Giusi Blanco

Five years survival

Ovarian cancer is not a single disease

High-grade serous ovarian cancer

•TP53: encodes a protein that

regulates the cell cycle

•BRCA1 and BRCA2: encode

proteins that are involved in

genome protection

Low-grade

serous

BRAF; KRAS

Mucinous

carcimoma

KRAS

Endometrioid

carcinoma

PTEN (low-grade);

TP53; BRCA 1/2

Clear cell

carcinoma

PTEN; PIK3CA;

ARID1A

Other subtypes

70%

2% 15%5% 5%

Ovarian cancer - not one disease: Outcome depends on histiotype

▪ GOG trials 111, 114, 132, 152, 158, 172

PF

S p

rob

ab

ilit

y

Time on study (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60

PFS

Serous 199 1.193 1.392Endometrioid 33 133 166Clear cell 15 47 62Mucinous 5 29 34

NP P Total

PF

S p

rob

ab

ilit

y

Time on study (months)

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60

OS

Serous 412 980 1.392NP P Total

Endometrioid 60 106 166Clear cell 21 41 62Mucinous 6 28 34

With/Without bevacizumab15 mg/kg for 15 months…

PLATINUM RESISTANT(PFI <6 months)

• Chemo + bevacizumab

• Monochemotherapy

• Clinical trials

PLATINUM SENSITIVE (PFI >12 months)

• Platinum based combinations

• Platinum-gemcitabine-bevacizumab

• Platinum based combination followed byolaparib (if BRCA mutated patient and if PR/CR)

• Non platinum combination if platinum contraindicated

• Trabectedin-PLD

• CEDIRANIB ICON-6

PLATINUM PARTIALLY SENSITIVE (6<PFI<12 months)

• Platinum based combinations

• Platinum-gemcitabine-bevacizumab

• Platinum based combination followed by olaparib(if BRCA mutated patient and if PR/CR)

• Non platinum combination

• Trabectedin-PLD

Olaparib can be used at every platinum sensitive

recurrence

Bevacizumab can be used only at first platinum sensitive recurrence

ADVANCED STAGE IIIB-C and IV OVARIAN CANCER

Carboplatin AUC 5 + paclitaxel 175 mg/m2

q21 x 6 cycles

In label but notreimbursed at the

moment

It can be used at firstor second platinumresistant recurrence

FRONT-LINE

Looking at the future: Ovarian cancer treatment algorithm

GOG 218

Chemo +bevacizumab

ICON7

Chemo + bev + olaparib

PAOLA 1 1WT M+

Chemo ± bevacizumab(if Mito 16-MaNGO-02 positive)

Chemo +bevacizumab

AURELIAplatinumresistant

OCEANSplatinumsensitive

Disease progression

Universal BRCA testing

Stage IIIb–IV

Chemo + olaparib

SOLO1

Ovarian cancer «Wilde Type»

FIRST LINE TREATMENT ALGORITHM

12 24 36

CP (arm I)CP + BEV (Arm II)

Pro

port

ion s

urv

ivin

g

Pro

gre

ssio

n-f

ree

Months since randomization

CP + BEV ➔ BEV (Arm III)

GOG-0218: Investigator-assessed PFS

1.0

0.5

0

12 24 36

Control

Pro

port

ion a

live

without

pro

gre

ssio

n

Time (months)

Research

ICON 7: Updated PFS

Four positive trials with antiangiogenic agents in front line

Not approved12 24 36

1.0

0.5

0

Pro

gre

ssio

n-f

ree s

urv

ival

Months since randomization

AGO-OVAR-12: Primary endpoint

TC + Nintedanib (n=911)

TC + Placebo (n=455)

12 24 36

1.0

0.5

0

Pro

gre

ssio

n-f

ree

surv

ival

Months since randomization

AGO-OVAR-16: Primary endpoint

Pazobanib

Placebo

Bevacizumab

PazopanibNintedanib

1.0

0.5

0Bevacizumab

PFS 14.1 vs 11.2

ICON 7

0 6 12 18 24 30 36 42 48 54 60

Pro

po

rtio

n a

liv

e

Time (months)

Modified ICON7

high-risk final OS

9.4

1.0

0.75

0.5

0.25

0.00

Control

Research

No. at risk

Control 254 208 156 101 82 21

Research 248 224 180 153 95 27

No. at risk

Control 254 109 43 24 18 6

Research 248 175 53 32 23 5

Come selezionare le pazienti

0 6 12 18 24 30 36 42 48 54 60

Pro

po

rtio

n a

liv

e w

ith

ou

t

pro

gre

ssio

n

Time (months)

Modified ICON7

high-risk PFS 2013 update

1.0

0.75

0.5

0.25

0.00

Control

Research

10.5 16.0 30.3 39.7

ICON7: Histological subgroup analyses using retrospective 63-gene

immune signature

CPCP + BEV

PF

S p

rob

abil

ity

(%)

Time (months)

"Immune subgroup" 41% (n=116)

0 10 20 30 40 50 60

100

80

60

40

20

0

PF

Sp

rob

abil

ity

(%)

Time (months)

"Pro-angiogenic subgroup" 59% (n=168)

0 10 20 30 40 50 60

100

80

60

40

20

018.5 35.8 12.3 17.4

CPCP + BEV

CPCP + BEV

OS

pro

bab

ilit

y(%

)

Time (months)

"Immune subgroup" 41% (n=116)

0 10 20 30 40 50 60

100

80

60

40

20

0

Univariate HR 2.00 (1.11–3.61), p=0.022

Multivariate HR 2.37 (1.27–4.41), p=0.007

OS

pro

bab

ilit

y(%

)

Time (months)

"Pro-angiogenic subgroup" 59% (n=168)

0 10 20 30 40 50 60

100

80

60

40

20

0

CPCP + BEV

Univariate HR 1.19 (0.80–1.78), p=0.386

Multivariate HR 1.10 (0.73–1.66), p=0.637

Test for interaction, p=0.015

Test for non-proportionality negative in both molecular subgroups

ICON7: Retrospective molecular TCGA subgroup analyses by the AGO

group

Proliferative and mesenchymal subtypes appeared to benefit most from the addition of bevacizumab

Pro

po

rtio

n a

live

wit

ho

ut

pro

gre

ssio

n

0

0.4

0.6

0.8

1.0

0.2

0

11.8

24 36 48

Time (months)

Pro

po

rtio

n a

live

wit

ho

ut

pro

gre

ssio

n

0 12 24 36 48

Time (months)

Proliferative

Immunoreactive

Pro

po

rtio

n a

live

wit

ho

ut

pro

gre

ssio

n

0 12 24 36 48

Time (months)

Pro

po

rtio

n a

live

wit

ho

ut

pro

gre

ssio

n

0 12 24 36

Time (months)

Mesenchymal

Differentiated

0

0.4

0.6

0.8

1.0

0.2

0

0.4

0.6

0.8

1.0

0.2

0

0.4

0.6

0.8

1.0

0.2

Bevacizumab

Control

21.9 12.4 20.6

17.0 20.8 17.9 21.6

Bevacizumab

Control

Bevacizumab

Control

Bevacizumab

Control

12

CP = carboplatin + paclitaxel

Caveats

• Differing tumour assessment schedules

• Prior neoadjuvant chemotherapy permitted in ROSiA

MITO 25 STUDY DESIGN

Primary end point: PFSSecondary end point :OS, ORR, PFS2

Summary for first line treatment of ovarian cancer

Treatment of

Platinum–sensitive relapse

Bevacizumab: Oceans study

Oceans Response Rate Results

CEDIRANIB

CEDIRANIB

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial

Laederman,Lancet 2016; 387: 1066–74

IMPLICAZIONI FUTURE

Summary for platinum–sensitive recurrence ovarian cancer

✓ Bevacizumab able to prolong PFS when associated to chemotherapy ( Carboplatino+ Gemcitabine)

✓ Cediranib able to prolong PFS when associated to caboplatin and paclitaxel

✓ Bevacizumab able to prolong PFS beyond progression

Treatment of platinum-resistant relapse

AURELIA TRIAL

Lauraine E JCO ,32-13, 2014

Mito-11

Primary end point : PFS

The investigators concluded: “The

combination of pazopanib plus paclitaxel is

not superior to paclitaxel in women with

recurrent ovarian cancer.”

Trinova trial

MONK JB ,Lancet 2014

ADVERSE EVENT TREBANANIB+CHT PLACEBO+CHT

OEDEMA 64% 28%

ASCITES 52% 8%

NEUTROPENIA 9% 6%

ABDOMINAL PAIN

5% 5%

Trinova trial

Conclusion:

✓ Treatment according to histotype is the future

✓ Antiangiogenic agents and parp inhibitors are changing the

natural history of ovarian cancer disease

✓ The best treatment algorytm is the one wich allows patients to

receive all the available and effective treatment options

GRAZIE

Paola-1