Uptodate do Tratamento de 1 0 linha do Câncer de Ovário Brasília 2012 Fernando Cotait Maluf Diretor do Serviço de Oncologia Clínica Beneficência Portuguesa.

Uptodate do Tratamento de 1 0 linha do Câncer de Ovário Brasília 2012 Fernando Cotait Maluf Diretor do Serviço de Oncologia Clínica Beneficência Portuguesa Médico Integrante da Clínica Oncovida (maluffc@uol.com.br)

Uptodate do Tratamento de 1 0 linha do Câncer de Ovário Enfoque: - esquemas de 1 0 linha - MITO-2: CD vs CP -esquemas de 1 0 linha com BEV - GOG 218 e ICON 7: CP-BEV vs CP

Piganta E et al, J Clin Oncol, 2011 Critério Inclusão: Câncer de ovário epitelialCâncer de ovário epitelial Estádio Ic-IVEstádio Ic-IV < 76 anos< 76 anos ECOG 0-2ECOG 0-2 RANDOMIZAÇÃORANDOMIZAÇÃO Carboplatina AUC 5 EV + Paclitaxel 175 mg/m 2 IV 3 cada 21 d x 6 ciclos Carboplatin AUC 5 EV + Doxo Lipossomal 30 mg/m 2 IV 1 h cada 21 d x 6 ciclos MITO-2

Sobrevida Livre de Progressão

Sobrevida Global

Análise de Subgrupo (SG)

Toxicidade Carboplatina/doxorrubicina lipossomal: menos alopecia e neuropatia Carboplatina/paclitaxel: menos mielosupressão

Phase III Trial of Bevacizumab in the Primary Treatment of Advanced Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer: A Gynecologic Oncology Group (GOG) Study R.A. Burger, 1 M.F. Brady, 2 M.A. Bookman, 3 J.L. Walker, 4 H.D. Homesley, 5 J. Fowler, 6 B.J. Monk, 7 B.E. Greer, 8 M. Boente, 9 S.X. Liang 10 1 Fox Chase Cancer Center, Philadelphia, PA; 2 Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3 University of Arizona Cancer Center, Tucson, AZ; 4 University of Oklahoma Health Sciences Center, Oklahoma City, OK; 5 Brody School of Medicine, Greenville, NC; 6 James Cancer Hospital at the Ohio State University, Hilliard, OH; 7 University of California, Irvine Medical Center, Orange, CA; 8 Seattle Cancer Care Alliance, Seattle, WA; 9 Minnesota Oncology and Hematology, Minneapolis, MN; 10 State University of New York at Stony Brook, Stony Brook, NY, USA

GOG-0218: Schema Stratification variables: PS Stage/debulking status BEV 15 mg/kg 15 months Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo BEV 15 mg/kg Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE I II III Arm 1:1:1

GOG-0218: Analysis Plan Primary analysis –Compare investigator-determined progression-free survival (PFS) for each BEV arm (CP + BEV; CP + BEV  BEV) vs control (CP) If both results positive, compare CP + BEV  BEV vs CP + BEV –Disease progression based on: RECIST, global clinical deterioration, or CA-125 1 –Planned sample size of 1800 based on: 90% power to detect PFS hazard ratio (HR)  0.77 –Median PFS shift: 14.0 months  18.2 months Secondary analyses: Overall survival (OS), safety, quality of life; correlative laboratory studies 1. Gynecologic Cancer Intergroup Criteria - Rustin et al. J Natl Cancer Inst 2004

GOG-0218: Key Eligibility Criteria Histologic diagnosis of epithelial OV, PP, or FT cancer Following maximal debulking surgery: stage III optimal (macroscopic residual disease  1 cm) or suboptimal (>1 cm), or stage IV No prior chemotherapy 1–12 weeks after initial surgery GOG PS 0–2 No history of significant vascular events No evidence of intestinal obstruction requiring parenteral support Written informed consent

GOG-0218: Study Conduct 1873 patients from 336 sites (US, Canada, South Korea, Japan), October 2005–June 2009 Key protocol amendments –Inclusion of optimally debulked (macroscopic residual disease) patients –Primary endpoint changed to PFS Final data analysis triggered by number of events in control arm Analyses –Efficacy population: n=1873 (intent to treat) –Safety population: n=1816 (intent to treat, as of cycle 2) Median follow-up: 17.4 months (range 0.0–50.7 months)

GOG-0218: Baseline Clinical Characteristics Characteristic Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV  BEV (n=623) Median age, years (range)60 (25–86)60 (24–88)60 (22–89) Race, n (%) Non-Hispanic white526 (84)519 (83)521 (84) Asian41 (7) 37 (6)39 (6) Non-Hispanic black25 (4) 28 (5)27 (4) Hispanic21 (3) 28 (5)25 (4) Other, specified8 (1)5 (<1)4 (<1) GOG PS, n (%) 0311 (50)315 (50)305 (49) 1272 (44)270 (43)267 (43) 242 (7)40 (6)51 (8) Percentages may not total 100% due to rounding or categorization

GOG-0218: Baseline Surgical–Pathologic Characteristics Characteristic, n (%) Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV  BEV (n=623) Stage/residual size III optimal (macroscopic)218 (35)205 (33)216 (35) III suboptimal254 (41)256 (41)242 (39) IV153 (25)164 (26)165 (27) Histology Serous543 (87)523 (84)525 (84) Endometrioid20 (3)15 (2)25 (4) Clear cell11 (2)23 (4)18 (3) Mucinous8 (1)5 (<1)8 (1) Tumor grade 3a3a 412 (66)435 (70)430 (69) 294 (15)77 (12)92 (15) 133 (5)28 (4)16 (3) Not specified/pending86 (14)85 (14) Percentages may not total 100% due to rounding or categorization a Grade 3 includes all clear cell tumors

GOG-0218: Patient Disposition Characteristic Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV  BEV (n=623) Median (range) number BEV/placebo cycles11 (0–22 a )12 (0–22 a )14 (0–21) On treatment at time of analysis, n (%)86 (14)82 (13)117 (19) Completed regimen, n (%)100 (16)104 (17)148 (24) Discontinued study treatment, n (%) Disease progression299 (48)264 (42)164 (26) Adverse events69 (11)86 (14)94 (15) Cycles 1–657 (9)73 (12)59 (9) Cycle ≥ 7 12 (2)13 (2)35 (6) Deaths8 (1)7 (1)13 (2) Patient refusal44 (7)55 (9)50 (8) Other19 (3)27 (4)37 (6) a One patient in each group received BEV/placebo in cycle 1 Percentages may not total 100% due to rounding or categorization

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) 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 neutropenia21 (3.5)30 (4.9)26 (4.3) Venous thromboembolic event35 (5.8)32 (5.3)41 (6.7) Arterial thromboembolic event 5 (0.8)4 (0.7) CNS bleeding002 (0.3) Non-CNS bleeding (grade ≥3)5 (0.8)8 (1.3)13 (2.1) RPLS01 (0.2) GOG-0218: Select Adverse Events Onset between cycle 2 and 30 days after date of last treatment RPLS = reversible posterior leukoencephalopathy syndrome a Perforation/fistula/necrosis/leak b p<0.05

GOG-0218: Investigator-Assessed PFS Arm I CP (n=625) Arm II CP + BEV (n=625) Patients with event, n (%) 423 (67.7) 418 (66.9) Median PFS, months10.311.2 Stratified analysis HR (95% CI) 0.908 (0.759–1.040) One-sided p-value (log rank)0.080 a + BEV (Arm II) CP (Arm I) a p-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0122436 Arm III CP + BEV  BEV (n=623) 360 (57.8) 14.1 0.717 (0.625–0.824) <0.0001 a

Burger et al. NEJM 2011;365 (26):2473–83 © Massachusetts Medical Society GOG-0218: subgroup analyses of PFS Risk factorTotal no. of patientsHazard ratio for Avastin (95% CI) Cancer stage and residual lesion size III, macroscopic ≤1cm Arm II vs Arm I Arm III vs Arm I 423 434 0.780 0.618 III, >1cm Arm II vs Arm I Arm III vs Arm I 510 496 0.981 0.763 IV Arm II vs Arm I Arm III vs Arm I 317 318 0.923 0.698 Histologic type Serous Arm II vs Arm I Arm III vs Arm I 1,066 1,068 0.913 0.701 Nonserous Arm II vs Arm I Arm III vs Arm I 184 180 0.893 0.713 Tumour grade 1 or 2 Arm II vs Arm I Arm III vs Arm I 232 235 1.039 0.578 3 Arm II vs Arm I Arm III vs Arm I 847 842 0.891 0.700 0.330.500.671.001.502.003.00 bevacizumab betterControl better

Burger et al. NEJM 2011;365 (26):2473–83 © Massachusetts Medical Society GOG-0218: subgroup analyses of PFS (cont’d) Risk factorTotal no. of patientsHazard ratio for Avastin (95% CI) GOG performance status score 0 Arm II vs Arm I Arm III vs Arm I 626 616 0.877 0.710 1 or 2 Arm II vs Arm I Arm III vs Arm I 624 632 0.961 0.690 Age <60 years Arm II vs Arm I Arm III vs Arm I 616 630 0.976 0.680 60–69 years Arm II vs Arm I Arm III vs Arm I 414 408 0.892 0.763 ≥70 years Arm II vs Arm I Arm III vs Arm I 220 210 0.841 0.678 0.330.500.671.001.502.003.00 bevacizumab betterControl better

GOG-0218: Overall Survival (OS) Events observed in 24% of patients at time of data lock After primary endpoint changed from OS to PFS –Unblinding to treatment assignment allowed at time of disease progression Outcome Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV  BEV (n=623) Deaths, n (%) 156 (25.0) 150 (24.0) 138 (22.2) 1-year survival, %90.690.491.3

GOG-0218: Overall Survival Analysis At time of final PFS analysis (January 2010) Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV  BEV (n=623) Patients with events, n (%) 156 (25.0) 150 (24.0) 138 (22.2) Median, months39.338.739.7 HR a (95% CI) 1.036 (0.827–1.297) 0.915 (0.727–1.152) One-sided p-value0.3610.252 Proportion alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 012243648 a Stratified analysis 625/625/623442/432/437173/162/17146/39/40 No. at risk

ICON7: A phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, GEICO, NCIC-CTG)

Patient population Histologically confirmed epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer Prior surgical debulking with the aim of maximal surgical cytoreduction undertaken AND no planned further surgical debulking before disease progression FIGO stage I – IIA if high risk: Grade 3 or clear cell histology (10%) IIB – IV: All grades and histological subtypes Patients with inoperable stage III/IV disease eligible after biopsy only if no further surgery planned ECOG performance status 0–2 28

Year 1Years 2–3Years 4–5 CTBaseline; after cycles 3 & 6; at 9 & 12 monthsEvery 6 monthsAs indicated CA-125/clinical assessment Every chemotherapy cycle; every 6 weeks during maintenance phase Every 3 monthsEvery 6 months Stratification variables: Stage & extent of debulking: I–III debulked ≤1cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III Timing of intended treatment start ≤4 vs >4 weeks after surgery GCIG group Schema Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing Paclitaxel 175 mg/m 2 Carboplatin AUC6 Paclitaxel 175 mg/m 2 18 cycles R n=1528* Bevacizumab 7.5 mg/kg q3w 29 1:1 *Dec 2006 to Feb 2009

Study endpoints Primary endpoint: Progression-free survival (PFS) Disease progression defined by RECIST guidelines on radiological, clinical or symptomatic progression CA-125 elevation alone not defined as disease progression 1520 patients randomised over 2 years (684 events) → 5% significance level, 90% power to detect: PFS hazard ratio (HR) of 0.78 Increase of median PFS from 18 to 23 months Secondary endpoints: Overall survival (due 2012), response rate, toxicity Substudies: Quality of life, health economics, translational research 30

Baseline characteristics (1) Characteristic Control (n=764) Research (n=764) Median age (range)57 (18–81)57 (24–82) ECOG PS, n (%) 0 1 2 358 (47) 354 (47) 43 (6) 334 (45) 366 (49) 45 (6) Origin of cancer, n (%) Ovary (epithelial) Fallopian tube Primary peritoneal Multiple sites 667 (87) 29 (4) 56 (7) 12 (2) 673 (88) 27 (4) 50 (6) 14 (2) Histology Serous Clear cell Endometrioid Mucinous Mixed/other 529 (69) 60 (8) 57 (7) 15 (2) 103 (13) 525 (69) 67 (9) 60 (8) 19 (2) 93 (12) Grade, n (%) 1 2 3 Unknown 56 (7) 142 (19) 556 (74) 10 41 (5) 175 (23) 538 (71) 10 31

Baseline characteristics (2) Characteristic, n (%) Control (n=764) Research (n=764) FIGO stage, n (%) I/IIA IIB–IIIB IIIC/IV 75 (10) 160 (21) 529 (69) 67 (9) 155 (20) 542 (71) Debulking surgery/residuum Optimal surgery (≤1 cm) Suboptimal surgery (>1 cm) No surgery 552 (74) 195 (26) 17 (2) 559 (74) 192 (26) 13 (2) FIGO stage and residuum* Stage I–III (≤1 cm) Stage I–III (>1 cm) Stage III (inoperable)/IV 508 (66) 150 (20) 106 (14) 518 (68) 140 (18) 106 (14) Intent to start chemotherapy* ≤4 weeks from surgery >4 weeks from surgery 328 (43) 436 (57) 326 (43) 438 (57) 32 * Stratification variable

Selected adverse events (all grades) ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leucoencephalopathy syndrome; VTE = venous thromboembolism Patients (%) 33

ATE = arterial thromboembolism; CHF = congestive heart failure; RPLS = reversible posterior leucoencephalopathy syndrome; VTE = venous thromboembolism Patients (%) 34 Selected grade ≥3 adverse events (grade ≥2)

Number at risk Control764723693556464307216143915025 Research764748715647585399263144733619 Progression-free survival 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 036912151821242730 ControlResearch Events, n (%) 392 (51)367 (48) Median, months 17.319.0 Log-rank test p=0.0041 HR (95% CI) 0.81 (0.70–0.94) 17.3 19.0 Control Research Academic analysis 35

Number at risk Control76471567652941924717591652616 Research764733696617546330232100621911 Progression-free survival 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 036912151821242730 ControlResearch Events, n (%) 392 (51)367 (48) Median, months 16.018.3 Log-rank test p=0.0010 HR (95% CI) 0.79 (0.68–0.91) 16.0 18.3 Control Research Regulatory analysis 36

Number at risk Control2342059836142 Research23121315956101 PFS: FIGO stage III suboptimal and FIGO stage IV with debulking 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 036912151821242730 Control (n=234) Research (n=231) Events, n (%) 173 (74)158 (68) Median, months 10.515.9 Log-rank test p<0.001 Hazard ratio (95% CI) 0.68 (0.55–0.85) Restricted mean 13.316.5 10.5 15.9 Control Research 37

No. of events/no. of patients Origin of cancer CP + Av7.5  Av7.5 CPHR Age<60202/449210/4500.84 60–69134/242142/2370.76 ≥7031/7340/770.82 ECOG PS0154/334145/3581.01 1175/366210/3540.66 227/4531/430.78 HistologySerous274/525278/5290.85 Mucinous12/1910/150.77 Endometroid26/6025/570.81 Clear cell22/6722/600.90 Hazard ratio (fixed) 0120.51.5 CP + Bev7.5  Bev 7.5 better CP better Age: Trend p=0.69, interaction p=0.83 ECOG: Trend p=0.027, interaction p=0.022 Histology: Interaction test p=0.085 Perren et al. NEJM 2011;365 (26):2482–2496 © Massachusetts Medical Society Subgroup analysis of PFS (1)

FIGO: Trend p=0.71, interaction p=0.91 Residual disease: Trend p=0.10 Grade: Trend p=0.76, interaction p=0.95 Perren et al. NEJM 2011;365 (26):2482–2496 © Massachusetts Medical Society Subgroup analysis of PFS (2) No. of events/no. of patients Origin of cancer CP + Av7.5  Av7.5 CPHR FIGOI6/549/650.73 II14/8319/800.72 III277/523290/5220.79 IV70/10474/970.69 Residual disease Optimal (≤1cm)226/559233/5520.87 Suboptimal (>1cm)131/192145/1950.68 GradeGrade 110/4116/560.76 Grade 286/17577/1420.77 Grade 3267/538294/5560.81 Hazard ratio (fixed) 0120.51.5 CP + Bev7.5  Bev7.5 better CP better

Perren et al. NEJM 2011;365 (26):2482–2496 © Massachusetts Medical Society Interim OS analysis, full population (regulatory request) 1.00 0.75 0.50 0.25 0 Proportion alive Time (months) 036912151821242730333639 Number at risk CP7647417247036726466235424213042121327126 CP + Av7.5 7647537377177026806575924593292281296919  Av7.5 CP CP + Av7.5  Av7.5 Deaths, n (%) 200 (26)178 (23) Median, months Not yet reached Log-rank test p=0.11 HR (95% CI) 0.85 (0.69–1.04) 1-year OS rate (%)9295

Number at risk CP2342191941661074615 CP + Av7.5 2312222081861346518  Av7.5 High-risk subgroup CP (n=234) CP + Av7.5  Av7.5 (n=231) Deaths, n (%) 109 (47)79 (34) Median, months 28.836.6 Log-rank test p=0.002 HR (95% CI) 0.64 (0.48–0.85) 1-year OS rate (%)8692 Perren et al. NEJM 2011;365 (26):2482–2496 © Massachusetts Medical Society OS: high-risk patients (FIGO stage III suboptimal and FIGO stage IV with debulking) 1.00 0.75 0.50 0.25 0 Time (months) 036912151821242730333639 Proportion alive

Data cut-off date: November 30, 2010 Perren et al. NEJM 2011;365 (26):2482–2496 © Massachusetts Medical Society Updated PFS CP CP + Av7.5  Av7.5 Events, n (%) 464 (61)470 (62) Median, months 17.419.8 Log-rank test p=0.04 HR (95% CI)0.87 (0.77–0.99) Proportion alive without progression Time (months) 17.4 19.8 764 693 716 474 599 350 430 221 229 114 107 39 27 Number at risk CP CP + Av7.5  Av7.5 0369121518212427303336 1.00 0.75 0.50 0.25 0

Conclusions Bevacizumab combined with chemotherapy and continued alone (7.5 mg/kg for 12 months) vs chemotherapy demonstrates Continued improvement in PFS with no crossing of curves Trend for improved OS continues in the total population Final analysis of OS is due in 2013 Treatment effect is greater in patients at high risk of recurrence, which may be of clinical relevance Perren, et al. NEJM 2011

Take Home Messages 1)MITO-2: carboplatina/doxil: considerado um esquema padrão de 1 o linha alternativo para pacientes com neuropatia e para aqueles que querem evitar alopécia 2)GOG 218 e ICON 7: carboplatina/paclitaxel/bevacizumabe (indução e manutenção) considerado uma opção de 1 o linha em pacientes selecionadas

Obrigado maluffc@uol.com.br

Uptodate do Tratamento de 1 0 linha do Câncer de Ovário Brasília 2012 Fernando Cotait Maluf Diretor do Serviço de Oncologia Clínica Beneficência Portuguesa.

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Uptodate do Tratamento de 1 0 linha do Câncer de Ovário Brasília 2012 Fernando Cotait Maluf Diretor do Serviço de Oncologia Clínica Beneficência Portuguesa.

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