Presentazione standard di PowerPoint€¦ · 1.0 0.8 0.6 0.4 0.2 0.0 0 1224 36 48 60 PFS Serous 199...
Transcript of Presentazione standard di PowerPoint€¦ · 1.0 0.8 0.6 0.4 0.2 0.0 0 1224 36 48 60 PFS Serous 199...
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