First line chemotherapy Chemioterapia I rzutu

First line chemotherapy Chemioterapia I rzutu Radosław Mądry Klinika Onkologii Uniwersytetu Medycznego im. K. Marcinkowskiego w Poznaniu ESGO Workshop / Warsztat ESGO 24.11.2011

Od cisplatyny do bewacizumabu 2

Alkeran Antracykliny Cisplatyna Pacli/Karbo Paklitaksel IP 5 letnie przeżycia 70 60 50 40 30 20 10 0 1975 1983 1986 1996 2003 2006 3

Podstawy terapii systemowej: Badania wykazujące wyższość schematu paklitaksel/cisplatyna nad cyklofosfamid/cisplatyna GOG Protocol 111 [1] EORTC-NCIC OV 10 [2] Badania wskazujące na co najmniej taką samą skuteczność paklitaksel/karboplatyna w porównaniu do paclitakselu/cisplatyny AGO Trial [3] GOG Protocol 158 [4] 1. McGuire WP, et al. N Eng J Med.1996 2. Piccart MJ, et al. J Natl Cancer Inst. 2000 4 3. DuBois A, et al. J Natl Cancer Inst. 2003. 4. Ozols RF, et al. J Clin Oncol. 2003

PFS +5 Mon. GOG111 p=0.001 N = 386, FIGO III/IV, >1cm Cisplatin/Cycloph. vs. Cisplatin/Paclitaxel Crossover to Paclitaxel 8% early 34% overall +14 Mon. p=0.001 OS Cyclo /Cisplatin Paclitaxel / Cisplatin PFS 13 18 Survival 24 38 McGuire WP et al, N Engl J Med 1996 5

OV10 PFS +4 Mon. p=0.0005 N = 680, FIGO IIB/IIC/III/IV 6-9x Cisplatin/Cycloph. vs. 6-9x Cisplatin/Paclitaxel Crossover to Paclitaxel Higher (49%) Cyclo /Cisplatin Paclitaxel / Cisplatin OS +10 Mon. p=0.0016 PFS 11.5 15.5 Survival 25.8 35.6 Piccart MJ et al, J Natl Cancer Inst 2000 6

GOG132 Bez statystycznej istotności +2,3 Mon. N = 614, FIGO IIB/IIC/III/IV Cisplatin. vs. Cisplatin/Paclitaxel vs. Paclitaxel PFS the high rate of early crossover to paclitaxel that had occurred in this single-agent platinum arm prior to progression (24%) Piccard 2003 OS High Cross-over Bez statystycznej istotności +3,9 Mon. 7 Muggia et al, J Clin Oncol, 2000

ICON3 PFS Bez statystycznej istotności HR 0,93 N = 2027, FIGO I-IV Carboplatin/Paclitaxel vs. Carboplatin vs CAP 1/3 cross-over to Paclitaxelu po progresji Bez statystycznej istotności HR 0,98 OS 8 ICON Group, Lancet, 2002

GOG 158 Bez statystycznej istotności PFS +1,3 Mon. N = 792, FIGO III, <1cm Cispl./Paclit. vs. Carbopl./Paclit. Bez statystycznej istotności +8,7 Mon. OS Paclitaxel /Cisplatin Paclitaxel /Carboplatin PFS 19.4 20.7 Survival 48.7 57.4 9 Ozols RF et al, J Clin Oncol 2003

OVAR-3 AGO N = 798, FIGO IIB-IV, <1cm Cispl./Paclit. vs. Carbopl./Paclit. PFS HR 1,05 Bez statystycznej istotności OS HR 1,05 Bez statystycznej istotności Paclitaxel /Cisplatin Paclitaxel /Carboplatin PFS 19.1 17.2 Survival 44.1 43.3 10 Du Bois A et al, J Natl Cancer Inst 2003

Wyniki po latach Long term follow up PFS p=0.001 OS p=0.001 +11% 11 Piccart MJ et al, Int J Gynecol Cancer 2003

I linia Alternatywa dla paklitakselu 13

Alternatywa dla paklitakselu PFS SCOTR0C N = 1077, FIGO IC-IV Carboplatin/ Paclitaxel vs. Carboplatin/Docetaxel Bez statystycznej istotności OS Bez statystycznej istotności 14 Vasey et al, J Natl Cancer Inst, 2004

I linia IP 15

Badania III fazy porównujące IV vs IP Badanie / autor / rok SWOG/GOG-104 (Alberts et al. 1996) Greece (Polyzos et al. 1999) GONO (Gadducci et al. 2000) GOG-114/SWOG (Markman et al. 2001) Taiwan (Yen et al. 2001) GOG-172 (Armstrong et al. 2006) Ramie kontrolne Ramie eksperymentalne FIGO / wielkość resztek CDDP 100 mg/m 2 IV CTX 600 mg/m 2 IV co 21 dni x 6 CRBPT 350 mg/m 2 IV CTX 600 mg/m 2 IV co 21 dni x 6 CDDP 50 mg/m 2 IV CTX 600 mg/m 2 IV Epi 60 mg/m 2 IV co 28 dni x6 CDDP 75 mg/m 2 IV TAX 135 mg/m 2 (24 hr) IV co 21 dni x6 CDDP 50 mg/m 2 IV CTX 500 mg/m 2 IV Epi/Adr 50 mg/m 2 IV co 21 dni x6 CDDP 75 mg/m 2 IV TAX 135 mg/m 2 (24 hr) IV co 21 dni x6 CDDP 100 mg/m 2 IP CTX 600 mg/m 2 IV co 21 dni x 6 CRBPT 600 mg/m 2 IV co 21 dni x 6 CDDP 50 mg/m 2 IP CTX 600 mg/m 2 IV Epi 60 mg/m 2 IV co 21 dni x 6 CRBPT AUC 9 IV co 28 dni x 2 CDDP 100 mg/m 2 IP TAX 135 mg/m 2 (24 hr) IV co 21 dni x 6 CDDP 100 mg/m 2 IP CTX 500 mg/m 2 IV Epi/Adr 50 mg/m 2 IV co 21 dni x 6 TAX 135 mg/m 2 (24 hr) IV CDDP 100 mg/m 2 IP TAX 60 mg/m 2 IP w 8 dniu co 21 dni x 6 Stage III < 2 cm Stage III < or > 2 cm Stage II-IV < 2 cm Stage III < 1 cm Stage III < 1 cm Stage III < 1 cm Liczba pacjentów 546 90 113 + 462 118 + 415 16

Badania III fazy porównujące IV vs IP Progression-free survival Badanie / autor / rok SWOG/GOG-104 (Alberts et al. 1996) Greece (Polyzos et al. 1999) GONO (Gadducci et al. 2000) Ramie kontrolne Ramie eksperymentalne FIGO / wielkość resztek ND ND Stage III < 2 cm 19 18 Stage III < or > 2 cm 25 42 Stage II-IV < 2 cm Istotność statystyczna GOG-114/SWOG (Markman et al. 2001) 22 28 Stage III < 1 cm P=0,01 Taiwan (Yen et al. 2001) ND ND Stage III < 1 cm GOG-172 (Armstrong et al. 2006) 18 24 Stage III < 1 cm p=0.05 17

Badania III fazy porównujące IV vs IP Overall survival Badanie / autor / rok SWOG/GOG-104 (Alberts et al. 1996) Greece (Polyzos et al. 1999) GONO (Gadducci et al. 2000) Ramie kontrolne Ramie eksperymentalne FIGO / wielkość resztek 41 49 Stage III < 2 cm 25 26 Stage III < or > 2 cm 51 67 Stage II-IV < 2 cm Istotność statystyczna P=0.02 GOG-114/SWOG (Markman et al. 2001) 52 63 Stage III < 1 cm P=0,05 Taiwan (Yen et al. 2001) 48 43 Stage III < 1 cm GOG-172 (Armstrong et al. 2006) 50 78 66 109 Stage III < 1 cm p=0.03 18

IP GOG Protocol 104 (SWOG 8501) [1] GOG Protocol 114 [2] GOG Protocol 172 [3] 1. Alberts DS, et al. N Eng J Med. 2006. 2. Markman M, et al. J Clin Oncol. 2001. 3. Armstrong D, et al. N Eng J Med. 2006 19

GOG 104 CISPLATIN IV vs. IP OS +8 Mon. n = 546 FIGO III, <2cm Cisplatin 100 mg/m2 i.v. vs. i.p. +Cyclophosphamid i.v. p=0.02 IV IP PFS OS 41 49 20 Alberts et al, N Engl J Med. 1996

GOG 114 CISPLATIN/PACLITAXEL vs. CARBO PACLITAXEL/CISPLATIN IP PFS +6 Mon. p=0.01 OS n = 462 FIGO III, <1cm 6x CP i.v. vs. 2x Carboplatin AUC9 6x Paclitaxel i.v. /Cisplatin i.p. +11 Mon. IV IP p=0.05 PFS 22 28 OS 52 63 21 Markman et al, J Clin Oncol, 2001

GOG 172 CISPLATIN/PACLITAXEL IV vs. IP p=0.05 +5,5 Mon. PFS n = 415 FIGO III, < 1 cm 6x CP vs. 6x Paclitaxel i.v. d1+ Cisplatin i.p. d2 + Paclitaxel i.p. d8 42% all 6 IP cycles p=0.03 OS +15,9 Mon. IV IP PFS 18 24 Survival 50 66 22 Armstrong et al, N Engl J Med., 2006

PFS GOG 172 CISPLATIN/PACLITAXEL IV vs. IP 1.0 0.8 HR 0,77 CDDP (IP) Paclitaxel (IP + IV) (n = 205) PFS 0.6 0.4 18 vs 24 mos PFS p=0.05 0.2 CDDP (IV) Paclitaxel (IV) (n = 210) +5,5 Mon. 0 0 12 24 36 48 60 Months 23 Armstrong et al, N Engl J Med., 2006

OS GOG 172 CISPLATIN/PACLITAXEL IV vs. IP 1.0 0.8 HR 0,73 CDDP (IP) Paclitaxel (IP + IV) (n = 206) p=0.03 OS 0.6 0.4 CDDP (IV) Paclitaxel (IV) (n = 210) 66 vs 50 mos survival 0.2 0.0 0 12 24 36 48 60 No macroscopic disease OS 78 vs 109 Months +15,9 Mon. 24 Armstrong et al, N Engl J Med., 2006

GOG 172 CISPLATIN/PACLITAXEL IV vs. IP 25 Armstrong et al, N Engl J Med., 2006

8 randomizowanych badań obejmujących 1819 kobiet Kobiety leczone chemioterapią dootrzewnową miały mniejsze ryzyko zgonu (hazard ratio (HR) =0.79; 95% confidence interval (CI): 0.70 to 0.90) a czas wolny od choroby był w tej grupie w sposób istotny statystycznie (HR =0.79; 95%CI: 0.69 to 0.90). Objawy toksyczne były częstsze w grupie leczonej za pomocą chemioterapii dootrzewnowej. 27

HAZARD RATIO dla wznowy (IP vs IV) HAZARD RATIO dla zgonu (IP vs IV) 28

Jeżeli jest tak dobrze to dlaczego ciągle o tym dyskutujemy To nie są sexy drug (J. Vermorken) Leczenie tą metoda jest nieporęczne Zawsze były powody aby powiedzieć ale GOG 104: nie jest lepiej niż paklitaksel GOG 114: ale przecież to było 8 podań GOG 172: to jest toksyczniejsze I nikomu na tym ze strony przemysłu nie zależy 29

Dose dense 31

Weekly paklitaksel / dose dense Randomized phase III trial of conventional paclitaxel and carboplatin (c-tc) versus dose dense weekly paclitaxel and carboplatin (dd-tc) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology Isonishi S. et al. ASCO 2008 32 Katsumata N. et all. Lancet 2009

Baseline characteristics of study patients 33 Katsumata N. et all. Lancet 2009

Proportion Surviving Progression Free c TC vs dd TC PFS PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 +10,8 Mon. c-tc dd-tc 0 6 12 18 24 30 36 42 48 54 Mos From Randomization p=0.0015 c-tc dd-tc C-TC conventional paclitaxel and carboplatin PFS 17.2 28 dd- TC dose dense weekly paclitaxel and carboplatin 34 Katsumata N. et all. Lancet 2009

Proportion Surviving c TC vs dd TC OS (3 letnie przeżycia) OS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 +7 Mon. 0 6 12 18 24 30 36 42 48 54 Mos From Randomization c-tc dd-tc p=0.03 % c-tc dd-tc C-TC conventional paclitaxel and carboplatin 3 yr survival 65,1 72,1 dd- TC dose dense weekly paclitaxel and carboplatin 35 Katsumata N. et all. Lancet 2009

The overall response rate was similar between groups (conventional regimen, 72 [53%] of 135 patients; dose-dense regimen, 82 [56%] of 147 patients; p=0 72). Because patients who underwent suboptimally debulked surgery (>1 cm of residual disease) were allowed to undergo interval debulking surgery in this study, response sometimes could not be confirmed on repeated imaging. Overall response If these unconfirmed responses are taken into account (44 patients), the overall response rate was 70% (94 of 135 patients) in the conventional treatment group compared with 71% (104 of 147 patients) in the dose-dense treatment group (p=0 90). 36 Katsumata N. et all. Lancet 2009

Progression free survival 37 Katsumata N. et all. Lancet 2009

Adverse events G-CSF was used in 187 (60%) patients assigned to the dosedense regimen and in 214 (67%) assigned to the conventional regimen. 38

Neoadjuwant 39

EORTC-GCG/NCIC-CTG randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIC-IV ovarian, fallopian tube and peritoneal cancer. Vegrote I et al. IGSC 2008 40 Vegrote I et al. NEJM 2010

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer EORTC-GCG/NCIC-CTG randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIC-IV ovarian, fallopian tube and peritoneal cancer IX 98 XII 06 Potwierdzenie hist-pat raka jajnika lub Sugestia cytologiczna + guz w miednicy zmiany przerzutowe 2 cm poza miednicą CA125/CEA 25 Follow up >9 lat Bez statystycznej istotności 41 Vegrote I et al. NEJM 2010

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer FIGO IIIC-IV 718 pts Operacja pierwotna 6 x chth z platyną 3x chth Operacja odroczona 3 x chth 42 Vegrote I et al. NEJM 2010

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer PFS Bez statystycznej istotności PDS NACT PFS 12 12 Primary Debulking Surgery (PDS) Neoadjuvant Chemotherapy (NACT) 43 Vegrote I et al. NEJM 2010

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer OS Bez statystycznej istotności PDS NACT OS 30 30 Primary Debulking Surgery (PDS) Neoadjuvant Chemotherapy (NACT) 44 Vegrote I et al. NEJM 2010

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer Operacja pierwotna neodajuwant Śmiertelność 28 dni 2,5% 0,7% Posocznica 8,1% 1,7% Krwawienie 3/4 7,4% 4,1% 45 Vegrote I et al. NEJM 2010

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer Primary Debulking Surgery (PDS) Neoadjuvant Chemotherapy (NACT) 46 Vegrote I et al. NEJM 2010

Wprowadzenia III leku Badania negatywne 49

Badania negatywne I rzutu Paclitaxel / carboplatin with or without epirubicin - Kristensen 2004 GOG 182 / ICON 5 Bookman (ASCO 2006 ) / JCO 2009 Paclitaxel / carboplatin with or without topotecan Scarfone 2006 Paclitaxel / carboplatin with or without epirubicin Du Bois 2006 Paclitaxel / carboplatin / 4x topotecan vs. follow up Pfisterer 2006 Cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel Hoskins 2008 Paclitaxel / carboplatin with or without gemcitabine Du Bois 2008 IGSC/ Herrstedt 2009 ASCO 50

NSGO-EORTC-NCIC-GEICO Bez statystycznej istotności The addition of epirubicin to the standard carboplatin and paclitaxel treatment did not improve progressionfree survival Kristensen 2004 ASCO Annual Meeting First line treatment of ovarian/tubal/peritoneal cancer FIGO stage IIb-IV with paclitaxel/carboplatin with or without epirubicin (TEC vs TC). A Gynecologic Cancer Intergroup study of the NSGO, EORTC GCG, and NCIC CTG. Results on 51 progression free survival.

MITO Bez statystycznej istotności Conclusions: The addition of topotecan to standard PC primary chemotherapy does not increase RR and TTP in stage III (residual tumor > 1 cm) or IV OC compared to PC alone. The TPC regimen was well tolerated with a minority of patients experiencing G3/4 hematological toxicity Scarfone G, Scambia G, Raspagliesi F, et al. A multicenter, randomized, phase III study comparing paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer. Presented at the 42nd Annual Meeting of the American Society of Clinical 52 Oncology; June 2 6, 2006; Atlanta, Ga. abstract 5003

AGO GINECO Bez statystycznej istotności HR 0,95 N = 1282, FIGO IIB-IV Carboplatin/ Paclitaxel vs. Carboplatin/Paclitaxel/Epirubicin HR 0,93 53 Du Bois et al, J Clin Oncol 2006

AGO OVAR GINECO Bez statystycznej istotności HR 0,97 HR 1,01 N = 1308, FIGO IIB-IV 6x Carboplatin/Paclitaxel 4x Topotecan vs. Follow up 54 Pfisterer et al, J Natl Cancer Inst, 2006

GOG 182 / ICON 5 Bez statystycznej istotności ASCO 2006 55

GOG 182 / ICON 5 Bez statystycznej istotności ASCO 2006 56

GOG 182 / ICON 5 / PFS Bez statystycznej istotności 57

GOG 182 / ICON 5 / OS Bez statystycznej istotności 58

NCIC-EORTC-GEICO OV16 Bez statystycznej istotności Hoskins PJ. A phase III trial of cisplatin plus topotecan followed by paclitaxel plus carboplatin versus standard carboplatin plus paclitaxel as first-line chemotherapy in women with newly diagnosed advanced epithelial ovarian cancer. A Gynecologic Cancer Intergroup Study of the NCIC CTG, EORTC, GCG, and GEICO. ASCO 2008 59

AGO OVAR9 Bez statystycznej istotności A phase III study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage IC IV (AGO-OVAR protocol OVAR-9) 60 A. du Bois 2008

Zastąpienie Paklitakselu PLD Badania negatywne 61

Doksorubicyna zamiast paklitakselu Carboplatin plus paclitaxel (CP) versus carboplatin plus pagyleted liposomal doxorubicin (PLD) as first line treatment for patients with advanced ovarian cancer: the MITO-2 randomized multicenter trial. stage IC-IV, CP (C AUC5; P 175 mg/m) vs to CLD (C AUC5: LD 30 mg/m) for 6 cycles. CLD as first-line treatment produced a similar activity, with a different toxicity profile, compared to CP. 62 Pignata S et al. ESMO 2010

Phase III Study: MITO-2 Ovarian cancer - Stage IC-IV - Age 75 - PS: 0-2 - Iº Endpoint: PFS R A N D O M I Z E Paclitaxel 175 mg/m 2 Carboplatin AUC 5 Every 3 weeks PLD 30 mg/m 2 Carboplatin AUC 5 Every 4 weeks Opened: 1/2003 Closed: 11/2007 N = 820 (needed 632 events for HR: 0.8, b=0.2) 63 Pignata S et al. ESMO 2010

Carboplatin plus paclitaxel (CP) versus carboplatin plus pagyleted liposomal doxorubicin (PLD) as first line treatment for patients with advanced ovarian cancer: the MITO-2 randomized multicenter trial. Bez statystycznej istotności 64 Pignata S et al. ESMO 2010

Bewacizumab Wprowadzenia III leku 65

Początek 66

Frontline / I linia Badanie GOG 218 ICON7 Populacja 1873 1528 Typ badania Podwójnie ślepe otwarte Ramiona badania 3 (625/625/623) 2 (768/768) Pierwotny punkt końcowy PFS po zmianie PFS FIGO III/IV High risk I/IIA, IIB-IV Wtórne punkty końcowe OS, TOX, RR, QOL OS, TOX, RR, QOL Dawka 15 mg/kg 7.5 mg/kg Follow up 17,4 miesięcy 19,4 miesięcy Ocena RECIST RECIST i CA125 PI Burger Perren Prezentracja ASCO 2010 ESMO 2010 67

ASCO 2010 68

Stage III: 74% optimally debulked (34%), sub-optimally debulked (40%), Stage IV: 26% Stage III optimal (macroscopic residual disease 1cm) or suboptimal (>1cm), or stage IV 69

Różnica 3,8 miesięcy P<0.0001 71

Różnica 6 miesięcy P<0.0001 72

Bez statystycznej istotności 73

ICON7 (AGO OVAR 11): a randomised, open-label, phase III trial Stage I IIa (grade 3 or clear cell) or Stage IIb IV (all grades/ histologic types) debulked 1 cm or >1 cm OC, PP, FTC (n=1,528) Stratification variables: R A N D O M I S E 1:1 Carboplatin AUC5 or 6* Paclitaxel 175mg/m 2 Carboplatin AUC5 or 6* Paclitaxel 175mg/m 2 Bevacizumab 7.5mg/kg q21 x 18 courses Stage and extent of debulking: I III debulked 1cm vs stage I III debulked >1cm vs stage IV and inoperable stage III Timing of intended treatment start: vs > 4 weeks after surgery 77

Różnica 1,7 miesiąca P=0.0041 RECIST + CA125 + ocena kliniczna 78

Proportion alive without progression PFS results ESMO 2010 1.00 0.75 0.50 15 % Control Research Events, n (%) 392 (51) 367 (48) Median, months 17.3 19.0 Log-rank test p=0.0041 HR (95% CI) 0.81 (0.70 0.94) Różnica 1,7 miesiąca 0.25 P=0.0041 0 Number at risk Control Research 17.3 19.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 764 764 693 715 464 585 216 263 91 73 25 19 79

Różnica 2,3 miesiąca P=0.001 RECIST 80

Różnica 5,4 miesiąca P<0.001 81

Comparing GOG-0218 to ICON7: cross-trial comparison of efficacy Results of primary analysis n PFS (HR) Median PFS, months PFS, months p value Results based on RECIST only (regulatory analysis*) n PFS (HR) Median PFS, months PFS, months p value Subgroup of advanced disease only (operated FIGO IV/IIIC 1cm+ residuals) N PFS (HR) Median PFS, months PFS, months p value *Censoring CA 125 GOG-0218 (Arm I vs III) 1,248 0.72 10.3 vs 14.1 3.8 <0.0001 1,248 0.65 12.0 vs 18.0 6 <0.0001 ICON7 1,528 0.81 17.3 vs 19.0 1.7 0.0041 1,528 0.79 16.0 vs 18.3 2.3 0.001 465 0.68 10.5 vs 15.9 5.4 <0.001 Burger, et al. ASCO 2010 83

ASCO 2011 84

ASCO 2011 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 Interim analysis on overall survival Gunnar Kristensen, Tim Perren, Wendi Qian, Jacobus Pfisterer, Jonathan Ledermann, Françoise Joly, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza on behalf of the GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, GEICO, NCIC-CTG) 85

Overview of analyses ICON7 was powered for both PFS and OS, designed to detect: PFS HR = 0.78 (684 events; 90% power) OS HR = 0.81 (715 events; 80% power) Median follow-up, months PFS events, n OS events, n (% of required events) Mature PFS analysis (cut-off Feb 28, 2010; ESMO 2010) Updated interim OS analysis requested by regulatory authorities (cut-off Nov 30, 2010; ASCO 2011) 19 759 241 (34%) 28 934 378 (53%) Final OS analysis 715 (due in 2013) 86

Proportion alive without progression PFS results ESMO 2010 1.00 0.75 0.50 15 % Control Research Events, n (%) 392 (51) 367 (48) Median, months 17.3 19.0 Log-rank test p=0.0041 HR (95% CI) 0.81 (0.70 0.94) Różnica 2,3 miesiąca 0.25 P=0.0041 0 Number at risk Control Research 17.3 19.0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 764 764 693 715 464 585 216 263 91 73 25 19 87

Proportion alive without progression Updated PFS 2011 1.00 0.75 0.50 Control Research Events, n (%) 464 (61) 470 (62) Median, months 17.4 19.8 Log-rank test p=0.039 HR (95% CI) 0.87 (0.77 0.99) Różnica 2,4 miesiąca 0.25 P=0.039 0 Number at risk Control Research 17.4 19.8 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 764 764 693 716 474 599 350 430 221 229 114 107 39 27 88

Proportion alive 1.00 Early OS analysis: ESMO 2010 Bez statystycznej istotności 0.75 0.50 0.25 Control Research Deaths, n (%) 130 (17) 111 (15) Median, months Not yet reached Log-rank test p=0.098 HR (95% CI) 0.81 (0.63 1.04) 1-year OS rate (%) 93 95 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) Number at risk Control 764 741 724 701 652 486 368 252 159 83 33 Research 764 753 737 716 678 525 404 259 162 89 40 89

Proportion alive Interim OS analysis Bez statystycznej istotności 1.00 0.75 0.50 0.25 Control Research 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 (%) 92 95 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) Number at risk Control 764 741 724 703 672 646 623 542 421 304 212 132 71 26 Research 764 753 737 717 702 680 657 592 459 329 228 129 69 19 90

Proportion alive OS: High-risk subgroup 1.00 p=0.002 0.75 0.50 0.25 0 High-risk subgroup Control (n=234) Research (n=231) Deaths, n (%) 109 (47) 79 (34) Median, months 28.8 36.6 Log-rank test p=0.002 HR (95% CI) 0.64 (0.48 0.85) 1-year OS rate (%) 86 92 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) Number at risk Control 234 219 194 166 107 46 15 Research 231 222 208 186 134 65 18 91

Proportion alive OS by risk groups 1.00 p=0.011 0.75 0.50 0.25 0 Control, low risk Research, low risk Control high risk Research high risk Low-risk subgroup Control (n=530) Research (n=533) Deaths, n (%) 91 (17) 99 (19) Median, months Not yet reached Log-rank test p=0.64 HR (95% CI) 1.07 (0.81 1.42) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) 92

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 Treatment effect is greater in patients at high risk of recurrence, which may be of clinical relevance These are interim OS results requested by regulatory authorities; final OS results are due in 2013 93

ESMO 2011 Jakość życia GOG 218 Jakość życia ICON 7 94

ESMO 2011 95

ESMO 2011 / GOG 218 Bevacizumab-containing therapy produced statistically significant QOL disruption during chemotherapy This difference was small and below the MID QOL was not adversely or favorably affected by prolonged bevacizumab delivery Relative to placebo, adding bevacizumab does not appear to improve or impair QOL The progression free survival advantage of adding bevacizumab in GOG 218 appears to be obtained without meaningful compromise to QOL 96

ESMO 2011 97

ESMO 2011 / ICON7 Perhaps unsurprisingly, women receiving bevacizumab had a statistically significant but clinically small detriment in global QoL at week 54 Women receiving bevacizumab had statistically significant but clinically small detriments in role function and finance scales 98

Podsumowanie Klasyczny schemat jakim jest karboplatyna i paklitaksel IV jest nadal schematem z wyboru w stopniu I wg FIGO. W pozostałych stopniach zaawansowania w chwili obecnej alternatywę są cisplatyna i paklitaksel podawany dootrzewnowo (IP) lub paklitaksel podawany co 7 dni z karboplatyną (DD) oraz chemioterapia neoadjuwantowa u nie operacyjnych pacjentek w stopniu IIIC i IV. Pacjentki po cytoredukcji z resztami poniżej 1 cm w stopniu od II wg FIGO i bez zrostów w jamie brzusznej są kandydatkami do leczenia IP, pozostałe chore powinny być leczone schematem DD. 99

PFS i OS w kluczowych badaniach dotyczących chemioterapii I rzutu od roku 1996 Badanie / rok publikacji Ramię kontrolne vs badane PFS OS R. kontrolne R. Badane R. kontrolne R.badane GOG 111 / 1996 CDDP/CTX vs CDDP/TAX 13 * 18 * 24 * 38 * GOG 158 / 2003 CDDP/TAX vs CRBPT/TAX 19,4 20,7 48,8 57,4 AGO-OVAR-3 / 2003 GOG 182 / ICON5 2009 CDDP/TAX vs CRBPT/TAX 19.1 17.2 44.1 43.1 CRBPT/TAX vs Triple 16,0 44,1 GOG-172 / 2006 CDDP/TAX vs CDDP/TAX IP 18 * 24 * 50 * 66 * Katsumata/ Lancet 2009 Vergote i wsp. / NEJM 2010 GOG 218 / ASCO 2010 ICON 7 / ASCO 2011 CRBPT/TAX vs CRBPT/TAX DD 17,2 * 28 * 65,1% $ 72,1% $ CRBPT/TAX vs neo CRBPT/TAX 11 11 29 30 CDDP/TAX vs CDDP/TAX + Bev + CDDP/TAX + Bev Bev CDDP/TAX vs CDDP/TAX + Bev Bev 10,3 * 14,1 * ND ND 17,4 * 19,8 * ND ND 100 CDDP: Cisplatyna; TAX: paklitaksel; CRBPT: karboplatyna, IV: wlew dożylny; IP: chemioterapia dootrzewnowej (intraperitoneal therapy) DD: chemioterapią o dużej gęstości dawki (dose dense chemotherapy) * Badania statystycznie istotne

NCCN FIRST LINE (2011) 101

Toczące się badania I rzutu 102

First-Line Therapy in Ovarian Cancer Trials 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) 2010 Vancouver Kanada A3: Is the 2004 GCIG-recommended standard comparator arm still valid? 103