Cancer ovarien: nouveaux concepts Nouvelle classification moléculaire J.Bauer Octobre 2011
Caractéristiques biologiques du CEO Hétérogénéité importante des sous types histologiques et de leur comportement clinique Evidence pour une instabilité clonale et génétique avec 2 catégories ( LMP et HMP) Interaction importante et intime avec le microenvironnement
Histologie Classification moléculaire des CEO Caractéristiques moléculaires I Low-grade serous carcinoma Mutations in KRAS and/or BRAF ( 60%) I Low-grade endometrioid Mutations in CTNNB1, PTEN and carcinoma PIK3CA with microsatellite instability I Mucinous carcinoma Mutations in KRAS; TP53 mutation associated with transition from borderline tumour to carcinoma I Clear cell carcinoma PTEN mutation or loss of heterozygosity; PIK3CA mutation II High-grade serous carcinoma TP53 mutation (up to 80%) and BRCA1 dysfunction II High-grade endometrioid carcinoma TP53 mutation and BRCA1 dysfunction; PIK3CA mutation Modified from Bast, 2009
Nouvelle classification Type I LMP/Low grade (%) Type II High grade (%) p53 inactivité rare 50-80 AKT surexpression rare 12-30 Mutation B-RAF K-RAS PTEN BRCA1/BRCA2 30-50 (séreux) 30-50 (mucineux) 20 (clear cell/endom) rare rare rare rare 10-15 (séreux) Histotype/précurseur Séreux/TB Mucineux/TB endometrioid/endometriose clear cell/endometriose séreux/de novo / kyste d inclusion - endometrioide/inclusion glands -
Mise à jour des thérapies ciblées antiangiogenèse PI3K/MEK inhibiteurs PARP inhibiteurs
GOG-0218 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 1:1:1 BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Arm I (CP) II (CP + BEV) Stratification variables: GOG performance status (PS) Stage/debulking status Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 BEV 15 mg/kg III (CP + BEV BEV) Cytotoxic (6 cycles) Maintenance (16 cycles) 15 months
GOG-0218: PFS selon investigateurs Proportion surviving progression free 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 CP (Arm I) + BEV (Arm II) Patients with event, n (%) Arm I CP (n=625) 423 (67.7) Median PFS, months 10.3 Stratified analysis HR (95% CI) One-sided p-value (log rank) + BEV BEV maintenance (Arm III) Arm II CP + BEV (n=625) 418 (66.9) 11.2 0.908 (0.759 1.040) 0.080 a 0 12 24 36 Months since randomization Arm III CP + BEV BEV (n=623) 360 (57.8) 14.1 0.717 (0.625 0.824) <0.0001 a a p-value boundary = 0.0116
Schema Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing 1:1 R n=1528* Carboplatin AUC6 Paclitaxel 175 mg/m 2 Carboplatin AUC6 Paclitaxel 175 mg/m 2 Bevacizumab 7.5 mg/kg q3w Stratification variables: Stage & extent of debulking: I III debulked 1cm vs I III debulked >1 cm vs IV and inoperable stage III Timing of intended treatment start 4 vs >4 weeks after surgery GCIG group *Dec 2006 to Feb 2009 18 cycles Year 1 Years 2 3 Years 4 5 CT Baseline; after cycles 3 & 6; at 9 & 12 months Every 6 months As indicated CA-125/clinical assessment Every chemotherapy cycle; every 6 weeks during maintenance phase Every 3 months Every 6 months
Proportion alive without progression 1.00 0.75 0.50 0.25 Progression-free survival Academic analysis 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) Control Research 0 17.3 19.0 0 3 6 9 12 15 18 21 24 27 30 Time (months) Number at risk Control 764 723 693 556 464 307 216 143 91 50 25 Research 764 748 715 647 585 399 263 144 73 36 19
ICON7: OS in patients with advanced disease (interim analysis, median follow-up 28 months) 1.00 FIGO III >1 cm /FIGO IV debulking 0.75 Proportion alive 0.50 High-risk subgroup CP (n=234) CP + Avastin Avastin (n=231) Events, n (%) 109 (47) 79 (34) 0.25 0 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 6 12 18 24 30 36 42 48 Time (months) Number at risk CP 234 219 194 166 107 46 15 CP + Avastin 231 222 208 186 134 65 18 Kristensen, et al. ASCO 2011 (abstract LBA5006)
OCEANS: trial design and patient eligibility Platinum-sensitive recurrent ovarian cancer Measurable disease ECOG PS 0/1 No prior chemotherapy for recurrent disease No prior Avastin (n=484) Carboplatin AUC4 q3w Gemcitabine 1,000mg/m 2, days 1, 8 q3w Placebo q3w Carboplatin AUC4 q3w Gemcitabine 1,000mg/m 2, days 1, 8 q3w Avastin 15mg/kg q3w PD PD Carboplatin/gemcitabine for 6 (up to 10) cycles Aghajanian, et al. ASCO 2011 (abstract LBA5007)
OCEANS: primary endpoint, inv.-assessed PFS Proportion progression free No. at risk CG + Av CG + Pl 1.0 0.8 0.6 0.4 0.2 0 0 8.4 12.4 CG + placebo placebo (n=242) CG + Avastin Avastin (n=242) Events, n (%) 187 (77.3) 151 (62.4) Median PFS, months (95% CI) Stratified HR (95% CI) Log-rank p-value 8.4 (8.3 9.7) 0.484 (0.388 0.605) <0.0001 12.4 (11.4 12.7) 6 12 18 24 30 Time (months) 242 203 92 33 11 0 242 177 45 11 3 0 Aghajanian, et al. ASCO 2011 (abstract LBA5007)
OCEANS: robustness of efficacy analysis Endpoint CG + placebo placebo CG + Avastin Avastin Median PFS (months) 8.4 12.4 HR p value 0.484 <0.0001 ORR (%) 57.4 78.5 p value <0.0001 Median duration of response (months) HR p value 7.4 10.4 0.534 <0.0001 Median OS (months) 29.9 35.5 HR p value 0.751 0.094 Robustness of investigator analysis of median PFS confirmed by independent review committee (12.3 vs 8.6 months [HR 0.451, p<0.0001]) Aghajanian, et al. ASCO 2011 (abstract LBA5007)
PARP-inh ET CANCER DE L OVAIRE PARP = Poly (ADP-ribose) Polymérases = Famille d enzymes réparatrices du DNA control du cycle cellulaire PARP 1,2 : critiques pour la fonction de BER (Base Excision repair) impliqué dans la réparation de SSB (Single strand breaks)
PARP-inh ET CANCER DE L OVAIRE «Synthetic Lethality»: Combinaison de 2 conditions qui, mises en commun induisent la mort cellulaire ex: PARP-inh + BRCA muté (5% des ovcar ) BRCAness: Tumeur sans mutation germinale (BRCA 1 ou 2) phénotypiquement «mutée» Olaparib (AZD 2281) Iniparib (BSI 201) Veliparib (ABT 888)
Olaparib chez des patientes sensibles au platine Phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of olaparib monotherapy in patients with platinum-sensitive serous ovarian cancer Patients had previously received 2 platinum-containing regimens and had an objective PR or CR and/or GCIG response prior to study enrolment Patients continued randomized treatment until disease progression Patients randomized 1:1 within 8 weeks of last dose of platinumcontaining regimen Olaparib 400 mg bid Matching placebo bid PR, partial response; CR, complete response; GCIG, Gynaecological Cancer InterGroup ClinicalTrials.gov NCT00753545