Controversies in the Management of Advanced Ovarian Cancer

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1 안녕하세요 Controversies in the Management of Advanced Ovarian Cancer Mansoor R. Mirza Nordic Society of Gynaecological Oncology (NSGO) & Rigshospitalet Copenhagen University Hospital, Denmark

2 Primary Debulking Surgery vs. Neoadjuvant Chemotherapy Dose-Dense Weekly vs. 3-Weekly Paclitaxel Intraperitoneal Chemotherapy Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Maintenance PARP Inhibitors or Bevacizumab in Platinum-Sensitive Relapse

3 Vergote I et al. New Engl J Med 2010

4 Vergote I et al. New Engl J Med 2010

5 The MRC CHORUS trial Clinical FIGO stage III/IV ovarian cancer + CA125:CEA ratio > 25 Randomize Imaging +/- clinical evidence of pelvic mass with extra-pelvic metastases Compatible with FIGO stage III/IV Serum CA 125:CEA ratio > 25 Investigation to exclude GI cancer mandated if 25 & serum CEA > ULN Primary surgery followed by chemotherapy Neoadjuvant chemotherapy followed by surgery then chemotherapy Planned to receive carboplatin-based chemotherapy Fit to undergo protocol treatment Written informed consent Kehoe S et al. Lancet 2015

6 Results from the MRC CHORUS trial Progression-Free Survival Proportion alive and progression free N PS NACT Progression Free Survival intention-to-treat population Time from randomisation (months) PS (N=276) NACT (N=274) Events Median (months) (95% CI) HR* (95% CI) 10.3 (9.4, 11.3) 0.90 (0.75, 1.07) 11.7 (10.4, 12.7) PS NACT Kehoe S et al. Lancet 2015 * HR adjusted for baseline stratification factors

7 Results from the MRC CHORUS trial Overall survival Proportion alive Overall survival intention-to-treat population PS (N=276) NACT (N=274) Events Median (months) (95% CI) 22.8 (19.1, 26.0) 24.5 (21.3, 29.1) HR* (95% CI) 0.87 (0.71, 1.05) 1-year OS rate 70% 76% 3-year OS rate 32% 34% 0.00 N PS NACT Time from randomisation (months) PS NACT Kehoe S et al. Lancet 2015 * HR adjusted for baseline stratification factors

8 If a man is offered a fact which goes against his instincts, he will scrutinize it closely, and unless the evidence is overwhelming, he will refuse to believe it. If, on the other hand, he is offered something which affords a reason for acting in accordance to his instincts, he will accept it even on the slightest evidence. The origin of myths is explained in this way. Bertrand Russell author, mathematician, & philosopher ( ), Nobel Prize Laureate

9 Trial in progress GCOG 602 Multicenter (34 specialized institutions), randomized phase III study Clinically diagnosed Stage III/IV ovarian, tubal, and peritoneal carcinoma Balancing factors Institution Stage III/IV PS 0-1/2-3 Age <60/ 60 R a n d o m i z a t i o n Standard arm (STD arm) PDS 4x TC PDS: primary debulking surgery Experimental arm (NAC arm) NAC (4x TC) IDS* IDS TC regimen Paclitaxel 175 mg/m 2 3h iv, day 1 Carboplatin AUC 6.0 iv, day 1, every 21 days 4x TC 4x TC * Optional for Pts with suboptimal PDS Mandatory for Pts with any Ut/Adn/OM not removed 4x TC IDS: interval debulking surgery Takashi Onda et al. Trial in Progress

10 Trial in Progress: TRUST Primary Endpoint: OS ITT population Secondary Endpoints PFS, resection rates, QOL, Fragility Index Strata: FIGO stage, Region, ECOG PS Site qualification process to ensure surgical quality S C P C P C P C P C P C P Site Qualification R Bevacizumab 15mg/sq x 15 C P C P C P S C P C P C P Bevacizumab 15mg/sq x 15 Accrual Status: 355/700 (May2017) S surgery C Carboplatin AUC5 P Paclitaxel 175 mg/sq Mahner S, Elser G, Fotopoulou C, et al. for TRUST

11 Primary Debulking Surgery vs. Neoadjuvant Chemotherapy Dose-Dense Weekly vs. 3-Weekly Paclitaxel Intraperitoneal Chemotherapy Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Maintenance PARP Inhibitors or Bevacizumab in Platinum-Sensitive Relapse

12 JGOG 3016: Dose-Dense weekly paclitaxel Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratified: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS I Paclitaxel 180 mg/m 2 Carboplatin AUC = 6 x6-9 II Carboplatin AUC = 6 x6-9 Paclitaxel 80 mg/m 2 /w x3 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel Accrual: 637 pts (intent-to-treat) Katsumata N. et al. Lancet, 2009

13 JGOG 3016: Updated Progression-Free Survival JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group median follow-up period: 6.4 years dd-tc c-tc Treatment n Event, n (%) Median PFS P value HR 95%CI dd-tc (63) 28.2 mos c-tc (72) 17.5 mos.

14 JGOG 3016: Updated Overall Survival JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group median follow-up period: 6.4 years Patients surviving (%) dd-tc c-tc Treatment n Deaths, n (%) Median OS 5-yr survival P value HR 95%CI dd-tc (45) not reached 58.7% c-tc (53) 62.2 mos. 51.1%

15 MITO 7: Weekly Carboplatin + Weekly paclitaxel [TITLE] Pignata S et al. ASCO 2013

16 MITO 7: Weekly Carboplatin + Weekly paclitaxel [TITLE] Pignata S et al. ASCO 2013

17 GOG262: Dose-Dense weekly paclitaxel Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer Suboptimal residual disease (optional NACT-ICS) Primary Endpoint: PFS Early perfusion-based CT imaging (ACRIN 6695) I Carboplatin AUC=6 Paclitaxel 80 mg/m 2 (d1,8,15) +/- Bevacizumab (C2-6) $ Bevacizumab q21d $ R II Carboplatin AUC=6 Paclitaxel 175 mg/m 2 (d1) +/- Bevacizumab (C2-6) $ Bevacizumab q21d $ $ Use of Bevacizumab elected prior to randomization Open: Closed: Target: 27-SEP FEB-2012 (ACRIN JUN-2013) 692 pts (randomized) Chan JK, et al. New Engl J Med, 2016

18 GOG262: Progression-Free Survival (+/- Bevacizumab) Proportion Progression-Free (+) BEV (-) BEV Schedule ( n ) PFS Three-Weekly Dose-Dense Weekly Three-Weekly Dose-Dense Weekly Months on Study Chan JK, et al. New Engl J Med, 2016

19 ICON 8 Design Clamp A et al. ESMO 2017 MRC Clinical Trials Unit at UCL

20 ICON 8 PFS ICON8 Progression Free Survival Arm 1 Arm 2 Arm 3 Standard Weekly Weekly carbopaclitaxel paclitaxel Total Patients N=522 N=523 N=521 Progressions 330 (63%) 335 (64%) 338 (65%) Median PFS 17.9 months 20.6 months 21.1 months Log rank (vs Arm1) p=0.45 p=0.56 HR vs Arm 1 (97.5% CI) 0.92 (0.77, 1.09) 0.94 (0.79, 1.12) Restricted means 24.4 months 24.9 months 25.3 months Accrual began 6 th June 2011 and ICON8 pathway closed to recruitment 28 th November 2014 Final recruitment figure = 1566 UK= 1397, ANZGOG= 70, GICOM= 43, KGOG= 32, ICORG= 24 Primary PFS analysis presented at ESMO Conclusions: although weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT. Clamp A et al. ESMO 2017 MRC Clinical Trials Unit at UCL

21 Primary Debulking Surgery vs. Neoadjuvant Chemotherapy Dose-Dense Weekly vs. 3-Weekly Paclitaxel Intraperitoneal Chemotherapy Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Maintenance PARP Inhibitors or Bevacizumab in Platinum-Sensitive Relapse

22 Intraperitoneal Chemotherapy 2 heterogeneity (5 d.f.)= 3.1, p=0.68 Hazard ratio is not reported for the GONO study but it is calculated from the available data reported. Hazard ratio is not reported for the Greek study. HR=0.784 (95%CI )

23 IP Chemotherapy GOG 252 Ovarian, Peritoneal, Tubal Cancer Stage II-IV Optimal & Suboptimal (until April 2011) Total Sample Size 1500 R Paclitaxel 80 mg/m 2 IV Days 1, 8, 15 Carboplatin AUC6 IV Day 1 Q3w 6 cycle Bevacizumab 15 mg/kg with chemo plus maintenance 11 cycle Paclitaxel 80 mg/m 2 IV Days 1, 8, 15 Carboplatin AUC6 IP Day 1 Q3w 6 cycle Bevacizumab 15 mg/kg with chemo plus maintenance 11 cycle Paclitaxel 135 mg/m 2 IV Day 1 Cisplatin 75 mg/m 2 IP Day 1 Paclitaxel 60 mg/m 2 IP Day 8 Q3w 6 cycle Bevacizumab 15 mg/kg with chemo plus maintenance 11 cycle

24 IP Chemotherapy GOG 252 Stage II or III Optimally Debulked

25 IP Chemotherapy NCIC OV21 / GCIG Ovarian, Peritoneal, Tubal Cancer Stage IIIC Suboptimal NACT 3cycles IDC Optimal Total Sample Size 830 R Paclitaxel 135 mg/m 2 IV Days 1 Carboplatin AUC6 IV Day 1 Paclitaxel 60 mg/m 2 IV Day 8 Q3w 3 cycle Paclitaxel 135 mg/m 2 IV Day 1 Cisplatin 75 mg/m 2 IP Day 1 Paclitaxel 60 mg/m 2 IP Day 8 Q3w 3 cycle Paclitaxel 80 mg/m 2 IV Day 1 Carboplatin AUC6 IP Day 1 Paclitaxel 60 mg/m 2 IV Day 8 Q3w 3 cycle Pick the Winner

26 IP Chemotherapy NCIC OV21 / GCIG PD Rate at 9 Months Following Randomization (Per-Protocol) Arm 9-month PD rate 95% CI P value Stratified P Value Unstratified % 29.1% to 48.8% PD Rate at 9 Months Following Randomization (ITT) % 16.6% to 34% Stratified: Cochrane-Mantel-Haenszel test Unstratified: Fishers Exact test

27 Intraperitoneal Chemotherapy Outstanding Issues No trial compared with standard chemotherapy with IV carboplatin + IV paclitaxel There are conflicting results on efficacy of IP chemotherapy as first-line therapy. IP is associated with higher toxicity and worsen quality of life compared to IV chemotherapy

28 ipocc Trial (GOTIC 001 / JGOG 3019) Ovarian, Peritoneal, Tubal Cancer Stage II-IV Optimal & Suboptimal Total Sample Size 654 R Paclitaxel 80 mg/m 2 Days 1, 8, 15 IV Carboplatin AUC6 IV Q3w 6-8 cycles Paclitaxel 80 mg/m 2 Days 1, 8, 15 IV Carboplatin AUC6 IP Q3w 6-8 cycles

29 Primary Debulking Surgery vs. Neoadjuvant Chemotherapy Dose-Dense Weekly vs. 3-Weekly Paclitaxel Intraperitoneal Chemotherapy Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Maintenance PARP Inhibitors or Bevacizumab in Platinum-Sensitive Relapse

30 Hyperthermic Intraperitoneal Chemotherapy (HIPEC) March 30 - April 2, 2014 Sheraton Sonoma County Petaluma, California Van Driel WJ et al. N Engl J Med 2018

31 Hyperthermic Intraperitoneal Chemotherapy (HIPEC) March 30 - April 2, 2014 Sheraton Sonoma County Petaluma, California Van Driel WJ et al. N Engl J Med 2018

32 HIPEC: Weaknesses in this trial Due to small number of patients (245) the survival benefit differs by only 15 patients. More unfavourable non-high-grade (mucinous, clear-cell, high-grade endometrioid, carcinosarcoma) tumors in surgery alone group (13 vs. 3). HIPEC resulted in more toxic effects and longer hospitalization Quality of life comparison not reported.

33 HIPEC: ESMO-ESGO Consensus HIPEC is not the standard of care as first-line treatment HIPEC should be limited to well-designed prospective randomized clinical trials.

34 HIPEC: ONGOIG TRIALS ClinicalTrials.gov Identifier: NCT (randomized); Suk-Joon Chang et al.; N=204 March 30 - April 2, 2014 Experimental arm: NAC-IDS-HIPEC Sheraton Sonoma County Under the clinicians' Petaluma, California decision, HIPEC procedures will be performed at the time of IDS. Procedure: HIPEC (paclitaxel 175mg/m2, 90min; open or closed technique) after IDS. IDS is recommended within 4 weeks after the 3rd NAC cycle. HIPEC procedure is allowed only in case of residual disease less than 5mm. No Intervention arm: NAC-IDS Under the clinicians' decision, HIPEC procedures will not be performed at the time of IDS. ClinicalTrials.gov Identifier: NCT (randomized); Pedro Villarejo Campos et al.; n=94 Experimental arm: HIPEC Primary ovarian cancer FIGO stage II, III or IV or recurrent Drug: HIPEC Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with Paclitaxel (175 mg/m2) for 60 minutes at degrees Active Comparator arm: No HIPEC Primary ovarian cancer FIGO stage II, III or IV or recurrent Cytoreductive surgery without HIPEC Procedure: No HIPEC

35 Primary Debulking Surgery vs. Neoadjuvant Chemotherapy Dose-Dense Weekly vs. 3-Weekly Paclitaxel Intraperitoneal Chemotherapy Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Maintenance PARP Inhibitors or Bevacizumab in Platinum-Sensitive Relapse

36 Antiangiogenic therapy Bevacizumab in Recurrent Ovarian Cancer: Platinum-Sensitive Relapse 2 positive trials Improved PFS by adding bevacizumab to platinum based chemo and subsequent maintenance therapy OCEANS: PFS CG+/-Bev HR 0.484; 95% CI , p<0.001 GOG 213: TC +/- Bev HR 0.61; 95%CI , p< Aghajanian C et al. J Clin Oncol 2012 Coleman RA et al. SGO 2015

37 Antiangiogenic therapy Bevacizumab in Recurrent Ovarian Cancer: Platinum-Resistant Relapse 1 positive trial Improved PFS by adding bevacizumab to non-platinum based chemo + QoL benefit in symptomatic pts. AURELIA: PFS NonPlat +/- Bev HR 0.48; 95% CI , p< AURELIA: Primary and sensitivity analysis of the primary hypothesis ( 15% improvement in symptomatic pts) Pujade-Lauraine E... Mirza MR et al. J Clin Oncol 2014 Stockler MR... Mirza MR et al. J Clin Oncol 2014

38 ENGOT-OV16 / NOVA Niraparib, as a selective PARP1/2 inhibitor, will provide a clinical benefit to all patients who have platinum-sensitive recurrent ovarian cancer who are in response to platinum, regardless of gbrca mutation status gbrcamut n 203 Platinum-Sensitive Recurrent High Grade Serous Ovarian Cancer Treatment with 4-6 Cycles of Platinum-based Therapy Response to Platinum Treatment n 553 Non-gBRCAmut n 350 2:1 Randomization 2:1 Randomization Niraparib 300 mg once daily Placebo Niraparib 300 mg once daily Placebo Treat until Progression of Disease Treat until Progression of Disease Mirza MR et al. N Engl J Med 2016;375:

39 ENGOT-OV16 / NOVA: PFS Phase 3 randomised trial of maintenance niraparib in platinum-sensitive high-grade serous relapse OC PFS: gbrcamut March 30 - April 2, 2014 Sheraton Sonoma PFS County Petaluma, Median California (95% CI) Treatment (Months) Niraparib 21.0 (N=138) (12.9, NE) 0.27 Placebo 5.5 (N=65) (3.8, 7.2) Hazard Ratio (95% CI) p-value (0.173, 0.410) p< % of Patients without Progression or Death 12 mo 18 mo 62% 50% 16% 16% Treatment Niraparib (N=234) Placebo (N=116) PFS: non-gbrcamut PFS Median (95% CI) (Months) 9.3 Hazard Ratio (95% CI) p-value (7.2, 11.2) (0.338, 0.607) (3.7, 5.5) p< % of Patients without Progression or Death 12 mo 18 mo 41% 30% 14% 12% Progression free Survival (%) Niraparib Placebo Time Since Randomization (months) Mirza MR et al. N Engl J Med 2016;375:

40 Available data from Maintenance Therapy in ovarian cancer Phase 3 NOVA 1 Phas 2 Study 19 2 Phase 3 SOLO2 3 gbrca patients Chemotherapy 6 months 5.5 n= n= n= n=74 Δ15-5 Δ6.9 Δ mo PFS 21 n= n=196 non-gbrca patients Chemotherapy 6 months 3.9 not studied n= n= n=57 n= mo PFS Δ5.4 Δ1.9 Phase 3 GOG213 5 OCEANS 6 BRCA status not determined Chemotherapy 6 months = = = = 8.4 n=242 n=337 n=242 n=337 Δ3.4 Δ4.0 Phase 3 ARIEL n= n=130 Δ11.2 not studied as a cohort PFS = progression free survival; BRCA = breast cancer gene Treatment Placebo 1. Mirza, M.R. et al., New England Journal of Medicine, vol. 375, no. 22, 2016, pp ; 2. Ledermann J. et al., Lancet Oncology, vol. 15, no. 8, 2014, pp ; 3. Pujade-Lauraine, E. et al., Lancet Oncology, vol. 18, no. 9, 2017, pp ; 4. Coleman, R.L. et al., Lancet, vol. 390, no , 2017, pp , 5. Coleman et al., Lancet Oncology, vol. 18, no. 6, 2017, pp ; 6. Aghajanian, C. et al., Journal of Clinical Oncology, vol. 30, no. 17, 2012, pp

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