Abordaje de la paciente con cáncer de ovario avanzado. 1 a línea de tratamiento

Transcripción

1 Tratamiento de quimioterapia en primera línea de cáncer ovario avanzado Antiangiogénico en cáncer de ovario avanzado. Cuándo recomendar?. Estado actual Valeria Caceres, M.D., Ph.D. Jefa del Departamento de Oncología Clínica Directora de la Carrera Universitaria de Especialistas en Oncología Instituto Angel H Roffo Universidad de Buenos Aires Abril de 2018

2 Abordaje de la paciente con cáncer de ovario avanzado 1 a línea de tratamiento

3 Cáncer de ovario según estadío: 2017 Edad mediana: 58 4% N: % 16% 5% E? (4) E I (16) E II (5) 58% E III (59) E IV (17) *E?: no se indica estadio en la planilla de recolección de datos

4 Cáncer de ovario avanzado : evolución Recaída (80%) Tratamiento primario Estadío III, IV Candidata a Platino No candidate a Platino QMT NA CDI Cirugía QMT 1 Línea Segunda remisión clínica 1 Remisión clínica Recaída (100%)

5 Factores pronósticos

6 El estadío IIIc es un subgrupo heterogéneo Omental cake Siembra miliar Ascitis voluminosa Ganglios paraaórticos IIIC: el cáncer se ha diseminado visiblemente más allá de la pelvis hasta el abdomen y tiene más de 2 cm, con o sin diseminación a los ganglios linfáticos retroperitoneales

7 ENFERMEDAD RESIDUAL

8 OS (%) Pacientes con FIGO III/IV y enfermedad residual necesitan mejores tratamientos Pacientes con enfermedad residual tienen pobre OS 1 Overall survival by debulking status mm vs 0 mm: HR (95% CI) 2.70 ( ) >10 mm vs 1 10 mm: HR (95% CI) 1.34 ( ) 60 p< mm (n=1,046) mm (n=975) >10mm (n=1,105) Time (months) 1. Du Bois, et al. Cancer 2009 Data combined from 3 randomised controlled trials performed by AGO-OVAR together with GINECO, n=3,388.patients enrolled had FIGO stage IIb IV epithelial ovarian cancer.

9 VOLUMEN TUMORAL INICIAL

10 Volumen tumoral como factor pronóstico GOG demonstrated that stage III with large-volume ovarian cancer before undergoing optimal cytoreduction had a worse prognosis [1]. SCOTROC showed that a clinically significant PFS benefit with optimal surgery in stage IIIC to IV disease was limited to patients with less-advanced disease [2]. Eisenkop et al. observed that the need to remove a large number of peritoneal implants correlates with biological aggressiveness and diminished survival, but not significantly enough to preclude long-term survival [3,4]. 1. Hoskins WJ. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 1992; 47: [PubMed: ] 2. Crawford SC, Vasey PA, Paul J, Hay A, Davis JA, Kaye SB. Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial. J Clin Oncol. 2005; 23: [PubMed: ] 3. Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003; 90: [PubMed: ] 4. Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003; 90: [PubMed: ]

11 Upper abdominal disease cephalad to the greater omentum (UAD) UAD was defined as metastatic implants involving the diaphragm, liver, porta hepatis, spleen, pancreas, stomach, celiac axis, and lesser sac. The presence and volume of UAD is a marker for the general intraabdominal tumor burden and carcinomatosis. UAD is associated with adverse prognostic and tumor-volume factors such as large-volume ascites and highly elevated serum CA-125 levels, 526 patients with FIGO stage IIIC ovarian cancer undergoing primary cytoreductive surgery followed by intravenous or intraperitoneal platinum-based chemotherapy from January 1, 1989 to December 31, The presence and size of UAD at the beginning of exploratory surgery was collected Zivanovik et al: Gynecol Oncol March ; 116(3): doi: /j.ygyno

12 Población se dividió en tres grupos First group: patients with no visible or palpable UAD on exploration; Second group: patients with minimal UAD (1 cm or less); Third group: patients with bulky UAD (larger than 1 cm) Optimal cytoreduction: 104/125 (83%), 106/158 (67%), and 104/243 (42%) Zivanovik et al: Gynecol Oncol March ; 116(3): doi: /j.ygyno

13 PFS por grupo First group: patients with no visible or palpable UAD on exploration;

14 PFS por grupo Second group: patients with minimal UAD (1 cm or less)

15 PFS por grupo Third group: patients with bulky UAD (larger than 1 cm)

16 Pronóstico en pacientes sin enfermedad residual Hamilton et al. Gynecol Oncol 2011

17 GOG 182-ICON5: Estadíos III/IV Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR Regimen I (control) Paclitaxel 175 mg/m 2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m 2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m 2 /d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m 2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m 2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IVd 3 Topotecan 1.25 mg/m 2 /d IV d 1-3 Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Regimen IV (sequential module B) Paclitaxel 175 mg/m 2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m 2 /d IV d 1, 8 Regimen V (sequential module B) Paclitaxel 175 mg/m 2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002.

18 GOG0182-ICON5: PFS y OS Median OS and HR (95% CI) ( ) ( ) ( ) ( ) Median PFS and HR (95% CI) ( ) ( ) ( ) ( ) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan

19 Carga de enfermedad (DS) y Score de Complejidad quirúrgica (CS): GOG 182 Carga de enfermedad (DS) DS Bajo: pelvis y retroperitoneo DS Moderado: Enfermedad abdominal adicional sin abdomen alto DS Alto: enfermedad abdominal alta con compromiso del diafragma, bazo, hígado ó páncreas Score de Complejidad quirúrgica (CS) Procedimientos individuales que componen un score que se suma en cada paciente CS Bajo: Score 1 a 3 CS Moderado : Score 4-7 CS Alto: score >8 Horowitz NS, JCO 2014,56,3106

20 DS: Impacto en PFS y OS: datos del GOG0182 Un DS bajo se asocia a PFS y OS mas prolongadas

21 Enfermedad residual por DS: PFS y OS: Datos del GOG 0182 R0 se asocia a mejor evolución Sin embargo RO, fue significativo solo en pacientes con DS bajo Las pacientes RO DS alto se comportan como las de DS Bajo con residuo

22 2004 GCIG quimioterapia standard de 1 línea La rama standard de tratamiento debe contener un taxano y una sal de platino por 6 ciclos El regimen recomendado es paclitaxel (175 mg/m 2 ) y carboplatino (AUC 5-6) cada 3 semanas. La PFS media es de meses La OS a 5 años de 30-35% Es aceptable adiciones ó variaciones en la dosis, esquema o ruta de administración y deben ser avaladas al menos por un estudio clínico que demuestre superioridad o no inferioridad a taxano/platino 3rd Ovarian Cancer Consensus Conference September 3 5, 2004 Baden-Baden, Black Forest, Germany Bookman, M. A. Et all. J Clin Oncol; 27:

23 Cáncer de ovario avanzado QT 1ª línea: Intentos fallidos de mejorar resultados Carboplatino AUC paclitaxel 175 mg/m 2 Tripletes: 6 GCIG triales, 4 drogas y 10,000 pacientes Dobletes secuenciales Sustitución de paclitaxel: SCOTROC (docetaxel); MITO-2 (PLD): igual RR, PFS y OS (diseño de superioridad) Consolidación/ Mantenimiento: SWOG 9701

24 Cáncer de ovario avanzado QT 1ª línea: Intentos exitosos de mejorar resultados: Administración intraperitoneal: GOG-104,114, 172, GOG 252 HIPEC Paclitaxel dosis densas: NCT Nuevas terapias: antiangiogénicos Alberts, N Engl J Med 1996 Dec (26) Amstrong,N Engl J Med 2006 Jan 5 354(1)34-43 MarkmanJ Clin Oncol 2001 Feb 15 19(4) Katsumata Lancet 2009 Oct (9698)1331-8

25 Cáncer de ovario avanzado QT 1ª línea: Intentos exitosos de mejorar resultados: Administración intraperitoneal Alberts, N Engl J Med 1996 Dec (26) Amstrong,N Engl J Med 2006 Jan 5 354(1)34-43 MarkmanJ Clin Oncol 2001 Feb 15 19(4) Katsumata Lancet 2009 Oct (9698)1331-8

26 Datos maduros del GOG meses

27 Limitaciones y complicaciones del GOG-172 QoL por FACT-O empeora al final del 3 y 6 ciclo 8% nunca empezaron 34% recibió solo 1 ó 2 ciclos Solo un 42% de las pacientes completaron los 6 ciclos planeados NO factible en la mayoría de los pacientes

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29 A PHASE III CLINICAL TRIAL OF BEVACIZUMAB WITH IV VERSUS IP CHEMOTHERAPY IN OVARIAN, FALLOPIAN TUBE AND PRIMARY PERITONEAL CARCINOMA NCI-SUPPLIED AGENT(S): BEVACIZUMAB (NSC #704865, IND #7921) NCT a GOG/NRG Trial (GOG 252) Joan L. Walker; Mark F Brady; Paul A Di Silvestro; Keiichi Fujiwara; David Alberts; Wenxin Zheng; Krishnansu Tewari; David E Cohn; Matthew Powell; Linda van Le; Stephen Rubin; Susan A Davidson; Heidi J Gray; Steven Waggoner; Tashanna Myers; Carol Aghajanian; Angeles Alvarez Secord; Robert S Mannel

30 GOG 252: IP chemo and dose dense Paclitaxel showed improved OS, both have toxicities; which is best?

31 1560 patients Stage III-84% Stage II-10% Grade 3 Serous 72%

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33 Across Study Comparisons for PFS

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38 Paclitaxel semanal en cáncer de ovario Estudio Japonés Japanese Gynecologic Oncology Group Trial FIRST LINE Stage II IV OVARIAN CANCER (including primary peritoneal fallopian tube) R A N D O M I Z E Paclitaxel 180 mg/m 2 day 1 Carboplatin AUC 6 day 1 Paclitaxel 80 mg/m 2 days 1,8,15 Carboplatin AUC 6 day 1 q 3w 6 9 cycles q 3w 6 9 cycles Primary endpoint: PFS Total accrual: 637 patients Katsumata N, et al. Lancet. 2009;374(9698): Katsumata N. et al.lancet Oncol 2013; 14:

39 Paclitaxel semanal en cáncer de ovario Estudio Japonés 62% (dd) vs 73% recibieron > 6 ciclos 36% (dd) vs 22% discontinuaron tto debido a AEs Estudios confirmatorios: GOG 262, MITO-7, ICON-8 Median PFS 28.2 months vs 17.5 months (HR 0.76, 95% CI ; p=0.0037). Median OS vs 62.2 months (HR 0.79, 95% CI ; p=0.039). Lancet Oncol 2013; 14:

40 MITO 7: diseño del estudio Control arm R an do m 1:1 Carboplatin AUC 6, d1 q21 Paclitaxel 175 mg/m 2, d1 q21 Treatment repeated for 6 cycles Weeks Experimental arm Strata: Center PS (0, 1, 2) Residual disease after surgery (absent, 1 cm, 1 cm, no surgery) Carboplatin AUC 2, d1, 8, 15 q21 Paclitaxel 60 mg/m 2, d1, 8, 15 q21 Treatment repeated for 6 cycles ClinicalTrials.gov NCT Presented Pignata by: S.Pignata et al. Lancet Oncol Apr;15(4):

41 Probability of progression-free survival PFS Analysis: March 2013, median follow-up 19.9 months Months Patients Events Median PFS Months (95% CI) Every 3-week ( ) Weekly ( ) Log-rank test p = 0.18 Unadjusted HR: 0.88 ( ) Patients at risk Every 3-week Weekly Presented Pignata by: S.Pignata et al. Lancet Oncol Apr;15(4):

42 MITO 7 Probability of survival Patients Events OS Months Median OS Months (95% CI) Every 3-week (47.9 n.a.) Weekly n.a. (36.3 n.a.) Log-rank test p = 0.24 Unadjusted HR: 1.20 ( ) Patients at risk Every 3-week Weekly Presented by: S.Pignata Analysis: March 2013, median follow-up 19.9 months Pignata et al. Lancet Oncol Apr;15(4):

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47 ICON8: A GCIG PHASE III RANDOMISED TRIAL EVALUATING WEEKLY DOSE-DENSE CHEMOTHERAPY INTEGRATION IN FIRST- LINE EPITHELIAL OVARIAN/FALLOPIAN TUBE/PRIMARY PERITONEAL CARCINOMA (EOC) TREATMENT: RESULTS OF PRIMARY PROGRESSION FREE SURVIVAL (PFS) ANALYSIS A. Clamp 1, I. McNeish 2, A. Dean 3, D. Gallardo 4, J.W. Kim 5, D.M. O Donnell 6, J. Hook 7, C. Coyle 8, S. Blagden 9, J. Brenton 10, R. Naik 11, T. Perren 7, S. Sundar 12, A. Cook 13, E. James 13, A.M. Swart 14, S. Stenning 13, R. Kaplan 13, J. Ledermann 15 1 The Christie NHS Foundation Trust, Manchester, UK; 2 Institute of Cancer Sciences, University of Glasgow, UK; 3 Oncology, St. John of God Hospital, Subiaco, Australia; 4 Clinical Oncology, Instituto Nacional de Cancerologia, Mexico; 5 Obstetrics and Gynaecology, Seoul National University Hospital, Seoul, Korea; 6 Cancer Trials Ireland, Dublin, Ireland; 7 St. James s University Hospital, Leeds, UK; 8 Imperial College London, Charing Cross Hospital, London, UK; 9 Churchill Hospital, University of Oxford, Oxford, UK; 10 Li Ka Shing Centre, Cancer Research UK, Cambridge Research Institute, Addenbrookes Hospital, Cambridge, UK; 11 Gynaecology Oncology Centre, Queen Elizabeth Hospital, Gateshead, UK; 12 Gynaecology Cancer Centre, University of Birmingham, Birmingham, UK; 13 MRC Clinical Trials Unit, Institute of Methodology, UCL, London, UK; 14 Norwich Medical School, University of East Anglia, Norwich, UK; 15 Cancer Research UK & UCL Cancer Trials Centre, UCL, London, UK esmo.org

48 ICON8 TRIAL SCHEMA Diagnosis of Stage IC-IV EOC/PPC/FTC After immediate primary surgery or planned to receive NACT plus delayed primary surgery Stratification factors: GCIG group Disease stage Timing and outcome of surgery Randomise 1:1:1 Arm 1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m 2 q3w Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m 2 q1w Arm 3 Carboplatin AUC 2 q1w Paclitaxel 80mg/m 2 q1w Six cycles chemotherapy mandated Delayed Primary Surgery cohort Cytoreductive surgery strongly advised after 3 cycles of chemotherapy Cycle 3 day 15 treatment omitted in arms 2 and 3 8

49 ICON8 PROGRESSION FREE SURVIVAL (PFS) Arm 1 Arm 2 Arm 3 Standard Weekly Weekly carbopaclitaxel paclitaxel Total Patients N=522 N=523 N=521 Progressions 330 (63%) 335 (64%) 338 (65%) Median PFS 17.9 months 20.6 months 21.1 months Log rank (vs Arm1) p=0.45 p=0.56 HR vs Arm 1 (97.5% CI) 0.92 (0.77, 1.09) 0.94 (0.79, 1.12) Restricted means 24.4 months 24.9 months 25.3 months 16

50 ICON8 PFS (BY IPS & DPS) Median PFS IPS Standard 49.3 months Weekly paclitaxel 43.2 months Weekly carbo-paclitaxel 43.7 months DPS Standard 13.8 months Weekly paclitaxel 14.6 months Weekly carbo-paclitaxel 15.4 months 17

51 ICON8 OVERALL SURVIVAL Arm 1 Arm 2 Arm 3 Standard Weekly Weekly carbopaclitaxel paclitaxel Total Patients N=522 N=523 N=521 No. of deaths 183 (35%) 167 (32%) 166 (32%) Log rank (vs Arm 1 only) p=0.21 p=0.3 Median OS 46.5 months 48.1 months 54 months 2 year survival (95% CI) 80% (76%, 83%) 82% (79%, 86%) 78% (74%, 81%) Data immature 602 events per comparison required (58% of required events included here) 19

52 Antiangiogénicos en primera línea Cuatro estudios positivos fase III con antiangiogénicos en 1 línea de cáncer de ovario Bevacizumab Pequeñas moléculas AGO-OVAR16 LUME AGO-OVAR12 Avanzado, estadío III/IV Inicial y avanzado Pazopanib, Solo mantenimiento Nindetanib Inicial y avanzado PFS HR= PFS HR= PFS HR= PFS HR= Alto riesgo Alto y Bajo riesgo Bajo riesgo Bajo riesgo 1. Burger, et al. NEJM 2011; 2. Perren, et al. NEJM Dubois ASCO 2013 ;

53 Phase III Double Blind Trial of Bevacizumab in the Primary Treatment of Advanced 53 Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer: A Gynecologic Oncology Group (GOG) StudyGOG-218 Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) R A N D O M I Z E Stratification variables: GOG performance status (PS) Stage/debulking status 1:1:1 >2/3 de las pacientes de alto riesgo Following maximal debulking surgery: stage III optimal (macroscopic residual disease 1cm) or suboptimal (>1cm), or stage IV Burger et al. ASCO 2010 BEV 15 mg/kg Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 BEV 15 mg/kg Maintenance (16 cycles) Arm I (CP) II (CP + BEV) III (CP + BEV BEV) 15 months

54 GOG-218 Características clínicas 54 Characteristic, n (%) Stage/residual size Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV BEV (n=623) III optimal (macroscopic) 218 (35) 205 (33) 216 (35) III suboptimal 254 (41) 256 (41) 242 (39) IV 153 (25) 164 (26) 165 (27) Histology Serous 543 (87) 523 (84) 525 (84) Endometrioid 20 (3) 15 (2) 25 (4) Clear cell 11 (2) 23 (4) 18 (3) Mucinous 8 (1) 5 (<1) 8 (1) Tumor grade 3 a 412 (66) 435 (70) 430 (69) 2 94 (15) 77 (12) 92 (15) 1 33 (5) 28 (4) 16 (3) Not specified/pending 86 (14) 85 (14) 85 (14) Burger et al. ASCO 2010

55 GOG-218 Toxicidad 55 Adverse event (grade when limited), n (%) Arm I CP (n=601) Arm II CP + BEV (n=607) Arm III CP + BEV BEV (n=608) GI events a (grade 2) 7 (1.2) 17 (2.8) 16 (2.6) Hypertension (grade 2) 43 (7.2) b 100 (16.5) b 139 (22.9) b Proteinuria (grade 3) 4 (0.7) 4 (0.7) 10 (1.6) Pain (grade 2) 250 (41.7) 252 (41.5) 286 (47.1) Neutropenia (grade 4) 347 (57.7) 384 (63.3) 385 (63.3) Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3) Venous thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7) Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7) CNS bleeding (0.3) Non-CNS bleeding (grade 3) 5 (0.8) 8 (1.3) 13 (2.1) RPLS 0 1 (0.2) 1 (0.2) RPLS = reversible posterior leukoencephalopathy syndrome a Perforation/fistula/necrosis/leak bp<0.05 Burger et al. ASCO 2010

56 GOG-218 Toxicidad GI G 2 AE, No. of patients Grade Arm I CP + PLA PLA (n=587) Arm II CP + BEV PLA (n=587) Arm III CP + BEV BEV (n=585) Total Total 10 (1.7%) 20 (3.4%) 20 (3.4%) 50 (2.8%) Fistula GI leak Necrosis Perforation % 1.8% 1.2% Bleeding Burger, JCO % 1.1% 0.8%

57 GOG-218 Momento del diagnóstico de la toxicidad GI No. of patients with a grade 2 GI AE Arm I CP + PLA PLA Arm II CP + BEV PLA Arm III CP + BEV BEV Cycle number Burger, SGO Marzo 2011

58 GOG-218 Modelo logístico de la asociación entre factores de riesgo y toxicidad GI Model covariate Estimated odds of grade 2 GI AE (95% CI) BEV treatment 2.15 ( ) En un modelo de regresión logística no hubo evidencia de Treatment for IBD 13.4 ( ) que bevacizumab exacerbara el Large bowel resection at primary surgery 2.05 ( ) riesgo de un EA GI cuando estos Small bowel resection at primary surgery 1.95 ( ) factores estuvieran presentes Burger, JCO 2014

59 Proportion surviving progression free GOG-218 SLP censurando progresión bioquímica (CA 125) Median follow-up: 17.4 months >20% I CP (n=625) III CP + BEV BEV (n=623) No. of patients with event, n (%) 339 (54.2) 255 (40.9) Median PFS, months Stratified analysis HR (95% CI) ( ) p value one-sided (log rank) < a Censored for CA-125, % CP (Arm I) + BEV BEV maintenance (Arm III) Months since randomisation Al comienzo del período de platino sensibilidad hay más de un 20 % de pacientes con bevacizumab que pudieron adquirir esta condición a p-value boundary = Burger et al. ASCO 2010

60 GOG 218: PFI Distribución de la enfermedad Platino Sensible a la recaída PC + PL PC + BV Intervalo Mediano libre de quimioterapia PFS a los 12 meses 9% 30% Recaída platino sensible 26% 42% Una mayor proporción de pacientes en la rama de BV están libres de progresión a 6 y 12 meses Esto implica un incremento de 2 a 3 veces del porcentaje de pacientes en la rama de bevacizumab que se beneficiaron de un período extendido sin quimioterapia Post last dose of carboplatin on study Reference Randall et al, submited to SGO 2013 Aghajanian et al. ESMO 2012

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64 GOG-0218: uso de terapias subsiguientes CP + Pla (n=625) CP + Bev Pla (n=625) CP + Bev Bev (n=623) Use of any non-protocol therapy 78% 79% 73% Chemotherapy 74% 74% 70% Use antiangiogenic treatments 39% 30% 17% Bevacizumab 28% 28% 15% Roche data on file

65 ICON-7 Schema Esquema de tratamiento Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing. study population included only patients who had undergone surgery with the aim of maximal debulking 65 1:1 R n=1528* *Dec 2006 to Feb 2009 Carboplatin AUC6 Paclitaxel 175 mg/m 2 Carboplatin AUC6 Paclitaxel 175 mg/m 2 Bevacizumab 7.5 mg/kg q3w 18 cycles Stratification variables: Stage & extent of debulking: I III debulked (n=1,528) 1cm vs stage I III debulked >1 cm vs stage IV and I IIA inoperable if high risk: stage grade III3 or Timing clear cell of histology intended treatment start IIB IV: all grades and 4 histological vs >4 weeks subtypes after surgery patients debulked 1 cm or >1 cm GCIG group (*also choice of AUC dose 5 [AGO, NSGO, GINECO] or 6) FIGO stage ECOG PS 0 2 OC, PP, FTC Year 1 Years 2 3 Years 4 5 >2/3 de los pacientes es de bajo riesgo CT Baseline; after cycles 3 & 6; at 9 & 12 months CA-125/clinical assessment Every chemotherapy cycle; every 6 weeks during maintenance phase Every 6 months Every 3 months As indicated Every 6 months

66 ICON-7 Características de las pacientes 66 Characteristic, n (%) FIGO stage, n (%) I/IIA IIB IIIB IIIC/IV Debulking surgery/residuum Optimal surgery ( 1 cm) Suboptimal surgery (>1 cm) No surgery FIGO stage and residuum* Stage I III ( 1 cm) Stage I III (>1 cm) Stage III (inoperable)/iv Intent to start chemotherapy* 4 weeks from surgery >4 weeks from surgery Control (n=764) 75 (10) 160 (21) 529 (69) 552 (74) 195 (26) 17 (2) 508 (66) 150 (20) 106 (14) 328 (43) 436 (57) Research (n=764) 67 (9) 155 (20) 542 (71) 559 (74) 192 (26) 13 (2) 518 (68) 140 (18) 106 (14) 326 (43) 438 (57)

67 Patients (%) ICON-7 Toxicidad grado Control (n=753) Research (n=745) ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leucoencephalopathy syndrome; VTE = venous thromboembolism Perren et al. ESMO 2010

68 Proportion alive without progression ICON-7 Sobrevida libre de progresión Regulatory analysis Control Research Events, n (%) 392 (51) 367 (48) Median, months Log-rank test p= HR (95% CI) 0.79 ( ) 0.25 Control Research Time (months) Number at risk Control Research Perren et al. ESMO 2010

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71 ICON7: PFS de acuerdo a residuo Subgroup HR (95% CI) PFS High risk (N=502) 0.71 ( ) Stage IIIb IV (N=1160) 0.81 ( ) Stage IIIb IV no residual disease (N=411) Stage IIIb IV residual disease (N=749) Bev better Reference better 0.77 ( ) 0.81 ( ) HR (95% CI) 2 Exploratory outcome analyses according to stage and residual disease in the ICON7 trial of front-line carboplatin/paclitaxel (CP) ± bevacizumab (BEV) for ovarian cancer (OC) Gonzalez Martin et al. ASCO 2015 (abstract 5548)

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74 Proportion alive without progression Preguntas después del GOG 218 y ICON7 : Duración de tratamiento óptima? 1.0 Maximo beneficio al final de la terapia con BEV Mediana no reflejaría el máximo beneficio de Bevacizumab TC TC + Bev Bev Time (months)

75 AGO-OVAR 17 Design 1:1 R Bevacizumab 15 mg/kg q21 days Paclitaxel 175 mg/m² Carboplatin AUC5 q21 days 15 Months = 22 Courses N = 900 Strata Residual tumor (yes vs no) FIGO Stage (IIB-III vs IV) Group Bevacizumab 15 mg/kg q21 days Paclitaxel 175 mg/m² Carboplatin AUC5 q21 days 30 Months = 44 Courses National Institutes of Health. Available at:

76 Bevacizumab en 1ª línea de cáncer de ovario Conclusiones La tolerabilidad es buena en la mayoría de las pacientes, siendo la toxicidad grave excepcional La incidencia de perforaciones GI es < 2% (inferior a la MCRC) Aumenta la SLP en dos ensayos fase III, independientemente del residuo Aumenta la OS en subgrupo de alto riesgo del ICON7 y en el Estadío IV del GOG-0218

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78 Y bevacizumab en neoadyuvancia?

79 Primary objective: evaluate the CRR at IDS in the BCP group (reference CRR rate defined as 45% CRR). A stopping rule based on bevacizumab- related adverse events (AEs) of special interest was implemented. Ninety-five patients randomised (2:1) to receive four cycles of neoadjuvant CP x 3 concomitant cycles of bevacizumab 15 mg/kg (BCP) followed by IDS.

80 Results: In the BCP group (N 58), IDS was performed in 40 (69%) patients. The CRR of this group was 58.6% (34 patients), statistically over predefined 45%. The CRR in the CP group was 51.4%: 22 (60%) patients underwent IDS. Grade 3 adverse events occurred in 62% of the BCP-treated patients and 63% of the CP-treated patients: mainly blood and lymphatic, gastrointestinal and vascular disorders, without more toxicity with BCP. Postoperative complications (mainly wound, infectious and gastrointestinal complications) occurred in 28% and 36% of the patients, respectively. The pre-specified safety stopping rule was not reached.

81 Conclusion: The primary objective was met as the CRR with BCP was significantly higher than the reference rate. Bevacizumab may be safely added to a preoperative program in patients deemed non-optimally resectable, whatever the final surgical decision. Bevacizumab s role in this setting should be further investigated.

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85 AGO-OVAR 16 Study Design Phase III randomized, placebo-controlled, double-blind, multicentre N= 940 patients randomized (1:1) from June 2009 to August 2010 Pazopanib administered at 800 mg daily for up to 24 months* FIGO stage II IV disease First-line surgery and chemotherapy (allowed: dosedense, IP, neoadjuvant) Screening baseline If not PD + Tu < 2cm R A N D O M I Z E Treatment period Pazopanib 24 months Placebo 24 months Post-treatment period Observation (to PD) Follow-up period Survival follow-up (post-pd) Median 7 months from diagnosis to randomization ICF Baseline first dose Treatment completion Disease assessments completion Study completion *Original design was for 12 months and later amended to 24 months Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium

86 AGO-OVAR 16 1st endpoint: Progression-free Survival (RECIST) Median time from Diagnosis: 7 months 1 Pazopanib: 472 pts. / 237 events median 17.9 [ ] mos Placebo: 468 pts. / 273 events median 12.3 [ ] mos Δ= 5.6 months 0,5 0 HR = [95% CI: ] Stratified Log-rank test : P = [months] Patients at risk Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium

87 P r o b a b i l i t y AGO-OVAR 16 Overall Survival: first analysis 1 0,5 First Interim analysis for OS: 551 events needed for final OS analysis so far, 190 events (20% of population) median observation: 24.3 months HR= [95% CI: 0.747; 1.321]; median not reached 0 Pazopanib: 472 pts. / 95 events - median not reached Placebo: 468 pts. / 94 events - median not reached Patients at risk [months] Presented by: Andreas du Bois on behalf of the AGO led Intergroup consortium

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89 Disease progression or a maximum of 120 weeks Phase III Trial of Nintedanib (LUME- Ovar1/AGO-OVAR12): Design Carboplatin q3w Nindetanib/ Placebo : - no intake on days of chemotherapy - dose: 200 mg po bid (combi + mono) - dose adaptation in case of undue toxicity - max. duration of 120 weeks in nonprogressing pts Paclitaxel q3w Front-line, FIGO stage IIB IV, ECOG 0 2 n=1,374 Nintedanib (200mg BID) Carboplatin q3w Paclitaxel q3w Placebo Multicenter, randomised, double-blind, Phase III trial to investigate the efficacy and safety of BIBF 1120 in combination with standard treatment of carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel patients with advanced ovarian cancer

90 Primary Endpoint: Progression-Free Survival RECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria 1 All patients (N=1366) Cut-off date: 29 April 2013 TC + Nintedanib (n=911) TC + Placebo (n=455) Events, n (%) 486 (53.3) 266 (58.5) Median, months ,5 HR* (95% CI) 0.84 (0.72, 0.98) p value Median months Time from randomization (months) A. Du Bois, ESGO *Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose

91 Estimated percentage alive and progression-free Exploratory Subgroup Analysis ICON 7 defined low-risk patients subgroup (FIGO II or FIGO III and 1cm residual postoperative tumor) 1 0,5 TC + Nintedanib (n=556) TC + Placebo (n=283) Events, n (%) 234(42.1) 149(52.7) Median, months HR (95% CI) 0.74 (0.61, 0.91) Línea de investigación discontinuada por el sponsor Time from randomization (months) 0 0 Patients at risk Nintedanib Placebo A. Du Bois, ESGO 2013 median PFS difference: months (similar to OVAR 16)

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93 Pacientes recaídas candidatas a platino

94 Estudio OCEANS Esquema del estudio Platinum-sensitive recurrent OC a Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) Stratification variables: Platinum-free interval (6 12 vs >12 months) CG + PL CG + BV Cytoreductive surgery for recurrent disease (yes vs no) CG for 6 (up to 10) cycles BV = bevacizumab; PL = placebo a Epithelial ovarian, primary peritoneal, or fallopian tube cancer Aghajanian et al. ASCO 2011 Carboplatin AUC 4 Gemcitabine 1000 mg/m 2, d1 & 8 q3w PL q3w until progression Carboplatin AUC 4 Gemcitabine 1000 mg/m 2, d1 & 8 q3w BV 15 mg/kg q3w until progression Published Ahead of Print on April 23, 2012 as /JCO

95 Proportion progression free Estudio OCEANS SLP (Comité revisor independiente) CG + PL (n=242) CG + BV (n=242) Events, n (%) 148 (61) 119 (49) Median PFS, months (95% CI) Stratified analysis HR (95% CI) Log-rank p-value 8.6 ( ) ( ) < ( ) No. at risk CG + PL CG + BV Months Aghajanian et al. ASCO 2011

96 Estudio OCEANS Análisis por subgrupos Baseline risk factor No. of patients Median PFS (months) CG + PL (n=242) CG + BV (n=242) HR (95% CI) All patients ( ) CG + BV better CG + PL better Platinum-free interval, months Cytoreductive surgery for recurrent disease ( ) > ( ) Yes ( ) No ( ) Age, years < ( ) ( ) Baseline ECOG PS ( ) ( ) HR Aghajanian et al. ASCO 2011

97 Proportion surviving OCEANS: Third Interim OS Analysis a GC + PL (n=242) GC + BV (n=242) Events, n (%) 142 (58.7) 144 (59.5) Median OS, months (95% CI) HR (95% CI) Log-rank P value 33.7 ( ) 33.4 ( ) ( ) p= Months Number at risk: GC + PL GC + BV a Data cutoff date: March 30, Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients)

98 GOG-213 Recurrent ovarian, PPT, and FT cancer TFI 6 mos Surgical candidate? Yes Randomize No Randomize PI: Coleman Surgery No surgery Carboplatin Paclitaxel To chemotherapy randomization ClinicalTrials.gov. NCT Carboplatin Paclitaxel Bevacizumab Bevacizumab

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102 Preguntas sin respuesta Reutilización de bevacizumab luego del la progresión La mejor quimioterapia para combinar con bevacizumab

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104 En BCRA mutadas candidatas a platino..

105 Pacientes recaídas no candidatas a platino

106 AURELIA diseño del estudio Platinum-resistant OC a 2 prior anticancer regimens Chemotherapy Treat to PD/toxicity Optional BEV monotherapy c No history of bowel obstruction/abdominal fistula, or clinical/ radiological evidence of rectosigmoid involvement R 1:1 BEV 15 mg/kg q3w b + chemotherapy Treat to PD/toxicity Investigator s choice (without BEV) Stratification factors: Chemotherapy selected Prior anti-angiogenic therapy Treatment-free interval (<3 vs 3 6 months from previous platinum to subsequent PD) Chemotherapy options (investigator s choice): Paclitaxel 80 mg/m 2 days 1, 8, 15, & 22 q4w Topotecan 4 mg/m 2 days 1, 8, & 15 q4w (or 1.25 mg/m 2, days 1 5 q3w) PLD 40 mg/m 2 day 1 q4w PD = progressive disease a Epithelial ovarian, primary peritoneal, or fallopian tube cancer; b Or 10 mg/kg q2w; c 15 mg/kg q3w, permitted on clear evidence of progression

107 Características de la población Characteristic CT (n=182) n (%) BEV + CT (n=179) n (%) Median age, years (range) (25 84) (25 80) Origin of cancer: Ovary 157 (86) 167 (93) Serous/adenocarcinoma at diagnosis 152 (84) 156 (87) Histologic grade at diagnosis 1 9 (5) 10 (6) 2/3 153 (84) 147 (82) Prior anti-angiogenic therapy a 14 (8) 12 (7) Two prior chemotherapy regimens 78 (43) 72 (40) PFI <3 months a,b 46 (25) 50 (28) ECOG PS 0 99 (54) 107 (60) 1/2 80 (44) 70 (39) Measurable disease 144 (79) 143 (80) Ascites 54 (30) 59 (34) PFI = platinum-free interval a Stratification factor. b From last platinum to subsequent PD

108 Estimated probability Sobrevida libre de progresión CT (n=182) BEV + CT (n=179) Events, n (%) 166 (91%) 135 (75%) Median PFS, months (95% CI) HR (unadjusted) (95% CI) Log-rank p-value (2-sided, unadjusted) 3.4 ( ) 0.48 ( ) < ( ) 0.2 No. at risk: CT BEV + CT Time (months) Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)

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110 Análisis de subgrupo de PFS Subgroup No. of patients Median PFS, months CT BEV + CT All patients Age, years <65 65 PFI, months b < HR a BEV + CT better CT better Measurable disease, cm No (<1) Yes (1 <5) Yes ( 5) Ascites Yes No Chemotherapy Paclitaxel PLD Topotecan a Unadjusted. b Missing n=8

111 Patients (%) Tasa de Respuesta p<0.001 a 30,9 27,3 12,6 11,8 11,6 Responders (RECIST and/or CA-125) (n=350) CT p=0.001 a RECIST responders (n=287) BEV + CT p<0.001 a 31,8 CA-125 responders (n=297) a Two-sided chi-square test with Schouten correction

112 Overall survival (%) OS: ITT population CT (N=182) BEV + CT (N=179) Events, n (%) 136 (75) 128 (72) Median OS, months (95% CI) HR (unadjusted) (95% CI) 13.3 ( ) 0.85 ( ) p=0.174 a 16.6 ( ) 25 No. at risk: CT BEV + CT Study not powered to detect a statistically 0 significant difference in OS Time (months) No systematic capture of post-progression therapy in either arm (except for BEV in the control arm) Data cut-off: 25 January Median duration of follow-up: 27.4 months in both arms ITT = intent to treat a 2-sided log-rank, unadjusted

113 Overall survival (%) Paclitaxel cohort: OS CT (N=55) BEV + CT (N=60) Events, n (%) 41 (75) 36 (60) Median OS, months (95% CI) ( ) ( ) HR (unadjusted) (95% CI) 0.65 ( ) 25 No. at risk: CT BEV + CT Time (months)

114 Updated safety results Grade 3 adverse events of special interest, n (%) CT (N=181) BEV + CT (N=179) Hypertension 2 (1.1) 14 (7.8) Grade 2 10 (5.5) 36 (20.1) Proteinuria 0 4 (2.2) Grade 2 1 (0.6) 23 (12.8) GI perforation 1 (0.6) 2 (1.1) Grade 2 1 (0.6) 3 (1.7) Fistula/abscess 0 2 (1.1) Grade (2.2) Wound-healing complication 0 2 (1.1) Bleeding 2 (1.1) 2 (1.1) Thromboembolic event Arterial Venous 1 (0.6) 7 (3.9) 3 (1.7) 6 (3.4) RPLS 0 1 (0.6) CHF 1 (0.6) 1 (0.6) RPLS = reversible posterior leucoencephalopathy syndrome; CHF = congestive heart failure

115 QOL: aumento del 15% en los síntomas abdominales EORTC QLQ-OV28 Martin R. Stockler et al. Published Ahead of Print on March 31, 2014

116 Cuales son las mejores opciones en Terapia de sostén platino resistencia Monoquimioterapia con un agente no platino La mejor opción es si se cuenta con acceso a bevacizumab, es la combinación de agente único no platino y terapia antiangiogénica (AURELIA) Prometedores resultados de trebananib en pacientes refractarias y pretratadas con antiangiogénicos aunque con mayor toxicidad

117 Evidencia clínica de estudios fase III del uso de Bevacizumab en pacientes con cáncer de ovario estadío III y IV e incorporación de nuevas moléculas Estadío IIIb/IV Cirugía primaria Quimioterapia Neoadyuvante Ciirugía del intervalo CIRUGÍA INICIAL EIIIB IIC IV SI CIRUGÍA INICIAL EI, EII, EIIa Bevacizumab + quimioterapia basada en platino Recurrencia GOG 213 Platinum sensible SI No AURELIA Tratar con quimioterapia Bevacizumab + quimioterapia Quimioterapia+bevacizumab Olaparib + QMT BCRA testing M+ WT

118 Reflexiones finales... A todas las pacientes con cancer de ovario se les debería ofrecer el testeo genético La alta carga tumoral inicial es un factor de mal pronóstico Las pacientes con cáncer de ovario avanzado, particularmente con enfermedad residual postquirúrgica necesitan un mejor tratamiento La inhibición del VEGF es un blanco terapéutico racional El tratamiento de primera línea con bevacizumab y carboplatino/paclitaxel por 6 ciclos y luego la terapia como agente único hasta 15 meses ( 21 CICLOS) o toxicidad inaceptable a 15 mg/kg cada 3 semanas, produce mejorías estadísticamente significativas en el PFS en pacientes con estadíos FIGO III B, III C y IV Las mujeres con enfermedad residual postcx obtienen un beneficio particularmente significativo con la adición de bevacizumab (OS) Las pacientes con recaída platino sensible y platino refractaria se benefician del tratamiento con quimioterapia en combinación con bevacizumab Las pacientes con recaída platino sensible y mutación de BRCA se benefician con un doblete con platino y mantenimiento con olaparib

119 Muchas gracias!!!!!