L ’anti-angiogenetico nel trattamento del carcinoma ovarico: la prima linea, la seconda linea e oltre la progressione

(1)

Giusi Blanco

(2)

Five years survival

(3)

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%

(4)

Ovarian cancer - not one disease: Outcome depends on histiotype

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

P FS proba bili ty

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 1.392 Endometrioid 33 133 166 Clear cell 15 47 62

Mucinous 5 29 34

NP P Total

P FS probabil ity

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 1.392

NP P Total

Endometrioid 60 106 166 Clear cell 21 41 62

Mucinous 6 28 34

(5)

With/Without bevacizumab 15 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 by

olaparib

(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/m

²

q21 x 6 cycles

In label but not reimbursed at the

moment It can be used at first

or second platinum

resistant recurrence

(6)

FRONT-LINE

Looking at the future: Ovarian cancer treatment algorithm

GOG 218

Chemo + bevacizumab

ICON7

Chemo + bev + olaparib

PAOLA 1 1

WT M+

Chemo ± bevacizumab

(if Mito 16-MaNGO-02 positive)

Chemo + bevacizumab

AURELIA platinum resistant OCEANS

platinum sensitive

Disease progression

Universal BRCA testing Stage IIIb–IV

Chemo + olaparib

SOLO1

(7)

Ovarian cancer «Wilde Type»

(8)

FIRST LINE TREATMENT ALGORITHM

(9)

(10)

12 24 36

CP (arm I)

CP + BEV (Arm II)

Proportion surviving Progression-free

Months since randomization CP + BEV ➔ BEV (Arm III)

GOG-0218: Investigator-assessed PFS

1.0

0.5

0 12 24 36

Control

Proportion alive without progression

Time (months)

Research

ICON 7: Updated PFS

Four positive trials with antiangiogenic agents in front line

Not approved

12 24 36

1.0

0.5

0

Progression-free survival

Months since randomization

AGO-OVAR-12: Primary endpoint

TC + Nintedanib (n=911) TC + Placebo (n=455)

12 24 36

1.0

0.5

0

Progression-free survival

Months since randomization

AGO-OVAR-16: Primary endpoint

Pazobanib Placebo

Bevacizumab

Pazopanib Nintedanib

1.0

0.5 Bevacizumab 0

(11)

(12)

(13)

PFS 14.1 vs 11.2

(14)

ICON 7

(15)

0 6 12 18 24 30 36 42 48 54 60

Proportion alive

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

Proportion alive without progression

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

(16)

ICON7: Histological subgroup analyses using retrospective 63-gene immune signature

CP CP + BEV

PFS probability(%)

Time (months)

"Immune subgroup" 41% (n=116)

0 10 20 30 40 50 60

100 80 60 40

20 0

PFSprobability(%)

Time (months)

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

0 10 20 30 40 50 60

100 80 60 40

20

18.5

35.8

0

12.3

17.4

CP CP + BEV

OS probability(%)

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 probability(%)

Time (months)

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

0 10 20 30 40 50 60

100 80

60 40 20 0

CP CP + 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

(17)

ICON7: Retrospective molecular TCGA subgroup analyses by the AGO group

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

Proportion alive without progression 0 0.4 0.6 0.8 1.0

0.2

0

11.8

24 36 48

Time (months)

0 12 24 36 48

Time (months)

Proliferative

Immunoreactive

0 12 24 36 48

Time (months)

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 12

(18)

CP = carboplatin + paclitaxel

Caveats

• Differing tumour assessment schedules

• Prior neoadjuvant chemotherapy permitted in

ROSiA

(19)

(20)

MITO 25 STUDY DESIGN

Primary end point: PFS

Secondary end point :OS, ORR, PFS2

(21)

Summary for first line treatment of ovarian cancer

(22)

Treatment of

Platinum–sensitive relapse

(23)

Bevacizumab: Oceans study

(24)

(25)

Oceans Response Rate Results

(26)

(27)

CEDIRANIB

(28)

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

(29)

(30)

(31)

IMPLICAZIONI FUTURE

(32)

(33)

(34)

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

(35)

Treatment of platinum-resistant relapse

(36)

(37)

(38)

AURELIA TRIAL

Lauraine E JCO ,32-13, 2014

(39)

(40)

(41)

(42)

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.”

(43)

Trinova trial

(44)

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

(45)

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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

(53)

GRAZIE

(54)

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Paola-1

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