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Napoli 20 Maggio 2016
Le terapie a bersaglio molecolare nel carcinoma
ovarico
Sandro Pignata
Direttore Dip Uro Ginecologico
Istituto Tumori di Napoli
Carcinoma ovarico
4800 nuovi casi nel 2015 in Italia
3251 decessi nel 2012
80 % III e IV stadi 20 % I e II stadi
Perché questa malattia è così letale?
E’ impossibile la diagnosi precoce (eccetto
che nelle pazienti BRCA mutate)
I numerosi trattamenti disponibili hanno
ritardato la progressione ma non ridotto la
mortalità
I farmaci biologici sono arrivati con ritardo a
causa di una biologia estremamente
complessa
OC subtypes: mutations
70 %
5%
20%
2%
•
5%
Romero I et al. Endocrinology 2012; 153: 1593-1602
80%
70%
60%
50%
40%
30%
20%
10%
4.9%
2.1%
0%
Response Rate in
Platinum-Sensitive
Response Rate in
Platinum-Resistant
All Recurrent Epithelial Ovarian
*75% received 1-2 prior chemo regimens
Recurrent LGSOC*
Sources: Gonzalez-Martin et al. Ann Oncol 2005; Kushner et al. J Clin Oncol
2004; Mutch et al. J Clin Oncol 2007; Abushahin et al. J Clin Oncol 2006;
Gershenson et al. Gynecol Oncol 2009
• LGSOC frequent mutations in RAS/RAF.
• 40 -60% LGSOC KRAS or BRAF mutated
• Never LGSOC with both KRAS and BRAF
• BRAF decrease in advanced stages.
Sources: a Singer et al. J Nat Canc Inst 2003; b Wong et al. Amer J Path
2010; c Grisham et al. Cancer 2012; d Jones et al. J Pathol 2012;
8
e Farley et al. Lancet Oncol
2013
Phase 3 trials: MILO
MEK Inhibitor in Low Grade Serous Ovarian Cancer
High grade serous: The Post Genome Era
Table of Contents
16 February 2001
Volume 291
Number 5507
The Human
Genome
Molecula subtypes
The Cancer Genome Atlas Research Network, Nature. 2011 Jun 29;474(7353):609-15
Serous Ovarian Cancer is a disease of
DNA repair abnormalities and resulting ‘
“genomic instability”
• Subsets of high grade serous OC do not
exist?
• Tumor can adapt rapidly
• may not be be able to be treated with
“targeted agents”
– TKIs, antibodies etc
• May not be “predictable.”
Personalized medicine:
angiogenesis
•
GOG-0218: Schema
Arm
Carboplatin (C) AUC 6
Front-line:
epithelial OV, PP
or FT cancer
● Stage III optimal
(macroscopic)
● Stage III suboptimal
● Stage IV
N=1873
R
A
N
D
O
M
I
S
E
Stratification variables
– GOG performance status
– Stage/debulking status
OV = ovarian; PP = primary peritoneal
FT = fallopian tube; Bev = bevacizumab
I
Paclitaxel (P) 175
mg/m2
(CP)
Placebo
1:1:1
Carboplatin (C) AUC 6
II
Paclitaxel (P) 175 mg/m2
Bev 15 mg/kg
Placebo
Carboplatin (C) AUC 6
(CP +
Bev)
III
Paclitaxel (P) 175 mg/m2
Bevacizumab 15 mg/kg
(CP + Bev
 Bev)
15 months
Burger et al. ASCO 2010
GOG-0218: Investigator-Assessed
PFS
Proportion surviving progression free
1.0
10.7 vs 11.2 vs 14.1 months p<0,0001
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
CP (Arm I)
+ BEV (Arm II)
0.1
+ BEV → BEV maintenance (Arm III)
0
0
12
24
Months since randomization
ASCO 2010
36
ap-value
boundary = 0.0116
Edinburgh dataset; unsupervised hierarchical clustering
Presented by:
Control arm ICON7
Immune and proangiogenic groups
BEVACIZUMAB
Adverse effect on PFS
in the immune
subgroup
Benefit in proangiogenic group
BEVACIZUMAB
Adverse effect on OS
in the immune
subgroup
Benefit in proangiogenic group
Gourley et al, ASCO 2015.
MITO 16/MANGO OV2 project:
Translational Project
Chemotherapy
associated genes
Angiogenesis-related
genes
miRNA-machineryrelated genes
APE1, ERCC1, hMLH1,hMSH2
hOGG 1, RAD51
XPD,XRCC1
XRCC3,CYP3A4
CYP3A5, CYP1B1
CYP2C8,
GSTM1
GSTT1, GSTM3
GSTP1, ABCG2
ABCC2, ABCB1
VEGF-A,VEGF-B
VEGF-C,VEGF-D
VEGF-E,VEGF-F
IGF-1, IGF-2, IGFR-1,PIGF
VEGF-R1,
VEGF-R2,
VEGF-R3,PGF
PDGFa, PDGFb
PDGFc,PDGFRa
PDGFRb, NRP1
HLFB,HIF1α
ADAR, Argonaute1 (EIF2C1),
Argonaute 2 (EIF2C2),
Argonaute4 (EIF2C4),
CNOT1 (o NOT1), CNOT2 (o
NOT2), CNOT3(o NOT3),
CNOT4 (o NOT4), CNOT6 (o
CCR4),
DGCR8 (o Pasha),Dicer, EDC4
(oHEDLS/Ge-1), FMRP,
GEMIN3 (o DDX20), GEMIN4,
GEMIN5,HIWI,hnRNP-A1,
LSM4, MOV10,p68 (DDX5
DEAD),POLR2A, Ran,RNASEN
(Drosha), SMAD1, SMAD2
SMAD3, SMAD5, SND1 (o
Tudor-SN), TNRC6A (o
GW182), TNRC6B
TRBP, TUT4, XPO5 (exportin-5)
Angiogenesis
• No predictive biomarker
• No biomarker for resistance
• All patients treated
Personalized medicine:
BRCA
Probability of
progression-free survival
Study 19: Olaparib maintenance therapy in platinum-sensitive
relapsed ovarian cancer
Primary analysis
(58% maturity; n=154/265)
1.0
0.9
0.8
PFS HR=0.35
(95% CI, 0.25–0.49)
P<0.00001
0.7
0.6
0.5
0.4
0.3
Randomized treatment*
Placebo (n=129)
Olaparib 400 mg bd monotherapy (n=136)
0.2
0.1
0
0
3
6
9
12
15
18
Time from randomization (months)
•
Interim OS analysis (38% maturity): HR=0.94; 95% CI, 0.63–1.39; P=0.75
Ledermann J et al. N Engl J Med 2012;366:1382–1392
PFS by BRCA mutation status
BRCAm (n=136)
Olaparib
Placebo
Events: total pts (%) 26:74 (35.1) 46:62 (74.2)
Median PFS, months
11.2
4.3
HR=0.18
95% CI (0.11, 0.31);
P<0.00001
1.0
Proportion of patients
progression-free
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
0.1
0
0
3
6
9
12
15
Time from randomization (months)
Number at risk
Olaparib BRCAm
74
59
33
14
4
0
Placebo BRCAm
62
35
13
2
0
0
• 82% reduction in risk of disease progression or death with olaparib
Ledermann JA et al . J Clin Oncol 2013;31(15S); abstr 5505
Study 19: Time to second subsequent therapy
BRCAm (n=136)
Events: total pts (%)
Median TSST, months
Proportion of patients receiving
study treatment or first
subsequent therapy
1.0
0.9
Olaparib
Placebo
42:74 (57%) 49:62 (79%)
23.8
15.2
HR=0.44
95% CI: 0.29, 0.67;
p<0.00013
0.8
0.7
0.6
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
0.1
0
0
5
10
15
20
25
30
35
40
45
Time from randomisation (months)
Number at risk
Olaparib BRCAm
74
70
65
50
38
33
30
23
9
0
Placebo BRCAm
62
60
46
31
21
18
11
9
2
0
Ledermann J et al. Lancet Oncol 2014
A uso esclusivo Medical Affairs – riservato – non promozionale
AstraZeneca raccomanda l'uso dei propri prodotti secondo il Riassunto delle Caratteristiche di prodotto
Solo 1
Olaparib
Carbo-taxolo
Placebo
Studio multicentrico di Fase III, randomizzato, in doppio cieco,
controllato con placebo, per valutare il trattamento di mantenimento
con Olaparib in monoterapia dopo una prima linea di chemioterapia
a base di platino in pazienti con carcinoma ovarico in stadio
avanzato (stadio FIGO III-IV) e mutazione del gene BRCA
PAOLA1
Platine, Avastin and OLAparib in 1st line of advanced
high grade epithelial ovarian, fallopian tube, or
primary peritoneal cancer
Randomized, Double-blind, Phase III Trial of olaparib vs. placebo in
combination with bevacizumab in women following first-line chemotherapy
plus bevacizumab for advanced high grade epithelial ovarian, fallopian
tube, or primary peritoneal cancer
30
BRCA
•
•
•
•
PARP inhibitors
More patients tested for BRCA mutation
Useful for selecting chemotherapy
All old trials should be revised?
BRCAness and genetic instability
PARP Inhibition in HRD deficient
61 % response rate in platinum
sensitive BRCA mut
32 % response rate in High LOH
8% response rate in Low LOH
Rucaparib Ariel 3
CD3+
TIL Present
55%
Stroma
TIL Absent
40%
Islet
Zhang, et al. N Engl J Med 2003
CD8 T -lymphocytes in Ovarian Cancer
Intratumoral T cells
Intratumoral T cells
No intratumoral T cells
No intratumoral T cells
Zhang, Conejo-Garcia, Katsaros, Gimotty, Massobrio, Regnani, Makrigiannakis, Gray, Schlienger, Liebman, Rubin, Coukos.
Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003
Clinical Efficacy of Nivolumab in
Platinum-resistant Ovarian Cancer
Response by Recist
Hamanishi, ASCO 2014
AVELUMAB and OC
Response by subgroup
PEMBROLIZUMAB and OC
CHANGE FROM BASELINE IN TUMOR SIZE
A. Varga, S. et al JCO ASCO Annual Meeting 2
Tumor infiltrating and peritumoral T cells and expression
of PD-L1 in BRCA1/2-mutated high grade serous OC
• These findings support trials of immune-checkpoint inhibitors targeting the
PD1/PDL1 pathway in BRCA1/2-mutated OC
• An elevated number of CD3+ and CD8+ in BRCA1/2-mutated OC may provide an
additional explanation for the improved clinical outcomes associated with these
mutations
Conclusions
• Ovarian cancer is a heterogenous
disease.
• BRCA
• Serous cancers have genomic
instability.
• Integration of genomics and clinical
biomarkers for prognosis and treatment.
• Personalized medicine and
immunotherapy is coming?