( O )varia. Gabe Sonke post-asco 2015

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2 ( O )varia Gabe Sonke post-asco 2015

3 Disclosure Onderzoeksgeld AstraZeneca, Novartis, Roche

4 Nieuws op ASCO PARP remming (McNeish #5508) Wee1 remming (Leijen #2507, Oza #5506) Bevacizumab endometrium (Lorusso #5502) WBRT bij hersenmeta s (Brown #LBA4) Varia

5 % overleving Ovariumcarcinoom Meest frequente oorzaak gyn sterfte ± nieuwe patiënten per jaar ± vrouwen 100% 80% 60% 40% 20% sterven per jaar 0% Aantal jaar sinds diagnose

6 Ovariumcarcinoom behandeling Stadium I IIa Chirurgische stagering carboplatin ± paclitaxel (graad 3) Stadium IIb IV Debulking chirurgie (primair of interval) carboplatin + paclitaxel (op indicatie intraperitoneaal) Recidief Rol chirurgie onzeker >6 maanden: platinum bevattend* BRCA: olaparib onderhoud <6 maanden: PLD, gemcitabine, etc* * evt icm bevacizumab

7 Progression-free survival PFS voordeel met name bij BRCA mutatie Olaparib BRCAm Placebo BRCAm Time from randomization (months) Olaparib (n=74) BRCAm (n=136) Placebo (n=62) Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months HR= % CI (0.10, 0.31); P< Ledermann JA et al. Lancet Oncol 2014;15:852 61

8 Proportion of patients alive Overall survival accounting for cross-over BRCAm (n=97) Olaparib (n=57) Placebo (n=40) Deaths: total pts (%) 28:57 (49.1) 22:40 (55.0) Median OS, months HR % CI P= Olaparib BRCAm Placebo BRCAm Matulonis; SGO 2015

9 Germline BRCA BRCA mutatie status Tumour BRCA Mutant Wild type TOTAL Mutant Wild type TOTAL Ledermann J et al. J Clin Oncol 2013;31(15S):abstr 5505

10 Results of ARIEL2:<br />A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis Presented By Iain McNeish at 2015 ASCO Annual Meeting

11 HRD causes genome-wide loss of heterozygosity (LOH) that can be measured by comprehensive genomic profiling based on NGS Presented By Iain McNeish at 2015 ASCO Annual Meeting

12 ARIEL2 designed to assess rucaparib efficacy in three prospectively defined molecular subgroups Presented By Iain McNeish at 2015 ASCO Annual Meeting

13 In BRCAwt tumors, the BRCA-like subgroup derives enhanced benefit from rucaparib Presented By Iain McNeish at 2015 ASCO Annual Meeting

14 Behandeling met PARPi Hoe te identificeren Verwijzing klinisch geneticus Somatisch testen? HRD test? Positie tov bevacizumab? Waar te behandelen 50 patienten per jaar in NL centreren Kosten per gewonnen levensjaar

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16 Slide 13 Presented By Elise Kohn at 2015 ASCO Annual Meeting

17 Slide 14 Presented By Elise Kohn at 2015 ASCO Annual Meeting

18 Phase II study with Wee1 inhibitor AZD1775 (MK-1775)<br />plus carboplatin in patients with p53 mutated ovarian cancer <br />refractory or resistant (<3 months) to standard first line therapy Presented By Suzanne Leijen at 2015 ASCO Annual Meeting

19 Study design: ovarian cancer patients Presented By Suzanne Leijen at 2015 ASCO Annual Meeting

20 Treatment schedule Presented By Suzanne Leijen at 2015 ASCO Annual Meeting

21 Clinical activity <br />Time on study & objective response Presented By Suzanne Leijen at 2015 ASCO Annual Meeting

22 An international, biomarker-directed, randomized, Phase II trial of AZD1775 plus paclitaxel and carboplatin for the treatment of women with platinum-sensitive, TP53-mutant ovarian cancer Presented By Amit Oza at 2015 ASCO Annual Meeting

23 Study design: International, multicenter, <br />Phase II trial Presented By Amit Oza at 2015 ASCO Annual Meeting

24 Progression-free survival by RECIST 1.1 Secondary objective: Progression-free survival by RECIST 1.1 Presented By Amit Oza at 2015 ASCO Annual Meeting

25 Wee1 conclusions AZD1775 is well tolerated in combination with carboplatin (± paclitaxel) in a 21 day schedule In women with TP53 mutant ovarian cancer: Shows encouraging anti-tumor activity in platinum refractory/resistant disease Was associated with significant improvement in PFS in platinum sensitive disease This concept warrants full development in these patient population

26 Identifying optimal Wee1 inhibitor settings

27 Endometriumcarcinoom behandeling Laag risico Chirurgische resectie Int. risico Chirurgische resectie brachytherapie Hoog risico Chirurgische resectie Uitwendige radiotherapie Carbo / taxol HR+: hormonaal Metastasen palliatie Palliatie HR-: chemotherapie (standaard CAP, praktijk carbo/taxol)

28 Randomized Phase II Trial of Carboplatin-Paclitaxel (CP) compared to Carboplatin-Paclitaxel-Bevacizumab (CP-B) in advanced (stage III-IV) or recurrent endometrial cancer: the MITO END-2 trial Presented By Domenica Lorusso at 2015 ASCO Annual Meeting

29 Study design Presented By Domenica Lorusso at 2015 ASCO Annual Meeting

30 Primary PFS analysis: INV-assessed Presented By Domenica Lorusso at 2015 ASCO Annual Meeting

31 Overall survival (secondary endpoint): immature Presented By Domenica Lorusso at 2015 ASCO Annual Meeting

32 Bevacizumab endometrium 4 maanden PFS winst OS niet significant (5,5 maand) Bekend risicoprofiel (wel oude pts) Fase-3 studie? Kosten per gewonnen levensjaar

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34 How important is whole brain radiotherapy?

35 NCCTG N0574 (Alliance): A Phase III Randomized Trial of Whole Brain Radiation Therapy in Addition to Radiosurgery in Patients with 1 to 3 Brain Metastases Presented By Paul Brown at 2015 ASCO Annual Meeting

36 Background Adjuvant WBRT Presented By Paul Brown at 2015 ASCO Annual Meeting

37 N0574 Design<br /> Presented By Paul Brown at 2015 ASCO Annual Meeting

38 Primary Endpoint: Cognitive Progression at 3 mos Presented By Paul Brown at 2015 ASCO Annual Meeting

39 Conclusions Presented By Paul Brown at 2015 ASCO Annual Meeting

40 Time to Intracranial Progression Presented By Paul Brown at 2015 ASCO Annual Meeting

41 Overall Survival Presented By Paul Brown at 2015 ASCO Annual Meeting

42 Conclusions Presented By Paul Brown at 2015 ASCO Annual Meeting

43 Varia Zoledronaat bij botmetastasen q 3 mnd = q 1 mnd Himelstein # % mammacarcinoom pts 2nd opinion, 3% switched van behandelaar; behandeling hetzelfde, tevredenheid hetzelfde Kurian #6508 Exercise oncology is safe and associated with significant improvements in physical functioning, fatigue, and QoL. #9505-#9508

44 Take home messages PARP remming bij ovarium denk aan BRCA testen (tumor of kiembaan) Wee1 remmers bij ovarium komen eraan Bevacizumab bij endometriumcarcinoom nieuwe indicatie? Bij beperkte hersenmeta s alleen lokale therapie, zonder WBRT Zoledronaat per 3 maanden

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