Quimiorradioterapia Definitiva em Câncer de Pulmão não Pequenas Células

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1 Quimiorradioterapia Definitiva em Câncer de Pulmão não Pequenas Células Gilberto de Castro Junior Professor Colaborador Livre-Docente Faculdade de Medicina da USP Serviço de Oncologia Clínica - Instituto do Câncer do Estado de São Paulo Centro de Oncologia - Hospital Sírio Libanês

2 Categorias Apoio em participação de eventos de cunho científico Investigador de ensaios clínicos patrocinados Potenciais conflitos de interesse Patrocinadores Roche, AstraZeneca, MSD, BMS, Boehringer-Ingelheim, Novartis, Bayer, Eurofarma Roche, Genetech, AstraZeneca, MSD, BMS, Pfizer, Merck Serono, Boehringer-Ingelheim, Eurofarma, Novartis, Astellas Aulas e apresentações Roche, AstraZeneca, BMS, MSD, Merck Serono, Eurofarma, Pfizer Consultorias científicas Roche, AstraZeneca, MSD, Merck Serono, Eurofarma, Boehringer- Ingelheim, Pfizer

3 CASO CLÍNICO Sexo feminino, 65 anos, ECOG - PS 0 AP: Ex-tabagista 50 a.m Tosse crônica progressiva + perda de peso (20Kg em 8m) Março/16 Internação no HC para investigação: Adenocarcinoma de pulmão - ct1bn3m0 EGFR selvagem -06/04/16 RNM encéfalo: SED -03/05/16 PET-CT: 1. Nódulo pulmonar no segmento superior do lobo inferior esquerdo 2. Conglomerado linfonodal infiltrativo no hilo pulmonar esquerdo, envolvendo o brônquio lobar superior esquerdo, invade a artéria e veia pulmonares esquerdas e mantém contato com tronco pulmonar e aorta descendente. 3. Linfonodos mediastinais bilaterais - Considerado irressecável

4 CASO CLÍNICO Junho- Julho/16 Tratamento definitivo com radioterapia concomitante a quimioterapia: -Cisplatina 50mg/m2 D1, D8, D29 e D36. -Etoposídeo 50mg/m2 --> D1, D8, D29, D /06/16 a 29/07/16: RDT 3D em pulmão e drenagem acometida com intuito radical com dose total de 60 Gy, em 30 frações. ATUAL Avaliação resposta: Out/16: TC com RP Jan/18: Resposta mantida (DE) Última consulta: 06/04/2018

5 Overall survival by clinical stage according eighth edition Peter Goldstraw, FRCS et al. Journal of Thoracic Oncology Vol. 11 No. 1:

6 Estudo Tipo Tratamento Resultados SWOG 9019 Albain KS et al JCO 2002 SWOG 9504 Gandara DR et al JCO 2003 HOG Hanna N et al JCO 2008 QRT + CONSOLIDAÇÃO Fase II EC IIIB 50 pts Fase II EC IIIB 83 pts Fase III Randomizado EC IIIA/B 147 pts Cisplatina + Etoposídeo RDT 61 Gy + Cisplatina + Etoposídeo x 2 Cisplatina + Etoposídeo RDT 61 Gy + Docetaxel q21d x 3 Cisplatina + Etoposídeo RDT 59.4 Gy + Docetaxel q21d x 3 X Observação SG: 15m SG 3a: 17%, 5a: 15% Toxicidades G3/4: Neutropenia, Esofagite actínica SG: 15m SG 3a: 17% Toxicidades G3/4: Neutropenia, esofagite, pneumonite. SG: 23,2 x 21,2 SG 3a: 26.1% x 27.1% Maior toxicidade

7 Estádio III Irressecável : N2 volumosos, N3, T4 irressecável Fase 3 NSCLC Inop. EC II-IIIB N = 610 R QT-RT sequencial QRT concomitante 1) CDDP 100 mg/m2 D1,D29 + Vinblastina 5 mg/m2 semanal x5 RT 60Gy 2) CDDP 100 mg/m2 D1,D29 + Vinblastina 5 mg/m2 semanal x5 + RT 60Gy 3) CDDP 50 mg/m2 D1, D8, D29, D36 + Etoposideo 50 mg 2x/d VO + RT 69Gy P 0.04 OS Mediana OS 5 anos QT-RT 14,6 10% QRT (2) 17,0 16% QRT (3) 15,6 13% Walter JC et al. J Natl Cancer Inst, 2011

8 Carboplatina + Paclitaxel: Alternativa? Paclitaxel 200 mg/m2 + Carboplatina AUC 6 q21d x2 -> RDT 63 Gy (7 semanas/34 frações) SG: 13m SG 3a:17% Fase II Randomizado EC IIIA/B FU 39,6m R Paclitaxel 200 mg/m2 + Carboplatina AUC 6 q21d x2 -> Paclitaxel 45 mg/m2/semana + Carboplatina AUC 2 + RDT 63 Gy (7 semanas/34 frações) SG:12,7m SG 3a:15% Paclitaxel 45 mg/m2/semana + Carboplatina AUC 2 + RDT 63 Gy (7 semanas/34 frações) -> Paclitaxel 200 mg/m2 + Carboplatina AUC 6 q21d x2 SG: 16,3m SG 3a: 17% Chandra PB et al. J Clin Oncol, 2005

9 Retrospectivo EC III N =1842 EP 1º: OS QRT com Cis-VP QRT com Carbo taxol HR, 1.07; CI: ; P= 0.42 J Clin Oncol 33:

10 PARSIMONY Análise Retrospectiva 5 INSTITUIÇÕES BRASILEIRAS Cisplatina/ Carboplatina + Etoposídeo/ Paclitaxel/ Vinorelbina + RDT Consolidação x Não Consolidação Endpoint 1º: SG J Global Oncol 2018 (in press)

11 PARSIMONY Fig. S1 - Overall survival (OS) Fig. S2 Progression-free survival (PFS) curves according to consolidation chemotherapy statu J Global Oncol 2018 (in press)

12 Cisplatina + Pemetrexede: alternativa? Fase 3, aberto, Multicentrico Estadio IIIA/B Histologia não-escamosa EP 1º: SG EP 2º: SLP, TR R N= 301 Pemetrexed + CDDP 3 ciclos, concomitante Permetrexed 500mg/m², 21d CDDP 75mg/m² RT 60-66Gy Pemetrexed (4x) N= 297 Etoposideo + CDDP 2 ciclos, concomitante RT 60-66Gy Doublet platina (2x) Etoposideo 50mg/m² D1-5, 28d CDDP 50mg/m² D1,D8, 28d Senan S et al. J Clin Oncol. 2016

13 Cisplatina + Pemetrexede: alternativa? SOBREVDA GLOBAL SG 3a 40% vs 37% SGm: 26.8m x 25m HR = 0.98, p= 0.8 PFS SLPm: 11.4 X 9.8 m HR = 0.88, p= 0.13 Toxicidades Pemetrexede/Cis Etoposídeo/Cis Graus % 76.8% Trombocitopenia 19.4% 31.3% Neutropenia 42.8% 54.8% Neut. febril 5.7% 10.3% Pneumonite 17% 10.7% Senan S et al. J Clin Oncol. 2016

14 CETUXIMABE Fase III Randomizado 1:1:1:1 EC IIIA/B inoperáveis R QT + RT 60 Gy QT + RT 74 Gy QT + RT 60 Gy + Cetuximabe QT + RT 74 Gy + Cetuximabe Consolidação: Paclitaxel 200 mg/m 2 + Carboplatina AUC 6 x2 q3 semanas Consolidação: Paclitaxel 200 mg/m 2 + Carboplatina AUC 6 x2 q3 semanas + Cetuximabe QT: Paclitaxel 45 mg/m2 + Carboplatina AUC 2 semanal Bradley JD et al. Lancet Oncol 2015; 16:

15 CETUXIMABE Radioterapia: FUp: 22.9m SGm: 28,7 vs 20,3m (HR 1,38 IC 95% 1,09-1,76) P: 0,004) Cetuximabe: FUp: 21.3m SGm: 25,0 vs 24,0m (HR 1,07 IC 95% 0,84-1,35) P: 0,29) Não houve benefício em sobrevida global com radioterapia em doses mais altas ou acréscimo de Cetuximabe ao tratamento padrão. Bradley JD et al. Lancet Oncol 2015; 16:

16 PACIFIC Study Design Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study Patients with stage III, locally advanced, unresectable NSCLC who have not progressed following definitive platinum-based ccrt ( 2 cycles) Durvalumab 10 mg/kg q2w for up to 12 months N=476 Co-primary endpoints PFS by BICR using RECIST v1.1* OS 18 years or older WHO PS score 0 or 1 Estimated life expectancy of 12 weeks Archived tissue was collected All-comers population 1 42 days post-ccrt R 2:1 randomization, stratified by age, sex, and smoking history N=713 Placebo 10 mg/kg q2w for up to 12 months N=237 Key secondary endpoints ORR (per BICR) DoR (per BICR) Safety and tolerability PROs *Defined as the time from randomization (which occurred up to 6 weeks post-ccrt) to the first documented event of tumor progression or death in the absence of progression. ClinicalTrials.gov number: NCT BICR, blinded independent central review; ccrt, concurrent chemoradiation therapy; DoR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes; PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization Antonia et al. NEJM 2017

17 PFS probability PACIFIC PFS Stratified hazard ratio, 0.52 (95% CI, ) Two-sided P< Durvalumab Placebo (N=476) (N=237) Median PFS (95% CI), months 16.8 ( ) 5.6 ( ) 12-month PFS rate (95% CI) 55.9% ( ) 35.3% ( ) 18-month PFS rate (95% CI) 44.2% ( ) 27.0% ( ) Placebo Durvalumab No. at risk Time from randomization (months) Durvalumab Placebo BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-freesurvival Antonia et al. NEJM 2017

18 PACIFIC PFS Antonia et al. NEJM 2017

19 % patients (95% CI) PACIFIC Antitumor Activity Objective Response Durvalumab (N=443)* Placebo (N=213)* Treatment effect (HR [95% CI]) ( ) 28.4 Durvalumab (N=443)* P<0.001 ( ) 16.0 Placebo (N=213)* Treatment effect (RR [95% CI]) : 1.78 ( ) Best overall response, n (%) Complete response 6 (1.4) 1 (0.5) Partial response 120 (27.1) 33 (15.5) Stable disease 233 (52.6) 119 (55.9) Progressive disease 73 (16.5) 59 (27.7) Non-evaluable 10 (2.3) 1 (0.5) Duration of response, months Median (95% Cl) NR 13.8 (6.0 NR) 0.43 ( ) Ongoing response at data cutoff,% At 12 months At 18 months Antonia et al. NEJM 2017

20 PACIFIC Incidence of New Lesions Durvalumab Placebo New lesion site* (N=476) (N=237) Any new lesion, n (%) 97 (20.4) 76 (32.1) Lymph nodes 27 (5.7) 27 (11.4) Brain 26 (5.5) 26 (11.0) Lung 56 (11.8) 41 (17.3) Liver 9 (1.9) 8 (3.4) Adrenal 3 (0.6) 5 (2.1) Bone 8 (1.7) 6 (2.5) Other 9 (1.9) 5 (2.1) *A patient may have had more than one new lesion site. Includes lesions in: abdominal wall, biliary tract, breast, chest wall, kidney, ovary, pancreas, pericardium, peritoneal fluid, peritoneum, retroperitoneum, skin, spleen, uterus and other (unspecified). Antonia et al. NEJM 2017

21 Probability of death or distant metastasis PACIFIC Time to Distant Metastasis or Death Durvalumab Placebo Time from randomization (months) No. at risk Durvalumab Placebo Stratified hazard ratio, 0.52 (95% CI, ) Two-sided P< Median time (95% CI), months Durvalumab Placebo 23.2 (23.2 NR) 14.6 ( ) BICR, blinded independent central review; ITT, intention-to-treat Antonia et al. NEJM 2017

22 PACIFIC Safety Summary Durvalumab (N=475) Placebo (N=234) Any-grade all-causality AEs, n (%) 460 (96.8) 222 (94.9) Grade 3/4 142 (29.9) 61 (26.1) Grade 5 21 (4.4) 13 (5.6) Leading to discontinuation 73 (15.4) 23 (9.8) Any-grade treatment-related AEs, n (%) 322 (67.8) 125 (53.4) SAEs, n (%) 136 (28.6) 53 (22.6) Any-grade immune-mediated AEs, n (%) 115 (24.2) 19 (8.1) Grade 3/4 16 (3.4) 6 (2.6) Antonia et al. NEJM 2017

23 PACIFIC Most Frequent AEs Durvalumab (N=475) Placebo (N=234) Event Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Any event, n (%) 460 (96.8) 142 (29.9) 222 (94.9) 61 (26.1) Cough 168 (35.4) 2 (0.4) 59 (25.2) 1 (0.4) Pneumonitis/radiation pneumonitis 161 (33.9) 16 (3.4) 58 (24.8) 6 (2.6) Fatigue 113 (23.8) 1 (0.2) 48 (20.5) 3 (1.3) Dyspnea 106 (22.3) 7 (1.5) 56 (23.9) 6 (2.6) Diarrhea 87 (18.3) 3 (0.6) 44 (18.8) 3 (1.3) Pyrexia 70 (14.7) 1 (0.2) 21 (9.0) 0 Decreased appetite 68 (14.3) 1 (0.2) 30 (12.8) 2 (0.9) Nausea 66 (13.9) 0 31 (13.2) 0 Pneumonia 62 (13.1) 21 (4.4) 18 (7.7) 9 (3.8) Arthralgia 59 (12.4) 0 26 (11.1) 0 Pruritus 58 (12.2) 0 11 (4.7) 0 Rash 58 (12.2) 1 (0.2) 17 (7.3) 0 Upper respiratory tract infection 58 (12.2) 1 (0.2) 23 (9.8) 0 Constipation 56 (11.8) 1 (0.2) 20 (8.5) 0 Hypothyroidism 55 (11.6) 1 (0.2) 4 (1.7) 0 Asthenia 51 (10.7) 3 (0.6) 31 (13.2) 1 (0.4) Back pain 50 (10.5) 1 (0.2) 27 (11.5) 1 (0.4) Antonia et al. NEJM 2017

24 Conclusões NSCLC estadio III, não candidato a cirurgia com intenção curativa QRT concomitante baseada em cisplatina, sem QT de consolidação parece ser a melhor alternativa de tratamento A seleção dos pacientes candidatos é crítica Durvalumabe por 1 ano após o final da QRT aumenta PFS Tratamento bem tolerado Melhor controle de doença a distância Novo padrão de tratamento