17th ESO-ESMO Masterclass Clinical Oncology

Transcription

1 Epithelial Ovarian Cancer Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium 17th ESO-ESMO Masterclass in Clinical Oncology, Nauen OT Gross Behnitz (Berlin), Germany, March 24-29, 2018

2 Conflict of Interest Disclosure Participates in Advisory Boards of: Lecturer fee from: Amgen, AstraZeneca, Boehringer Ingelheim, Innate Pharma, Merck KGaA, Merck Sharp & Dome Corp, PCI Biotech, Synthon Biopharmaceuticals, Merck-Serono, Sanofi, Bristol Myers Squibb

3 Outline Epidemiology, risk factors, pathology and staging Standard management of early and advanced EOC Various ways to improve results beyond PAC-CARBO Potential roles of targeted therapies Types of relapsed ovarian cancer Strategies towards treatment of relapsed disease Take-home messages

4 Epithelial Ovarian Cancer Epidemiology Life-time risk is 1 in 54 The crude incidence of ovarian cancer in the European Union is 18/ women per year, the mortality is 12/ women per year The median age at diagnosis is 63 years. The incidence increases with age and peaks in the 8th decade. Between the age of years the age-specific incidence is 57/ women per year * ESMO minimum Clinical Recommendations 2008 and 2013 (Ann Oncol )

5 Epithelial Ovarian Cancer Risk factors Age, older Multiple pregnancies Nulliparity Breast feeding Early menarche Oral contraceptives Late menopause Tubal ligation Obesity and use of talcum Positive family history - first degree relative with OC 2 fold increased risk BRCA-1 mutation 15%-45% OC risk ( 85% BC risk) BRCA-2 mutation 10%-20% OC risk ( 85% BC risk) Ledermann et al. Ann Oncol 2013; 24 (suppl.6): vi24-vi32)

6 Common Epithelial Tumors Serous Endometrioid Clear cell Mucinous Brenner (transitional cell) Mixed epithelial tumors Undifferentiated Unclassified Ovarian Cancer Pathology Scully RE, Sobin LH, Serov SF, 1999 (WHO classification of Ovarian Epithelial Tumors)

7 Molecular Pathogenis in Ovarian Cancer Type 1* Low grade Early stage Slow growing Resistant to platinum-based therapy KRAS, BRAF, ERBB2, PTEN, PIK3A, ARID1A mu IGFR expression Wild-type p53 Type 2** High grade Advanced stage Agressive Responsive to platinum-based therapy Frequently associated with TP53 mutations BRCA1/2 mutations (20%) Activation of the PI3K pathway *Low grade serous, endometrioid, mucinous, clear cell and malignant Brenner: ** HGSC, HGEC, malignant MMT and undifferentiated tumors Bast Jr RC, Ann Oncol 2011 (Suppl 8): viii5-viii15; Ledermann JA, Ann Oncol 2013 (Suppl 6): vi24-vi32

8 Epithelial Ovarian Cancer: Subtypes HGSC CCC EC MC LGSC Percentages: FIGO I-II FIGO III-IV 39% 86% 33% 2% 22% 7% 5% 2% 1% 3% Genetic Risk BRCA1/2 HNPCC HNPCC None known None known Other Risk Factors Risk with OC, pregnancy None known Risk with OC, Risk with HRT None known None known Precursors STIC Endometriosis Endometriosis Unknown SBT Presentation Ascites, GI sxs Adnexal mass Adnexal mass Adnexal mass GI sxs Pattern of Spread Chemotherapy Response Molecular Genetics Targets Peritoneal, nodal Sensitive, then resistant p53, BRCA1/2, PI3K, HRD PARP, Angiogenesis Valencia Meeting 2015 (Bookman) Peritoneal, nodal, distal Peritoneal, nodal, distal Peritoneal +/- Pseudomyxoma Peritoneal, nodal Resistant Sensitive Resistant Resistant PI3K, ARID1A, MSI PTEN, catenin, ARID1A, MSI KRAS, HER2 Angiogenesis ER, PR, mtor HER2/neu BRAF, KRAS, NRAS BRAF, MEK/ERK

9 Ovarian Cancer: FIGO Staging Surgical exploration Diagnostic Vertical incision Peritoneal fluid cytology (or saline irrigation) Scrupulous inspection - right diaphragm - liver, serosa, parenchyma Biopsies of contralateral ovary, retroperitoneal LN and suspicious changes on the peritoneum, omentum Therapeutic Early disease TAH + BSO, omentectomy, LND Advanced disease debulking surgery

10 FIGO Staging (2008) Ovarian Cancer IA IB IC IIA IIB IIC III IIIA IIIB IIIC IV Confirmed to one ovary, no ascites, intact capsule Confirmed to both ovaries (same criteria as IA) IA or IB + tumor surface/capsule rupture/pos. cells Extension to the uterus or tubes Extension to other pelvic tissues IIA or IIB + tumor surface/capsule rupture/pos. cells One or both ovaries + extension outside pelvis or limited to true pelvis + extension to small bowel or omentum LN Θ, extension only microscopically LN Θ, extension not exceeding 2 cm in diameter LN + (RP/inguinal) and/or extension >2 cm in diameter One or both ovaries + DM (or parenchymal liver mets)

11 Epithelial Ovarian Cancer Milestones Surgery according to FIGO guidelines At least LND and peritoneal staging in early ovarian cancer Upfront maximal surgical debulking in advanced ovarian cancer Chemotherapy evolution Introduction of platinum compounds Introduction of taxanes The set-up of international collaboration (1997)

12 Management of Early-Stage Ovarian Cancer FIGO I-IIa Grade and completeness of staging are the most strongest prognostic factors Low risk patients do not need chemotherapy as an adjuvant treatment (5-yr survival 95%) High-risk patients do need adjuvant platinum-based chemotherapy: combined analysis of ICON-1 and ACTION trial* showed 5-yr OS 82%vs 74%, p=.008 Three vs six cycles: no significant difference in outcome, but recurrence rate with 6 cycles was 24% lower than with 3 cycles, and significantly more toxic** *Trimbos et al, JNCI 2003; **Bell et al, Gynecol Oncol 2006

13 GOG0157: Histologic Subsets Early-Stage HGSC should be treated similar to advanced-stage HGSC. The role of adjuvant chemotherapy in earlystage non-hgsc remains to be established. Chan JK, et al. Gynecol Oncol 116:301-6, 2010

14 Management of Advanced-Stage Ovarian Cancer Stages IIb-III (IV) Upfront radical cytoreductive surgery* In case this is not possible, a second attempt should be made Platinum-taxane based chemotherapy Six cycles No second-look 2nd Consensus Meeting 1998 Bergen (The Netherlands) *5th Consensus Meeting 2015 Tokyo (Japan): PCS or NACT ±ICS

15 Prognostic Factors in Advanced-Stage Ovarian Cancer Stages IIb-IV Postsurgery During Relapse Pre-chemotherapy Chemo Residual disease Type of chemo Time since last CT Performance status CA 125 fall** Disease bulk Stage Interval debulking Histology Grade No. disease sites Age Perf. Status Ascites Time since DX Histology Proliferation markers Quantitative pathol. features Ploidy Molecular markers* Eisenhauer EE et al. Ann Oncol 1999 (modified) *Bookman MA et al. Ann Oncol 2017 (including gbrca1/2 and sbrca1/2) ** McGee J et al. Ann Oncol 2017 (A failure of HE4 to normalize at completion of treatment indicator of poor prognosis)

16 Optimal Cytoreduction after PDS the Most Important Prognostic Factor in ADOVCA Bookman, M. A. et al. J Clin Oncol 2009 Du Bois et al. Cancer 2009

17 Stage III Disease: Role of Histology Data from GOG 111, 114,132, 142,158, 172 (IV only) Winter WE, J Clin Oncol 25: , 2007

18 Advanced Ovarian Cancer Treatment 3-weekly paclitaxel + carboplatin (TC) Generally agreed standard Control Arm of most recent randomized trials* No other regimen shown to outperform it However, results far from perfect: Median TTP: mo 5-Year OS: <35% *Bookman MA et al, Ann Oncol 2017; 28 (suppl 8): viii30-viii35 (Report of 5th OCCC, Tokyo, Japan [2015]);

19 How to Improve Outcome in Advanced OC Beyond PAC-CARBO Increase rate of optimal cytoreduction NACT followed by IDS of benefit for some patients Increase efficacy of cytotoxic chemotherapy Adding a third cytotoxic drug no OS benefit Maintenance/consolidation with cytotoxics no OS benefit Maintenance with targeted therapy improves PFS Dose-dense therapy with taxanes improves PFS/OS?? Modulate resistance modulating agents no benefit in the clinic Intraperitoneal chemotherapy improves OS (12 mo in OD pts) The use of targeted therapies anti-angiogenic compounds and PARP inhibitors beneficial

20 Selection of Patients for NACT Two trials of NACT-ICS vs PDS in advanced stage III and IV EOC similar poor outcome* NACT reduction in perioperative morbidity related to - venous thromboembolism - infection - wound healing Candidates for NACT bulky tumor deposits, large volume ascites, advanced physiologic age, comorbidities * Vergote et al. NEJM 2010; 363: and Kehoe et al. JCO 2013; 31: (suppl; abstr 5500)

21 Dose-Dense Weekly vs 3-weekly Paclitaxel Randomized trials Study Stages No. PFS/OS JGOG II-IV 637 mpfs 28.0 vs 17.2 mo* 3-yr OS 72.1 vs 65.1%** MITO-7 IC-IV 810 mpfs 17.3 (3 wkly) vs 18.3 mo (wkly) MRC-UK ICON8 IC-IV 1556 mpfs 17.9 (3wkly) vs 20.6 (T wkly) vs 21.1 (TC wkly) GOG262-ACRIN6695 II-IV 692 mpfs 14.7 vs 14.0 mo *p=0.0015; **p=0.03 JGOG (Katsumata et al, Lancet 2009; MITO (Pignata et al, Lancet 2014; ICON8 (Clamp et al ESMO 2017): GOG262-ACRIN6695 (NEJM 2016)

22 IPCT vs IVCT in Advanced Ovarian Cancer Overall survival Investigators No. of Overall survival (mo) year published pts Control arm Exp. Arm Alberts et al, Polyzos et al, Gadducci et al, Markman et al, Yen et al, Armstrong et al, p = 0.02; 2 p = 0.05; 3 p = 0.03

23 OS by Treatment and BRCA1 Expression GOG 172 Lesnock JL et al Br J Cancer :1231-7

24 IP Chemotherapy in ADOVCA It requires expertise and should be standard of care for optimally resected EOC Vermorken JB. Ann Oncol 2006; 17 (suppl. 10): x241-x246 Walker JL. Ann Oncol 2013; 24 (suppl. 10): x41-x45 patients

25 Stage II to IV ovarian, primary peritoneal, or fallopian tube cancer Including suboptimal Cases R A N D O M I Z E ipocc Trial Paclitaxel 80 mg/m 2 /1h IV, weekly, Cycles 1-6 Carboplatin AUC 6 IV, Day 1, Cycles 1-6 Paclitaxel 80 mg/m 2 /1h IV, weekly, Cycles 1-6 Carboplatin AUC 6 IP, Day 1, Cycles 1-6 Accrual: 655 pts (closed OCT2016) Primary Endpoint: PFS Secondary Endpoints: OS, Toxicity, QOL, Cost/Benefit

26 Studies with Neoadjuvant Chemotherapy followed by IPCT or HIPEC Provencher et al OV21/PETROC Van Driel et al. HIPEC study Ann Oncol 2018; 29: N Engl J Med 2018; 378; Arm 1: IV TC 3-weekly Three cycles NACT. When at least stable and debulkable Arm 2: IP cisplatin + paclitaxel IV (d1) and IP (d8) to 10 mm ICS either with or without HIPEC with Arm 3: IP carboplatin + paclitaxel IV (d1) and IP (d8) cisplatin 100 mg/m 2. Primary endpoint PD9 arm 3 vs arm 1 (24.5% vs 38.6%; p=0.065) Primary endpoint: PFS (HR %CI ;p=0.003)

27 Target Targeted Therapies in Ovarian Cancer ErbB kinases MUC1 / PEM MUC16 (CA 125) mtor / AKT PARP EpCAM Apoptosis pathway Angiogenesis Endothelial cells Drug(s) Gefitinib, erlotinib, lapatinib, canertinib, cetuximab, pertuzumab, matuzumab, trastuzumab Pemtumomab Oregovomab Temsirolimus, everolimus, deforolimus Oleparib, veliparib, nirapanib Catumaxomab AEG35156, OGX-011 Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib Combretastatin, Oxi4503 Matrix metalloproteinases BAY , marimastat

28 Primary and Subgroup Analysis of PFS According to Treatment Group Burger RA et al, N Engl J Med 2011; 365:

29 Primary Anti-vascular Therapy with Maintenance or Only Maintenance in OC Primary Endpoint Secondary Endpoint Maintenance duration GOG 218 First Line with Maintenance 1 PFS (RECIST/CA 125/ clinical) ICON 7 First Line with Maintenance 2 PFS (RECIST) Pazopanib Maintenance 3 PFS (RECIST) OS OS, RR OS, Safety, PFS by GCIG, 3 yr PFS, QOL 15 months maximum 12 months maximum 24 months maximum Stopping rules GCIG (CA125) RECIST PD RECIST PD Results (PFS in months) 6 months (censored for CA125 only events) 5.4 months (high risk subgroup) Results (OS) NS NS (all stages) NS 5.6 months 1 = Burger et al. NEJM 356: 2011, 2 = Perren et al. NEJM 365: 2011, 3=Dubois et al. ASCO 2013 (LBA 5503)/JCO 32:2014 Presented by: Paul Sabbatini, MD; ASCO 2013

30 ICON 7 Trial Final Outcome Results Survival of ICON 7 by Risk Group (High Risk: Residual disease >1 cm/ Stage IV) Oza et al Lancet Oncol 2015

31 Primary Anti-vascular Therapy with Maintenance or Only Maintenance in OC GI Perforation (> G 2) GOG 218 First Line with Maintenance 1 ICON 7 First Line with Maintenance 2 Selected Adverse Events (> G 3 unless specified) 0.2% 1.3% 0 Proteinuria 2.2% 1 % 1% HTN (> G 2) Pazopanib Maintenance 3 17 % 18 % 31 % (grade ¾) Diarrhea n/r 0% 8 % Liver toxicity n/r 0% 9 % Neutropenia 10 % 1 = Burger et al. NEJM 356: 2011, 2 = Perren et al. NEJM 365: 2011, 3=Dubois et al. LBA 5503 / JCO 2014

32 Recurrent Ovarian Cancer Vermorken JB. Second line randomized trials in epithelial ovarian cancer; Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66

33 Recommended Guidelines for Chemotherapy in Relapsed Ovarian Cancer Platinum resistant Platinum-free interval <6 months Non-platinum single agent: PLD, wkl paclitaxel, gemcitabine, topotecan Partially Platinum sensitive 6-12 months Combination chemotherapy: Platinum-based or trabectedin-pld Fully Platinum sensitive >12 months Carboplatin combination: PLD, paclitaxel, gemcitabine Valencia Meeting 2015 (E.Pujade-Laurain) PLD: pegylated liposomal doxorubicin

34 Trials of Anti-Angiogenic Therapy in ROC Platinum-refractory/resistant AURELIA trial* Single agent non-pt vs non-pt+bev PFS with combo MITO-11 trial** Wkly paclitaxel vs same plus pazopanib PFS with combo Platinum-sensitive disease OCEANS trial + GCx6 vs GC/bevx6 bevacizumab maintenance PFS ICON 6 trial ++ Pt-based CTx6 vs Pt-based CTx6 plus cediranib vs Pt-based CTx6+cediranib cediranib maintenance PFS. * JCO 2014; **Lancet Oncol 2015; + JCO 2012; ++ ECCO 2013; ASCO 2017

35 Two Noval Approaches in ROC with Potential Impact for First-line Treatment The use of PARP inhibitors - Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a key enzyme in the repair of DNA. Inhibition of PARP leads to accumulation of breaks in DS-DNA and cell death. - 30%-50% of HGSC may be susceptible to PARPi due to mutations in o other HR repair genes in inhibition of BRCA function Immunotherapy, using immune checkpoint inhibitors (ICIs) - There are currently no approved immune therapies in ovarian cancer

36 Randomized Trial of Maintenance Olaparib in Platinumsensitive High-Grade Serous Relapsed Ovarian Cancer Study aim and design Patients: Platinum-sensitive high-grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy was platinum-based to which they had a maintained PR or CR prior to enrolment Stable CA-125 Ledermann J, et al. N Engl J Med 2012;366: Olaparib 400 mg po bid Randomized 1:1 Placebo po bid 265 patients Primary end point : PFS Treatment until disease Progression

37 PFS in BRCA mutated patients Ledermann et al. Lancet Oncol. 2014;15(8): HR 0.18 (95% CI: )

38 Confirmatory Studies in Platinum-Sensitive ROC with Germline BRCA Mutation Study Drug formul. Pts Median PFS (HR) Ledermann Olaparib caps vs 4.3 (0.18) Pujade Olaparib tabl vs 5.5 (0.30) Coleman Rucaparib tabl vs 5.4 (0.23) Mirza Niraparib caps vs 5.5 (0.27) Ledermann Lancet Oncol 2014; Pujade Lancet Oncol 2017; Coleman Lancet Oncol 2017; Mirza NEJM 2016

39 Mirza MR et al. N Engl J Med 2016 Kaplan-Meier estimates of PFS Kap

40 Toxicity with Niraparib Most common grade 3 or 4 adverse events reported in the niraparib group were: - thrombocytopenia (33.8%) - anemia (25.3%) - neutropenia (19.6%) 14.7% of patients who received niraparib discontinued because of an AE (vs 2.2% with placebo) No on treatment deaths. During FUP 3 patients died from MDS or AML (1 in niraparib group, 2 in placebo group) Mirza et al. N Engl J Med, 2016

41 Randomized Trial of Olaparib ± Cediranib in Pt-sensitive relapsed ovarian cancer Dx platinumsensitive recurrent ovarian cancer BRCA mutation status Carrier Non-carrier Unknown Prior platinum-free interval 6-12 months >12 months Number of prior lines Randomize 1:1 Olaparib (N = 46) 24 (52.2%) 11 (23.9%) 11 (23.9%) 26 (56.5%) 20 (43.5%) 17 (37.0%) 18 (39.1%) 11 (23.9%) Olaparib capsules 400mg BID Cediranib 30mg daily + Olaparib capsules 200mg BID Cediranib/olaparib (N = 44) 23 (52.3%) 12 (27.3%) 9 (20.5%) 23 (52.3%) 21 (47.7%) 26 (59.1%) 10 (22.7%) 8 (18.2%) Disease progression by RECIST v1.1 criteria P-value Presented by J. Liu (ASCO 2014; LBA #5500) and discussed by JA Ledermann Published on-line in Lancet Oncology; September 10,

42 Combining Olaparib and Cediranib Increased overall response ( n=90) 47.8 % versus 79.6 % ( p=0.002) Improved progression-free survival Median PFS 9.0 versus 17.7 months ( HR 0.42; 95% CI ) Presented by J. Liu (LBA abstract #5500) and discussed by JA Ledermann Published on-line in Lancet Oncology: September 10, 2014

43 Algorithm for selecting biological therapy in PS-ROC 2017 BEV 1L: YES BRCA wt Carbo Combo BEV 1L: YES BRCA mut Carbo Combo Olaparib maintenance PFI > 6 months BRCA? Previous BEV 1L? BEV 1L: NO BRCA wt Carbo-Gem- BEV Carbo- Pacli-BEV Trabectedin-PLD If platinum is not an option Carbo-Gem- BEV Carbo- Pacli-BEV BEV 1L: NO BRCA mut Carbo Combo Olaparib maintenance

44 Basis for Immune therapy Immune Escape Presented by: Tanguy Seiwert Melero I et al. Clin Cancer Res 2013;19: Expression of PD-L1 on a) tumor cells & b) macrophages can suppress immune surveillance. In mouse models antibodies blocking PD-1 / PD-L1 interaction lead to tumor rejection Clinical prognosis correlates with presence of TILs and PD-L1 expression in multiple cancers.

45 Drugs Interacting with PD-L1/PD1 Pathway in Ovarian Cancer* Drug #Pts Previous lines Response % Nivolumab 20 4 in 55% 15 Pembrolizumab 26 5 in 38.5% 11.5 Avelumab in 65.3% 9.7 Atezolizumab 12 6 in 58% 25 Durvalumab 20 median 4 NR *From Pujade-Lauraine, ESGO 2016

46 Biological Agents integrated in First-line Trials: Impact? Study Trial Number Anti-A PARPi CPI Type drug Boost (AGO) NCT Bev 15 vs 30 mo MGOG3005 NCT Veliparib 3 arm CT+V M PAOLA-1 NCT Bev Olaparib Olaparib M added SOLO-1 NCT Olaparib Olaparib M (mbrca) PRIMA NCT Niraparib Niraparib M JAVELIN100 NCT Ave Ave M, Ave+CT+M IMAGYN50 NCT Bev Ate Ate M added to Bev Ledermann JA. 11th Valencia Symposium, 2017 (Ann Oncol 2017; 28 (suppl 8): viii46-viii50 Bev= bevacizumab; Ave= avelumab; Ate= Atezolizumab; M= maintenance

47 Incidence rates have fallen from between 1975 and 2013 from 16.3 to 11.4 per and death rates from 9.8 to 7.2 per (during on average a fall of 1.9% vs 2.2% each year for incidence and mortality, respectively). Presented by E.A. Eisenhauer at the Valencia meeting, March 3, 2017

48 Take-Home Messages (1) Upfront surgery 6 x TC-based CT standard for ADOVCA NACT with IDS reasonable alternative for some patients Three-weekly paclitaxel/carboplatin (TC) still standard IPCT is standard in patients with optimally resected EOC Anti-angiogenic agents added to cytotoxic therapy in first line may lead to survival benefit in far advanced disease

49 Take-Home Messages (2) Anti-angiogenic (AA) drugs of benefit in patients with ROC : true for bevacizumab, also for oral TKIs with AA proporties PARP inhibitors of benefit in patients with HGSC, in particular in patients with BRCAm Combining olaparib and cediranib may herald beginning of treatments that avoid cytotoxic chemotherapy in some OC pts Reactivation of immune surveillance by blocking PD1 interaction with its ligands a promising approach for OC?

50 HARBOR DIAMOND Thank you UZA DESIGN

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