Bondarenko, 3 Alexander Luft, 4 Piotr Serwatowski, 5 Fabrice Barlesi, 6 Raju Chacko, 7 Martin Sebastian, 8 Jean-Marie Cuillerot, 9 and Martin Reck 10 1 Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT; 2 Stanford Cancer Center, Stanford, CA; 3 City Clinical i l Hospital, Dnipropetrovsk, Ukraine; 4 Leningrad dr Regional lcli Clinical i l Hospital, St. Petersburg, Russia; 5 Oddzial Chemioterapii, Szczecin, Poland; 6 University of Mediterranée Assistance Publique Hopitaux de Marseille, Marseille, France; 7 Christian MedicalCollege College, Vellore, India; 8 Universitaetsmedizin Mainz, Mainz, Germany; 9 Bristol Myers 12 Squibb Research and Development, Wallingford, CT; 10 Hospital Grosshansdorf, Department of Thoracic Oncology, Grosshansdorf, Germany.

13 METHODS Figure 1. Trial CA Study Design Chemo: Paclitaxel (175 mg/m 2 )/Carboplatin (AUC=6) IV C: chemotherapy doublet IPI: Ipilimumab (10 mg IV) p: Placebo Note: 13 Steroids were given as premedication

14 Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701 OS: Squamous NSCLC Subset 1.0 Regimen Events/ Patients Median mo HR Prop portion Alive Control Concunrret Phased 14/15 17/21 13/ Patients at risk Concurrent Phased Control Months

15 Response Activity by Baseline Histology Patient group Phased-Ipi vs Control Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701 Concurrent-Ipi vs Control All irpfs Non-Squamous Squamous All mwho-pfs Non-Squamous Squamous All OS Non-Squamous Squamous HR and 95% CI HR and 95% CI Favors Favors Phased Control Concurrent Control In the Phased-ipilimumab arm, improvements in irpfs, mwho-pfs and OS vs. Control appeared greater for squamous histology than for non-squamous No such trends in the Concurrent-ipilimumab arm 15Small sample size warrants caution in interpretation

16 Anti PD-1 Nivolumabe (BMS ) Phase I trial N= 296 com vários tumores (122 com CPNPC) Nivolumabe 0,1 10,0mg/Kg, EV, q14d Objective Response No Objective Response / 17 Proportion of Patients / 25 16/ Positive (N=25) PD-L1 Status 0/ 17 Negative (N=17) Topalian, N Engl J Med 2012;366:

17 Imunoterapia

18 MPDL3280A Imunoterapia Anticorpo monoclonal contra o ligante PD L1 Estudo fase I de escalonamento de dose. Feita análise de taxa de resposta e pesquisa do status EGFR e KRAS e expressão de PD L1 n = 85 CPNPC 3ª linha Doses: 0,3 a 20 mg/kg Não houve toxicidade dose limitante

19 MPDL3280A Imunoterapia Sobrevida livre de progressão em 6 meses de 46%

20 MPDL3280A Melhores respostas: Imunoterapia Tabagistas EGFR Selvagem KRAS Selvagem

21 J Clin Oncol Mar 10;31(8):

22 Significantly mutated genes in lung SCC TCGA. Nature 2012

23 Fibroblast Growth Factor Receptor 1 Gene Amplification Is Associated With Poor Survival and Cigarette Smoking Dosage in Patients With Resected Squamous Cell Lung Cancer Kim HR et al. HR, 1.83; IC95%, 1.15 to 2.89; p 0.01

24 DDR2 : Receptor de discoidina Receptor de membrana ligada a TK Mutação frequente de 2.2a 4% dos CEC Localizado em 1q23 com mutações em 10 códons diferentes do gene

25 Dasatinibe inibidor multi quinase com atividade contra receptor DDR2 Estudos fase II bloqueando a via apresentam taxa de controle de doença entre 43 60% Clinicaltrials.com : 2 estudos específicos para CEC

26 Significantly mutated genes in lung SCC TCGA. Nature 2012

27 - Male pt, 58 y.o. -Pulmonary SCC T4 N2 M1 (pleural and lymphangitic pulmonary involvement) - Former smoker 45 p.y. - Gem-DDP x 4, PR - Oct 2012: enrolled in the CBKM120D2201 trial (mutated PTEN, exon 5) - BKM120 was started in 06/Nov/ Oct 2012: Baseline chest CT, with extensive right involvement 27 Nov 2012 : d21 BKM120 - PR

28 Conclusões Quimioterapia citotóxica Resistência a pemetrexede Nab-paclitaxel Contra-indicação a bevacizumab Moduladores da resposta imune Benefício com mabs direcionados a receptores B7 Terapias de alvo molecular FGFR e PI3K