Epithelial Ovarian Cancer (EOC)

Jan B. Vermorken, MD, PhD

Department of Medical Oncology

Antwerp University Hospital

Edegem, Belgium

6th ESO-ESMO-EEBR Masterclass in Medical Oncology, Split, Croatia, April 12-17, 2019ESO-ESMO E

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Conflict of Interest Disclosure

• Participated in Advisory Boards of:

AstraZeneca, Boehringer Ingelheim, Debiopharm

Innate Pharma, Merck Serono, Merck Sharp &

Dome Corp, PCI Biotech, Synthon

Biopharmaceuticals, WntResearch

• Lecturer fee from:

MSD, Merck-Serono, Sanofi, and BMS

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Epithelial Ovarian Cancer

Epidemiology

• Life-time risk is 1 in 54

• The crude incidence of ovarian cancer in the European

Union is 18/100.000 women per year, the mortality is

12/100.000 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 70-74 years the age-specific

incidence is 57/100.000 women per year

* ESMO minimum Clinical Recommendations 2008 and 2013 (Ann Oncol )ESO-ESMO E

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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)

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Epithelial Ovarian Cancer: Histologic 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,

pregnancyNone known

Risk with OC,

Risk with HRTNone known None known

Precursors STIC Endometriosis Endometriosis Unknown SBT

Presentation Ascites, GI sxs Adnexal mass Adnexal mass Adnexal mass GI sxs

Pattern of

Spread

Peritoneal,

nodal

Peritoneal,

nodal, distal

Peritoneal,

nodal, distal

Peritoneal +/-

Pseudomyxoma

Peritoneal,

nodal

Chemotherapy

Response

Sensitive, then

resistantResistant Sensitive Resistant Resistant

Molecular

Genetics

p53, BRCA1/2,

PI3K, HRD

PI3K, ARID1A,

MSI

PTEN,

catenin,

ARID1A, MSI

KRAS, HER2BRAF, KRAS,

NRAS

TargetsPARP,

AngiogenesisAngiogenesis ER, PR, mTOR HER2/neu

BRAF,

MEK/ERK

Valencia Meeting 2015 (Bookman)

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Epithelial Ovarian Cancer

Milestones

• Surgery according to FIGO guidelines

– 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

– Targeted therapy

• The set-up of the GCIG in 1997

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Incidence rates have fallen from between 1975 and 2013 from 16.3 to 11.4 per 100.000 and death rates from 9.8 to 7.2 per

100.000. (during 2004-2013 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

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Prognostic Factors and 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

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GOG0157: Histologic Subsets

Chan JK, et al. Gynecol Oncol 116:301-6, 2010

• “Early-Stage” HGSC should be treated similar to

advanced-stage HGSC.

• The role of adjuvant chemotherapy in early-

stage non-HGSC remains to be established.

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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-based chemotherapy

• Six cycles

• No second-look

Consensus meeting, 1998 Bergen (the Netherlands)

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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 et al, 1999 (modified)

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Stage III Disease: Role of Histology

Winter WE, J Clin Oncol 25:3621-3627, 2007

Data from GOG 111, 114,132, 142,158, 172 (IV only)

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Advanced Ovarian Cancer

1998-2019 Treatment

• 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: 12-18 mo

– 5-Year OS: <35%

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Improvement Strategies in Advanced OC

Beyond paclitaxel/carboplatin

• 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

- Dose-dense therapy with taxanes improves PFS/OS?

- High-dose chemotherapy with ABMT→ no OS benefit

• 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 beneficialESO-ESMO E

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Targeted Therapies in Ovarian Cancer

Target Drug(s)

ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab,

pertuzumab, matuzumab, trastuzumab

MUC1 / PEM Pemtumomab

MUC16 (CA 125) Oregovomab

mTOR / AKT Temsirolimus, everolimus, deforolimus

PARP Oleparib, veliparib, nirapanib, rucaparib

EpCAM Catumaxomab

Apoptosis pathway AEG35156, OGX-011

Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib

Endothelial cells Combretastatin, Oxi4503

Matrix metalloproteinases BAY 12-9566, marimastat

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Primary Anti-vascular Therapy with

Maintenance or Only Maintenance in OCGOG 218 First Line

with Maintenance1

ICON 7 First Line

with Maintenance2

Pazopanib

Maintenance3

Primary

Endpoint

PFS (RECIST/CA

125/ clinical)

PFS (RECIST) PFS (RECIST)

Secondary

Endpoint

OS OS, RR OS, Safety, PFS

by GCIG, 3 yr

PFS, QOL

Maintenance

duration

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)

5.6 months

Results (OS) NS NS (all stages) NS

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

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ICON 7 Trial

Final Outcome Results

Oza et al Lancet Oncol 2015

Survival of ICON 7 by Risk Group

(High Risk: Residual disease >1 cm/ Stage IV)

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Recurrent Ovarian Cancer

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Partially Platinum

sensitive

6-12 months

Recommended Guidelines for Chemotherapy

in Relapsed Ovarian Cancer

Fully Platinum

sensitive

>12 months

Combination

chemotherapy:

Platinum-based or

trabectedin-PLD

Carboplatin

combination:

PLD, paclitaxel,

gemcitabine

Platinum

resistant

Platinum-free

interval <6 months

Non-platinum

single agent:

PLD, wkl paclitaxel,

gemcitabine,

topotecan

PLD: pegylated liposomal doxorubicinValencia Meeting 2015 (E.Pujade-Laurain)

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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

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Impact of Germline BRCA1/2 Mutations and

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.

• Germline BRCA1/2 mutations are prognostic, and identify a population

with improved outcomes, regardless of treatment

• Mutations are also predictive for response to DNA-targeted

chemotherapy (in general) and PARP inhibitors (in particular)

• PARP inhibitors might also be effective in high-grade serous tumors

with BRCAness (loss of BRCA function)

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Randomized Trial of Maintenance Olaparib in Platinum-

sensitive High-Grade Serous Relapsed Ovarian Cancer

‘

Olaparib

400 mg po bid

Randomized 1:1

Placebo

po bid

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

Treatment

until

disease

Progression

Study aim and design

Primary end point : PFS

265 patients

Ledermann J, et al. N Engl J Med 2012;366:1382–92

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PFS in BRCA mutated patients

HR 0.18 (95% CI: 0.10-0.31)

Ledermann et al. Lancet Oncol. 2014;15(8):852–861

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Confirmatory Studies in Platinum-Sensitive

ROC with Germline BRCA Mutation

Study Drug formul. Pts Median PFS (HR)

• Ledermann Olaparib caps 136 11.2 vs 4.3 (0.18)

• Pujade Olaparib tabl 295 19.1 vs 5.5 (0.30)

• Coleman Rucaparib tabl 196 16.6 vs 5.4 (0.23)

• Mirza Niraparib caps 203 21.0 vs 5.5 (0.27)

Ledermann Lancet Oncol 2014; Pujade Lancet Oncol 2017; Coleman Lancet Oncol 2017; Mirza NEJM 2016ESO-ESMO E

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Olaparib

(N = 46)

Cediranib/olaparib

(N = 44)

P-value

BRCA mutation status

Carrier

Non-carrier

Unknown

24 (52.2%)

11 (23.9%)

11 (23.9%)

23 (52.3%)

12 (27.3%)

9 (20.5%)

0.92

Prior platinum-free interval

6-12 months

>12 months

26 (56.5%)

20 (43.5%)

23 (52.3%)

21 (47.7%)

0.83

Number of prior lines

1

2

3+

17 (37.0%)

18 (39.1%)

11 (23.9%)

26 (59.1%)

10 (22.7%)

8 (18.2%)

0.11

Randomized Trial of Olaparib ± Cediranib

in ‘Pt-sensitive’ relapsed ovarian cancer

Dx platinum-

sensitive

recurrent

ovarian cancer

Randomize 1:1

Cediranib

30mg daily +

Olaparib

capsules

200mg BID

Olaparib

capsules

400mg BID

Disease

progression by

RECIST v1.1

criteria

Presented by J. Liu (ASCO 2014; LBA #5500) and discussed by JA Ledermann

Published on-line in Lancet Oncology; September 10, 2014

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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 -.23-0.76)

Presented by J. Liu (LBA abstract #5500) and discussed by JA Ledermann

Published on-line in Lancet Oncology: September 10, 2014

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PARP-inhibitors Moving to First-Line*

Study PARPi Type of study

GOG3005 (Abbvie) veliparib TC+placebo→placebo vs

TC+veliparib →placebo vs

TC+veliparib→veliparib

PAOLA-1 (GINECO) olaparib TC+Bev→Bev+olaparib vs

TC+Bev→Bev+ placebo

SOLO-1 (AZ) olaparib Olaparib vs placebo maintenance

in BRCAm OC after Pt-based CT

PRIMA (tesaro) niraparib Niraparib vs placebo maintenancei

in BRCAm OC after Pt-based CT

Vermorken JB. ONCOhemato 2018

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SOLO-1: Study Design

Randomise

2:1 at end of

chemotherapy

N=344

Olaparib 300mg

bid

until

progression

Placebo bid

until

progression

Newly

diagnosed

Stage III-IV

CR/PR/no

evidence of

disease

upon

completion

of 1st line

platinum

PF

S

OSuntil progression

(Max. 2 yrs for CR)

Primary Endpoint:

PFS (RECIST, BICR)

Key Secondary Endpoints

• OS, PFS2

• TFST, TSST, TDT

• HRQoL

• Safety

Moore, N Engl J Med, 2018. 379(26): p. 2495-2505ESO-ESMO E

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Moore, N Engl J Med, 2018; 379: 2495-2505

SOLO-1: Progression-free Survival

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Basis for Immune Therapy – Immune Escape

Melero et al. Clin Cancer Res 2013; 19: 997-1008

Concept and examples of agonist and antagonist mAbs

directed toward activatory or inhibitory receptors of

immune system cells;

Antibodies blocking PD-1/PD-L1 interaction lead to

tumor rejection in mouse models

Clinical prognosis correlates with presence of TILs and

PD-L1 expression in multiple cancers

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Drugs Interacting with PD-L1/PD1

Pathway in Ovarian Cancer*

Drug #Pts Number of ORR ORR ORR

Previous line PD-L1+ PD-L1-

% % %

Nivolumab 20 ≥ 4 in 55% 15 12.5 25

Pembrolizumab 26 ≥ 5 in 38% 11.5 11.5 -

Avelumab 124 ≥ 3 in 65% 9.6 11.5 7.9

Atezolizumab 12 ≥ 6 in 58% 25 - -

Durvalumab 20 median 4 NR

*From Pujade-Lauraine, ESGO 2016 and Gonzalez Martin, Valencia 2019ESO-E

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class

2019

Negative Trials with Avelumab in ROC

Javelin 200 study Javelin 100 study

Negative Press release 19 November 2018 Negative Press release 21 December 2018

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Rationale for Combining Anti-VEGF or PARPi

with IO drugs

Presented by Gonzalez Martin at the Valencia Meeting, February 2019

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Algorithm for selecting biological therapy in PS-ROC

2018

Trabectedin-PLD

If platinum is not an option

PFI > 6 months

BRCA?

Previous BEV 1L?

BEV 1L: YES

BRCA wt

Carbo Combo

BEV 1L: YES

BRCA mut

Carbo Combo

Olaparibmaintenance

BEV 1L: NO

BRCA wt

Carbo-Gem-BEV Carbo-Pacli-BEV

BEV 1L: NO

BRCA mut

Carbo-Gem-BEV Carbo-Pacli-BEV

Carbo Combo

Olaparibmaintenance

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Take-Home Messages (1)

• Upfront surgery 6 x TC-based CT standard for ADOVCA

• NACT with IDS reasonable alternative for some patients

• Three-weekly TC is still standard

• IPCT is a 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

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Galuzzi et al. Oncotargets 2014

Ckeck-pointinhibitors

Anti-cancervaccines

AntibodyDrug

Conjugates

Presented at Valencia Meeting, February 2019

by Gonzalez Martin

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Mirvetuximab Soravtansine (IMGN853)

High affinity, humanized FRbinding MAb

sulfo-SPDB Linker• stable in the circulation• optimized to resist MDR, promote bystander cell killing

DM4 payload• maytansine derivative with anti-microtubule activity• 100-1000-fold more potent than vinca alkaloids• ~3.4 DM4/MAb

Presented at Valencia Meeting, February 2019 by Gonzalez Martin

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Mirvetuximab SoravtansinePhase I data

46 Platinum-resistantpatients

FRα positivity by IHC (≥ 25% of tumor cells)

6.0 mg/kg (AIBW)

ORR 26%

(1CR/11PR)

Median PFS 4.8 months

Median DOR 19.1 weeks

K. Moore et al. J Clin Oncol 35, no. 15_suppl (May 20 2017) 5547.K Moore et al. J Clin Oncol 2017 Apr 1;35(10):1112-1118

FRα positivity by IHC ≥ 50%

Presented at Valencia Meeting, February 2019 by Gonzalez Martin

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42

DCVAC manufacturing and

treatment cycle

• Single leukapheresis at qualified

centers

• Monocytes are enriched and grown

ex vivo into immature dendritic

cells (DCs)

• Tumor cell lines (different for each

indication) are prepared and killed

by immunogenic cell death

• DC Maturation: Immature DCs are

pulsed with HHP-killed tumor cells

• Mature DCs express on the surface

antigens from selected tumor cells

• ≥15 doses of DCVAC are

produced and frozen

• Patient receives DCVAC on an

ongoing basis

1

2

3

4

5

6

7Tumor cell lines killed by

High Hydrostatic Pressure (HHP)

Kloudova et al., Oncotarget, 2016 Jul 19;7(29):46120-46126

Fucikova et al., J Transl Med., 2011 Dec 30;9:223

Urbanova et al., Immunology Letters, 2017, 187: 27–34

+ IL-4

+ GM-CSF

CD80

CD86

CD83

MHC-II

IL-1β, NO

IL-6, IL-12

IL-10

DCVAC Cellular Immunotherapy Platform

Presented at Valencia Meeting, February 2019 by Gonzalez Martin

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Study Design in First-Line Setting

Presented By Lukas Rob at 2018 ASCO Annual Meeting

SOV01

Presented at Valencia Meeting, February 2019 by Gonzalez Martin

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PFS<br />~ 6-month Benefit in mPFS and 57% Decrease<br />in The Hazard of Progression in Arm B

Presented By Lukas Rob at 2018 ASCO Annual Meeting

Presented at Valencia Meeting, February 2019 by Gonzalez Martin

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OS<br />A Trend Towards Improved OS in Arm B

Presented By Lukas Rob at 2018 ASCO Annual Meeting

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Phase II, randomized, open-label, parallel group, multi-center clinical trial

of DCVAC/OvCa added to standard chemotherapy in women with

relapsed platinum-sensitive epithelial ovarian carcinoma

Patients

N=711:1 randomization

Women with ovarian carcinoma who had

complete remission after first-line platinum-based chemo, had confirmed

relapse after >6 months of remission, and were

selected to receive second-line chemo

Regimen

Group A:DCVAC/OvCa + standard

chemotherapy (carboplatin and gemcitabine)

Group B:Standard chemotherapy

(carboplatin and gemcitabine)

End Points

Primary: PFS 18 monthsafter randomization

Secondary/exploratory:OS, ORR, biological PFI, immune response, AEs,

changes in QoL (FACT-O)

Study

2012 2013 2014 2015 2016 2017 2018 2019 2020 2021

First patient in Last patient in Primary analysis Final OS analysis performed in August 2018

SOV02: Concomitant DCVAC/OvCa with Chemo in Relapsed Platinum-Sensitive Ovarian Carcinoma

Selected for oral presentation at the2019 SGO

ENGOT lead pivotalphase III trial underdiscussion

Presented at Valencia Meeting, February 2019 by Gonzalez Martin

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Immunomodulatory MoAbCheck-point inhibitors

PD-1

CTLA-4

Inhibitory Receptors*Activating Receptors*

TIM-3

LAG-3

Checkpoint Inhibitors

Agonistic Antibodies

CD27

OX40

CD137

TremelimumabIpilimumab

Nivolumab PembrolizumabDurvalumab†,

Atezolizumab†, and Avelumab†

(PD-L1)

BMS-986016

MOXR0916

Urelumab

T cell

Varlilumab

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