NOVITA NEL TRATTAMENTO DELLE NEOPLASIE GINECOLOGICHE: OVAIO

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1 SUPERNOVAE IN ONCOLOGIA Pisa Novembre 2015 Domenica Lorusso Gynecologic Oncologic Unit National Cancer Institute-Milan NOVITA NEL TRATTAMENTO DELLE NEOPLASIE GINECOLOGICHE: OVAIO

2 % of Patients Surviving Five Years year survival rates % % % Year of Diagnosis

3 1995 The challenge of going beyond carboplatin/paclitaxel: key trials worldwide Trial n Regimens compared Outcome GOG Cis + either 24 h or 96 h pac Efficacy similar AGO-GINECO 1,282 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent MITO Carbo/pac x6 topo x4 or surveillance GOG IV cis/iv pac vs IP cis/ip pac No PFS benefit with topo maintenance IP has better efficacy/worse toxicity and QoL GCIG 887 Carbo/pac vs carbo/pac/epirubicin No benefit of a third agent AGO-GINECO 1,308 Carbo/pac topo x4 or surveillance No benefit of topo maintenance 2010 GOG GOG ,312 OV Cis/pac pac x3 vs x12 cycles in patients in CR Carbo/pac vs carbo/pac/gem (2 regimens) vs carbo/pac/topo vs carbo/pac/pld Carbo/pac x8 vs cis/topo x4 carbo/pac x4 PFS improved with pac x12 cycles/no OS difference in a selected patient population No benefit of a third agent Efficacy similar; tolerability better with carbo/pac AGO-OVAR9 1,742 Carbo/pac vs carbo/pac/gem No benefit of a third agent Carbo = carboplatin; cis = cisplatin; CR = complete response; cyclo = cyclophosphamide; gem = gemcitabine; IP = intraperitoneal; IV = intravenous; pac = paclitaxel; PLD = pegylated liposomal doxorubicin; topo = topotecan

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5 The Angiogenic Switch and Antiangiogenic Therapy Somatic mutation Small avascular tumor Tumor secretion of proangiogenic factors stimulates angiogenesis Rapid tumor growth and metastasis Angiogenic inhibitors may reverse this process

6 GOG Phase II studies: Response Rates Tumor Type Dose ORR (PR+CR) Ovarian Cancer 15mg/kg q3wk 16-21% Renal Cell 10mg/kg q2wk 10% Met Breast Cancer 3-20mg/kg q2wk 7% NHL 10mg/kg q2wk 5% CRC 10mg/kg q2wk 3% HRPC 10mg/kg q2wk 0%

7 Antiangiogenic agents in ovarian cancer: 10 positive randomized phase III trials in 4 years: First line Trial Chemotherapy Schedule PFS HR Bevacizumab GOG (n=1873) Paclitaxel Carboplatin Concurrent and maintenance 15 mg/kg q3w (3-arm placebo) 0.72 Bevacizumab ICON7 2 (n=1528) Paclitaxel Carboplatin Concurrently only 7.5 mg/kg q3w (2 arm) 0.81 Pazopanib AGO-OVAR 16 Paclitaxel carboplatin Only maintenance 800 mg (2 arm, placebo) 0.76 Nintedanib AGO-OVAR 12 Paclitaxel carboplatin Concurrent and maintenance (2 arm-placebo) 400 mg/die 0.84

8 Front-line: epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV N=1873 GOG-0218: Schema Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m 2 Placebo Carboplatin (C) AUC 6 Stratification variables Paclitaxel (P) 175 mg/m 2 GOG performance status Stage/debulking status Bevacizumab 15 mg/kg OV = ovarian; PP = primary peritoneal FT = fallopian tube; Bev = bevacizumab R A N D O M I S E 1:1:1 Bev 15 mg/kg Burger et al. ASCO 2010 Arm I (CP) II (CP + Bev) III (CP + Bev Bev) 15 months

9 Primary Endpoint: PFS Proportion surviving progression free CP (Arm I) + Bev (Arm II) Patients with event (%) Median PFS, months Arm I CP (n = 625) Arm II CP + Bev (n = 625) + Bev Bev maintenance (Arm III) Months since randomization Arm III CP + Bev Bev (n = 623) Hazard ratio One-sided p-value < With permission from Burger RA et al. Proc ASCO 2010;Abstract LBA1.

10 Proportion alive GOG-0218: Overall Survival Analysis At time of final PFS analysis Months since randomization ASCO 2010

11 OS estimate OS benefit is suggested with chemotherapy + Avastin and continued single-agent Avastin in stage IV disease CPP CPB CPB Deaths, n (%) Median survival (months) 93 (61) 99 (60) 81 (49) HR (95% CI) 0.98 ( ) 0.72 ( ) CPP (n=153) CPB15 (n=165) CPB15+ (n=165) Time (months) CPP CPB CPB Randall, et al. SGO 2013: Abstract 80 Randall, et al. SGO 2013: Abstract 80

12 Second line Antiangiogenic agents in ovarian cancer: 10 positive randomized phase III trials in 4 years: Platinum resistant Bevacizumab Aurelia 3 (n=361) Caelyx Topotecan Paclitaxel Concurrent 10 mg/kg q2w (2 arm) 0.48 Platinum resistant Pazopanib MITO 11 Weekly Paclitaxel Concurrent 800 mg/die 0.42 OS 0.6 Platinum resistant and partially sensitive Trebananinb Trinova 1 Weekly Paclitaxel Concurrent AMG mg/kg 0.66 Platinum sensitive Bevacizumab OCEANS 4 (n=484) Gemcitabine Carboplatin Concurrent 15 mg/kg q3w (2 arm) 0.48 Platinum sensitive Bevacizumab GOG 213 Carboplatin Paclitaxel Concurrent 15 mg/kg q3w (2 arm) 0.6 OS 0.8 Platinum sensitive Cediranib Icon 6 Carboplatin Paclitaxel Manteinance 0.57 OS 0.7

13 AURELIA (GINECO) Platinum-resistant OC, PP, FTC, (PFI <6 months) Prior bevacizumab allowed n=360 (4/2011) Chemotherapy to progression Chemotherapy to progression P R O G R E S S I O N Physician s choice: SOC or bevacizumab 15 mg/kg q3w SOC (Optional bevacizumab) Stratification variables: Chemotherapy regimen Previous anti-angiogenic therapy PFI <3 vs 3 6 months Bevacizumab 10 mg/kg q2w* to progression Chemotherapy options (physician s choice): Weekly paclitaxel 80 mg/m 2 Topotecan (4 mg/m 2 d1, 8, 15 OR 1.25 mg/m 2 d1 5 q3w) Pegylated liposomal doxorubicin 40 mg/m 2 d1 q4w Primary endpoint: PFS Secondary endpoints: ORR, PFI bio, OS, QoL, safety *15 mg/kg q3w if combined with topotecan q3w

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15 Overall survival (%) Paclitaxel cohort: OS CT (N=55) BEV + CT (N=60) Events, n (%) 41 (75) 36 (60) Median OS, months (95% CI) 13.2 ( ) 22.4 ( ) HR (unadjusted) (95% CI) 0.65 ( ) 25 No. at risk: CT BEV + CT Time (months)

16 OCEANS Platinumsensitive, recurrent OC, PP, FTC No prior bevacizumab n=480 Stratification variables: Time to recurrence Cytoreductive surgery Carboplatin AUC 4 Gemcitabine 1000 mg/m 2 d1/8 Placebo to progression Carboplatin AUC 4 Gemcitabine 1000 mg/m 2 d1/8 Bevacizumab 15 mg/kg to progression Primary endpoint: PFS Secondary endpoints: ORR, OS, DR, safety Exploratory endpoints: IRC, CA 125 response, ascites IRC present

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18 Proportion surviving progression-free GOG-0213: primary analysis of PFS Carboplatin + Paclitaxel (n=337) Carboplatin + Paclitaxel + Avastin (n=337) Events, n (Total) Median (months) HR, adj. (95% CI) ( ) p-value p<0.0001* % reduction in risk of PD or death Coleman, et al. SGO 2015 (Abstract 3)

19 Proportion surviving GOG-0213: primary analysis of OS Carboplatin + Paclitaxel (n=337) Carboplatin + Paclitaxel + Avastin (n=337) Events, n Median (months) HR, adj. (95% CI) ( ) 2 tailed p-value p= % reduction in risk of death 5-month difference in median overall survival, favouring Avastin arm Time (months on study) Coleman, et al. SGO 2015 (Abstract 3)

20 Limitations of OS analysis GOG 218 and AURELIA trials : 40% of patients initially randomised to CT alone crossed over to BEV monotherapy after progression AURELIA Study not powered to detect a statistically significant difference in the secondary endpoint, OS No systematic capture of post-progression therapy in no trial (except for BEV in the control arm)

21 Significant OS Improvements are More Difficult to Measure as Patients Survive Longer after Progression The chance of obtaining a significant OS improvement depends on the length of time that patients live after progression (post-progression survival [PPS]) 1 If PPS is longer than 12 months, there is a less than 30% chance that a trial will report a significant OS, even after reporting a PFS improvement at a high level of significance (p<0.001) 1 PPS is longer than 12 months in all three phase III trials of first-line Bevacizumab in mbc 2 4 The influence of PPS means that a lack of statistical significance in OS does not imply lack of improvement in OS 1 1. Broglio, Berry. J Natl Cancer Inst Gray, et al. J Clin Oncol Robert, et al. ASCO Miles, et al. SABCS 2009

22 Chemotherapy + Avastin with continued single-agent Avastin improves progression-free interval (cont d) The proportion of patients progression-free 6 and 12 months after last dose of carboplatin is increased with Avastin-based therapy (70.6 vs 52.7) at 6 months and (41.7 vs 25.9) at 12 months GOG analysis Randall, et al. SGO 2013: Abstract 287 Randall, et al. SGO 2013: Abstract 287

23 23 Study design Epithelial ovarian, fallopian tube or primary peritoneal cancer: Stage IIB IV Grade 3 stage I/IIA Clear-cell carcinoma (any stage) Carcinosarcoma Maximally debulked (prior neoadjuvant chemotherapy allowed) ECOG PS 0 2 Dec 2010 May 2012: 1021 patients enrolled IV carboplatin AUC 5 6 q3w (4 8 cycles) a IV paclitaxel 175 mg/m 2 d1 or 80 mg/m 2 d1, 8, 15 q3w (4 8 cycles) b BEV 15 or 7.5 mg/kg IV q3w for up to 36 cycles (2 years) or until disease progression or unacceptable toxicity Patients without progression at cycle 36 could continue therapy after discussion with the Steering Committee Primary endpoint: Safety (AEs by NCI-CTCAE version 4.03) Secondary endpoints: PFS, ORR, duration of response, overall survival Exploratory objectives: Optional translational research a Cisplatin permitted in patients with hypersensitivity to carboplatin b A change from one paclitaxel regimen to the alternative during the study was not permitted ECOG PS = Eastern Cooperative Oncology Group performance status; ORR = overall response rate

24 Estimated probability of PFS 24 PFS in ROSiA and ICON7 (ITT populations) 1.00 Caveats Differing tumour assessment schedules Prior neoadjuvant chemotherapy permitted in ROSiA ICON7 BEV 7.5 mg/kg + CP 1,2 ROSiA BEV 15 (or 7.5) mg/kg + CP Time (months) CP = carboplatin + paclitaxel 1 Avastin SmPC; 2 Roche data on file 2012 (ICON7 CSR addendum).

25 ENGOT Ov-15 Trial AGO-OVAR 17 Study Design 1:1 R N= 900 Bevacizumab 15mg/kg q21 days Paclitaxel 175 mg/m² Carboplatin AUC5 q21 days Bevacizumab 15mg/kg q21 days Paclitaxel 175 mg/m² Carboplatin AUC5 q21 days 15 months = 22 cycles 30 months = 44 cycles Strata macroscopic residual tumor (yes vs no) FIGO Stage (IIB-IIIC vs IV) Study Group Primary endpoint: PFS (non inferiority -> superiority) Main question: treatment duration Bev

26 Bevacizumab in ovarian cancer: four pivotal trials: Dose? Duration? Setting? First line Second line Platinum resistant Platinum sensitive Trial Chemotherapy Bevacizumab PFS HR GOG (n=1873) ICON7 2 (n=1528) Aurelia 3 (n=361) OCEANS 4 (n=484) Paclitaxel Carboplatin Paclitaxel Carboplatin Caelyx Topotecan Paclitaxel Gemcitabine Carboplatin Concurrent and maintenance 15 mg/kg q3w (3-arm placebo) Concurrently only 7.5 mg/kg q3w (2 arm) Concurrent 10 mg/kg q2w (2 arm) Concurrent 15 mg/kg q3w (2 arm) Burger et al. N Engl J Med Perren et al. N Engl J Med Pujade-Laurain et al. J Clin Oncol Aghajanian et al. J Clin Oncol 2012

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28 Histopathological subtypes of ovarian cancer Mucinous Clear cell High-grade serous Soslow. Int J Gynecol Pathol 2008 McCluggage. Pathology 2011

29 Ovarian cancer not one disease 8704 patients from 7 randomised trials Adenoca: adenocarcinoma Mackay et al. Int J Gynecol Cancer 2010

30 CARCINOMA OVAIO il punto di vista del patologo 5 TIPI ISTOLOGICI SIEROSO ALTO GRADO SIEROSO BASSO GRADO CELLULE CHIARE ENDOMETRIOIDE MUCINOSO SEDE ORIGINE presunta Tuba fimbria o metaplasia tubarica in cisti inclusione OSE Tumore Sieroso Borderline Endometriosi Adenofibroma Borderline Endometriosis Adenofibroma Borderline Adenoma Borderline Teratoma Richio Genetico BRCA1/2?? HNPCC? Stadio alla diagnosi Avanzato Precoce Avanzato Precoce Precoce Precoce ALTERAZIONI MOLECOLARI p53 p16 prb pathway BRAC-HRD BRAF or K-ras HNF-1β IL6/JAK2/STAT3 PI3K MSI PTEN; β-catenin, K-ras, MSI ARID1A K-ras HER2 ARID1A Risposta chemioterapia POTENZIALI TARGTES 80% 26-28% 15%? 15% PARPi Angiogenesi BRAF MEK Angiogenesi Come rene? Terap Ormo mtor Come colon?

31 50% of HGOC patients may have alterations in the HR pathway per TCGA Presented By Iain McNeish at 2015 ASCO Annual Meeting

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33 References/year BRCA-Ovarian cancers median survival Sporadic cancer Median survival Pharoah et al (BRCA1), 16 (BRCA2) months 19.5 months Aida et al months of DF Interval months of DF Interval Boyd et al months 25 months Cass et al months 54 months Johannsson et al % of BRCA1 pts at 5-years 45% control pts at 5-years Ben David et al months 37.8 months Zweemwer et al % 5-years 46% 5-years Ramus et al months BRCA1 49 months BRCA2 35 months Buller et al years 4.6 years Kringenm et al % BRCA1 5-years 23% 5-years Pal et al % BRCA1 4 years 87% BRCA2 4-years 12% 4 years Chetrit et al months 37.9 months

34 Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer Stan B. Kaye et al. JCO 2012;30:

35 Phase II prospective study on trabectedin in BRCA mutated and BRCAness phenotype advanced ovarian cancer patients: the MITO 15 trial Lorusso D, Ferrandina G, Pignata S, Sorio R, Pietragalla A, Mosconi A, Pisano C, Mangili G, Martinelli F, Masini C, Artioli G, Narducci F, Di Napoli M, Raspagliesi F, Scambia G Abstract #5530

36 Results PR n=46 PS n=42 CR (%) 0 4 (9.5) PR (%) 15 (32.6) 17 (40.5) ORR (%) 15 (32.6) 21 (50) SD (%) 12 (26.1) 10 (23.8) PD (%) 19 (41.3) 11 (26.2) Toxicities (% per cycle) Grade 3-4 Neutropenia 17.3 Leukopenia 7.7 Anemia 2.7 Thrombocytopenia 2.3 Grade 3 Transaminitis 5.2 PFS (weeks) OS (weeks) 40 NR CR, complete response; PR, partial response; ORR, overall response rate SD, stable disease; PD, progressive disease; PFS, progression-free survival; OS, overall survival Presented by: Domenica Lorusso

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39 Proportion of patients progression-free PFS by BRCAm status Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAm Placebo BRCAm BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months Time from randomization (months) HR= % CI (0.11, 0.31); P< % reduction in risk of disease progression or death with olaparib

40 Proportion of patients alive Study 19 updated overall survival: all patients Number at risk Randomized treatment Placebo Olaparib 400 mg bd Time from randomization (months) Overall population (n=265) Olaparib 400 mg bd 48 Placebo Deaths: total pts (%) 77:136 (56.6) 77:129 (59.7) Median OS, months HR= % CI (0.64, 1.21); 80% CI (0.72, 1.09) P=0.438 Placebo Olaparib 400 mg bd At the interim OS data cut-off (26 Nov 2012), 154/265 (58.1%) patients had died Interim OS analysis (38% maturity): HR=0.94; 95% CI, ; P=0.75

41 QoL in patients with a BRCAm FACT-O domain Olaparib Placebo TOI improved, n (%) 16/64 (25.0) 10/53 (18.9) Odds ratio (OR) >1 favours olaparib In patients with a BRCAm: OR, % CI , P=0.49 No statistically significant differences were observed in improvement rates or time to worsening of TOI, FOSI and Total FACT-O A numerically higher proportion of patients reported improvements in TOI, FOSI and Total FACT-O following treatment with olaparib vs placebo TOI, Trial Outcome Index; FACT-O, functional assessment of cancer therapy for ovarian cancer; FOSI, FACT-O Symptom Index Presented by: Jonathan Ledermann

42 Phase III trials with PARP inhibitors Recruiting: SOLO 1 and 2 (olaparib) Randomised maintenance trials in first line and platinum-sensitive recurrent BRCAm ovarian cancer NOVA (niraparib) Randomised maintenance trial following platinum-based chemotherapy in BRCAm and BRCAwt high-grade serous cancer ARIEL 3 (rucaparib) Randomised maintenance trial following platinum-based chemotherapy in BRCAm and BRCAwt high-grade serous cancer with companion diagnostic

43 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

44 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

45 Initial genomic LOH cutoff derived from public data and prospectively tested in ARIEL2 Presented By Iain McNeish at 2015 ASCO Annual Meeting

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

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

48 Primary efficacy analysis: PFS in BRCAmut and BRCA-like versus Biomarker Negative patients Presented By Iain McNeish at 2015 ASCO Annual Meeting

49 A Randomized Phase 2 Trial Comparing Efficacy of the Combination of the PARP-inhibitor Olaparib and the Anti-angiogenic Cediranib Against Olaparib Alone in Recurrent Platinumsensitive Ovarian Cancer Presented By Joyce Liu at 2014 ASCO Annual Meeting

50 Cediranib and olaparib have synergistic activity in vitro Presented By Joyce Liu at 2014 ASCO Annual Meeting

51 Study Design Presented By Joyce Liu at 2014 ASCO Annual Meeting

52 Primary Outcome: Cediranib/olaparib significantly increased PFS compared to olaparib alone Presented By Joyce Liu at 2014 ASCO Annual Meeting

53 Cediranib/olaparib significantly increased PFS in patients without a BRCA mutation Presented By Joyce Liu at 2014 ASCO Annual Meeting

54 Response to platinum-based chemotherapy in Platinum-sensitive relapsed ovarian cancer Presented By Jonathan Ledermann at 2014 ASCO Annual Meeting

55 Platine, Avastin and OLAparib in 1 st line of advanced high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer Randomized, double-blind, Phase III Trial of olaparib vs. placebo in patients with advanced high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with standard first-line treatment, combining platinum-taxane chemotherapy and bevacizumab concurrent with chemotherapy and in maintenance.

56 Recurrent platinum sensistive trial: ICON 9 Randomised Trial of Cediranib and Olaparib Maintenance in Patients with Relapsed Platinum Sensitive Ovarian Cancer Shibani Nicum and Jonathan Ledermann For the NCRI Clinical Studies Group

57 PD-1/ PD-L1 pathway in suppressing anti-tumor immunity Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

58 Efficacy and safety of anti-pd-1 antibody (Nivolumab: BMS , ONO-4538) in patients with platinum-resistant ovarian cancer Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

59 Clinical Effect : Best Overall Response Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

60 A Responder with Clear cell carcinoma :<br />Nivolumab 3mg/kg Presented By Junzo Hamanishi at 2014 ASCO Annual Meeting

61 BRCA and Ovarian cancer: conclusions Treatment according to histotype is the future! Antiangiogenic therapies and PARP inhibitors are changing the treatment algorytm of ovarian cancer Up to 50% of high grade serous and endometrioid tumors present a malfunctioning of HR In up to 30% of patients without a family history of breast and ovarian cancer BRCA genes are mutated Olaparib and Cediranib combination the first non chemotherapy treatment in recurrent platinum sensitive disease and a promising combination The future is very dynamic!!!!