Cancer ovarien: nouveaux concepts. Nouvelle classification moléculaire

Transcription

1 Cancer ovarien: nouveaux concepts Nouvelle classification moléculaire J.Bauer Octobre 2011

2 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

3 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

4 Nouvelle classification Type I LMP/Low grade (%) Type II High grade (%) p53 inactivité rare AKT surexpression rare Mutation B-RAF K-RAS PTEN BRCA1/BRCA (séreux) (mucineux) 20 (clear cell/endom) rare rare rare rare (séreux) Histotype/précurseur Séreux/TB Mucineux/TB endometrioid/endometriose clear cell/endometriose séreux/de novo / kyste d inclusion - endometrioide/inclusion glands -

5 Mise à jour des thérapies ciblées antiangiogenèse PI3K/MEK inhibiteurs PARP inhibiteurs

6 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

7 GOG-0218: PFS selon investigateurs Proportion surviving progression free 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) ( ) a Months since randomization Arm III CP + BEV BEV (n=623) 360 (57.8) ( ) < a a p-value boundary =

8 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 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

9 Proportion alive without progression Progression-free survival Academic analysis Control Research Events, n (%) 392 (51) 367 (48) Median, months Log-rank test p= HR (95% CI) 0.81 ( ) Control Research Time (months) Number at risk Control Research

10 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) Median, months Log-rank test p=0.002 HR (95% CI) 0.64 ( ) 1-year OS rate (%) Time (months) Number at risk CP CP + Avastin Kristensen, et al. ASCO 2011 (abstract LBA5006)

11 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)

12 OCEANS: primary endpoint, inv.-assessed PFS Proportion progression free No. at risk CG + Av CG + Pl 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 ( ) ( ) < ( ) Time (months) Aghajanian, et al. ASCO 2011 (abstract LBA5007)

13 OCEANS: robustness of efficacy analysis Endpoint CG + placebo placebo CG + Avastin Avastin Median PFS (months) HR p value < ORR (%) p value < Median duration of response (months) HR p value < Median OS (months) HR p value 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)

14 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)

15 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)

16 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 NCT

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