Paclitaxel

XVIII Congresso Nazionale Cipomo
La Gestione della Complessita’ in
Oncologia
Lazise 15-17 Maggio 2014
Domenica Lorusso
Gynecologic Oncologic Unit
National Cancer Institute-Milan
Complessita’ Clinico Professionali e
l’Innovazione dei Trattamenti nel
Carcinoma dell’Ovaio
FIGO Annual Report
Carcinoma of the Ovary: 5-yr Survival Rates
% of Patients Surviving Five Years
46
44
42
40
5-year survival rates
38


36

34
Year of Diagnosis
1990-1992 42.5%
1993-1995 43.5%
1996-2003 45%
The challenge of going beyond carboplatin/paclitaxel: key
trials worldwide
Trial
1995
GOG-0162
AGO-GINECO
324
1,282
Regimens compared
Outcome
Cis + either 24 h or 96 h pac
Efficacy similar
Carbo/pac vs carbo/pac/epirubicin
No benefit of a third agent
MITO-1
273
Carbo/pac x6  topo x4 or surveillance
No PFS benefit with topo
maintenance
GOG-0172
429
IV cis/IV pac vs IP cis/IP pac
IP has better efficacy/worse
toxicity and QoL
GCIG
887
Carbo/pac vs carbo/pac/epirubicin
No benefit of a third agent
Carbo/pac  topo x4 or surveillance
No benefit of topo maintenance
277
Cis/pac  pac x3 vs x12 cycles in
patients in CR
PFS improved with pac x12
cycles/no OS difference in a
selected patient population
4,312
Carbo/pac vs carbo/pac/gem (2
regimens) vs carbo/pac/topo vs
carbo/pac/PLD
No benefit of a third agent
819
Carbo/pac x8 vs cis/topo x4 
carbo/pac x4
Efficacy similar; tolerability better
with carbo/pac
1,742
Carbo/pac vs carbo/pac/gem
No benefit of a third agent
AGO-GINECO
GOG-0178
GOG-0182
OV16
2010
n
AGO-OVAR9
1,308
Carbo = carboplatin; cis = cisplatin; CR = complete response; cyclo = cyclophosphamide; gem =
gemcitabine; IP = intraperitoneal; IV = intravenous; pac = paclitaxel; PLD = pegylated liposomal
doxorubicin; topo = topotecan
Katsumata et al.(JGOG) Lancet 2009
Dose dense weekly paclitaxel
• Epithelial ovarian cancer FIGO stage II-IV (80% Stage III-IV)
• RT< 1 cm: 45%; Clear Cell 10%
• 637 patients
Carboplatino AUC 6
Paclitaxel 180 mg/mq
RANDOM
EVERY 21 DAYS
Carbo AUC 6 ogni 21
Paclitaxel 80 mg/mq 1, 8, 15
OVARIAN CANCER TREATMENT:
PERSPECTIVES
• INDIVIDUALIZE THERAPY
- TOXICITY CRITERIA
- HYSTOTIPE
- GENETIC OR EPIGENETIC MUTATIONS
• CHRONIC DISEASE
- MAINTENANCE THERAPIES
- ARTIFICIAL PROLONGATION OF PLATINUM
FREE INTERVAL
A randomized multicentre phase III study comparing
weekly vs every 3 weeks carboplatin plus paclitaxel
in patients with advanced ovarian cancer:
MITO-7 (Multicentre Italian Trials in Ovarian cancer) – ENGOT-ov-10
(European Network of Gynaecological Oncological Trial Groups) - GCIG
(Gynecologic Cancer Intergroup) trial.
Sandro Pignata1,Giovanni Scambia2, Rossella Lauria3, Francesco Raspagliesi4, Pierluigi Benedetti Panici5,
Gennaro Cormio6, Dionyssios Katsaros7, Roberto Sorio8, Giovanna Cavazzini9, Gabriella Ferrandina10,
Enrico Breda11, Viviana Murgia12, Cosimo Sacco13, Nuria Maria Asensio Sierra 14, Carmela Pisano1,
Vanda Salutari2, Beatrice Weber15, Eric Pujade-Lauraine16, Ciro Gallo17, Francesco Perrone1
on behalf of the MITO-7 Investigators
1 National
Cancer Institute – “G.Pascale” Foundation, Napoli, Italy; 2 Catholic University of the Sacred Heart, Rome, Italy;
3 Federico II University, Napoli, Italy; 4 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy;
5 "Sapienza" University of Rome, Rome, Italy; 6 University of Bari, Bari, Italy; 7 S. Anna Hospital, University of Torino, Italy;
8 National Cancer Institute CRO, Aviano (PN), Italy; 9 “C.Poma” Hospital, Mantova, Italy; 10 Catholic University of the Sacred Heart, Campobasso, Italy;
11 Fatebenefratelli Hospital, Rome, Italy; 12 Santa Chiara Hospital, Trento, Italy; 13 University Hospital "S. Maria della Misericordia", Udine, Italy;
14 Arcispedale “S. Maria Nuova” IRCCS, Reggio Emilia, Italy; 15 Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France;
16 Hôpitaux Universitaires Paris-Centre, site Hôtel-Dieu, AP-HP, Université Paris Descartes, Paris, France; 17 Second University of Napoli, Napoli, Italy.
1.0
Progression-free survival
Analysis: March 2013, median follow-up 19.9 months
0.8
Every 3-week
403
214
16.5 (14.6 – 20.0)
Weekly
405
196
18.8 (17.1 – 22.0)
0.2
0.4
0.6
Log-rank test p = 0.18
Unadjusted HR: 0.88 (0.72 – 1.06)
0.0
Probability of progression-free survival
Patients Events
Median PFS
Months (95% CI)
0
Patients at risk
Every 3-week 403
Weekly
405
6
12
18
354
346
217
231
118
124
24
30
36
42
48
38
36
14
20
1
9
-
Months
Presented by: S.Pignata
72
71
1.0
Overall survival
0.6
0.4
Patients Events
Median OS
Months (95% CI)
Every 3-week
403
76
47.9 (47.9 – n.a.)
Weekly
405
89
n.a. (36.3 – n.a.)
0.2
Probability of survival
0.8
Analysis: March 2013, median follow-up 19.9 months
0.0
Log-rank test p = 0.24
Unadjusted HR: 1.20 (0.88 – 1.63)
0
Patients at risk
Every 3-week 403
Weekly
405
6
12
18
380
372
303
294
193
190
24
30
36
42
48
75
68
31
32
5
10
2
-
Months
Presented by: S.Pignata
120
123
QoL: FACT-O TOI, first 9 weeks
90
Treatment:time interaction p<0.0001
FACT-O TOI mean score
80
Weekly
Every 3-week
70
*
60
*
**
50
**
**
* p<0.05 vs. baseline
** p<0.001 vs. baseline
40
Week
0
1
2
3
4
5
6
7
8
9
Pts (weekly)
308
266
254
237
239
238
218
212
223
177
Pts (q3w)
301
229
208
250
209
195
221
193
177
169
In all scales, higher values represent better outcome.
All tests are adjusted by performance status, stage, residual disease after surgery, age category, and size of the institution
Presented by: S.Pignata
Ovarian cancer not one disease
8704 patients from 7 randomised trials
Adenoca: adenocarcinoma
Mackay et al. Int J Gynecol Cancer 2010
Mutations typically associated with ovarian
carcinoma subtypes
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
Other
subtypes
Low-grade
serous
BRAF; KRAS
Mucinous
carcinoma
KRAS
TP53, tumour protein 53
Romero I et al. Endocrinology 2012;153:1593–1602
Endometrioid
carcinoma
PTEN (low grade);
TP53; BRCA1/2
Clear cell
carcinoma
PTEN; PIK3CA;
ARID1A
mEOC
A multicentre randomised factorial trial
comparing oxaliplatin + capecitabine,
bevacizumab and carboplatin + paclitaxel in
patients with previously untreated mucinous
Epithelial Ovarian Cancer (mEOC)
mEOC is an intergroup study with two identical protocols
from GOG and NCRI with a single analysis
Cancer Research UK & UCL Cancer Trials Centre
International Cooperative Phase III Study
for Clear Cell Carcinoma
TC
-Clear Cell Ca
-Stage I~IV
RANDOMIZATION
GCIG Study
Paclitaxel 175 mg/m2 (d1)
Carboplatin AUC 6 (d1)
Every 3 wk x 6
CPT-11/CDDP
CPT-11 60 mg/m2 (d1, 8, 15)
Cisplatin 60 mg/m2 (d1)
Every 4 wk x 6
326 patients in each arm, 652 total for 4.25 years
Patients with Recurrent or
Persistent Low-grade Serous
Carcinomas of the Ovary,
Fallopian Tube or Primary
Peritoneum
Must have received prior
platinum-containing therapy,
but no more than 3 prior
chemotherapies; unlimited
prior hormonal therapy
N = 300
MEK162
45mg BID
Randomization
2:1
Stratification
Platinum-Free Interval:
≤6 months vs. > 6 months
Prior Systemic Tx:
1-2 vs. >2
N=300
Paclitaxel 80 mg/m² d1,8,
15 q 4 wks, or
PLD 40 mg/m² q 4 wks, or
Topotecan 1,25 mg/m²
d1-5 q 3 wks
Primary endpoint: PFS (Assumed true HR = 0.60, 7 vs 11.67 months)
Key secondary endpoint: OS
Other secondary: ORR, DOR, DCR, Safety, QOL, TR (predictive markers)
FPI planned: May 2013
Sponsor: Array
ENGOT Model: C
18
High grade serous Muellerian cancer is a disease of
homologous recombination dysfunction
BRCA1
germline
8%
other
34%
CCNE1
amp 15%
MMR
germline
2%
BRCA2
germline
6% BRCA1
somatic
3%
BRCA2
somatic
3%
BRCA1
methyl’n
11%
EMSY ampl
6%
PTEN loss
other
5%
Other
HRD HRD
7%:
7%
TP53, RAD51C,
PALB2, RAD50,
MRE11A, BARD1,
CHEK2, BRIP1,
FANCD2, ATR, ATM
TCGA, Nature 2011; Swisher et al, PNAS 2011 in press; Turner, et al NatRevCancer 2004; Weberpals, et al JCO 2008;
Tan et al, JCO 2008; Mendes-Pereira et al, EMBO Mol. Med. 2009
Study 19: Olaparib maintenance therapy in platinumsensitive relapsed ovarian cancer
Patients were randomized after response to platinum-based chemotherapy
Probability of
progression-free survival
•
1.0
Primary analysis
(58% maturity; n=154/265)
0.9
0.8
0.7
PFS hazard ratio=0.35
(95% CI, 0.25–0.49)
P<0.00001
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
*Patients were treated until disease progression
Ledermann J et al. N Engl J Med 2012;366:1382–1392
Presented by: Jonathan Ledermann
PFS by BRCAm 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
Presented by: Jonathan Ledermann
Parp inibitori in mantenimento dopo
chemioterapia in pazienti BRCA mutate e
fenotipi BRCAness
• Trial Solo1 Olaparib Prima linea
• Trial Solo2 Olaparib Recidiva platino sensibile
• Trail Tesaro Nova Niraparib Recidiva platino sensibile
• Trail ARIEL 3 Rucaparib Recidiva platino sensibile
The Angiogenic Switch and
Antiangiogenic Therapy
Somatic
mutation
Small
avascular
tumor
Tumor secretion of
proangiogenic
factors stimulates
angiogenesis
Rapid tumor growth and
metastasis
Angiogenic inhibitors
may reverse this process
The essential role of VEGF in
ovarian cancer
Moghaddam, et al. Cancer Metastasis Rev 2012
GOG Phase II studies: Response Rates
Tumor Type
Dose
ORR (PR+CR)
Ovarian Cancer
15mg/kg q3wk
16-21%
Renal Cell
10mg/kg q2wk
10%
Met Breast Cancer
3-20mg/kg q2wk
7%
NHL
10mg/kg q2wk
5%
CRC
10mg/kg q2wk
3%
HRPC
10mg/kg q2wk
0%
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
•
Stratification variables
– GOG performance status
– Stage/debulking status
R
A
N
D
O
M
I
S
E
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
(CP + Bev)
Placebo
Carboplatin (C) AUC 6
III
Paclitaxel (P) 175 mg/m2
(CP + Bev
 Bev)
Bevacizumab 15 mg/kg
15 months
OV = ovarian; PP = primary peritoneal
FT = fallopian tube; Bev = bevacizumab
Burger et al. ASCO 2010
GOG 218- Significant PFS improvement, censored
for CA-125 events and non-protocol therapy
1.0
CP + Pl  Pl
(n=625)
CP + Bev15 
Bev15
(n=623)
12.0
18.2
Median PFS (months)
0.8
Stratified analysis HR
(95% CI)
0.62
(0.52–0.75)
PFS estimate
p value one-sided (log rank)
<0.0001*
0.6
0.4
0.2
CP + Pl  Pl
CP + Bev15  Bev15
0
0
6
12
*p value boundary = 0.0116
Data cut-off date: September 29, 2009
18
24
PFS (months)
30
36
42
48
N Engl J Med 365;26,2011
OS estimate
OS benefit is suggested with chemotherapy + Avastin and continued
single-agent Avastin in stage IV disease
CPP
CPB
CPB15
93 (61)
99 (60)
81 (49)
1.0
Deaths, n
(%)
32.8
32.9
40.6
0.8
Median
survival
(months)
0.98
(0.74–1.31)
0.72
(0.53–0.97)
HR
(95% CI)
0.6
0.4
CPP (n=153)
CPB15 (n=165)
CPB15+ (n=165)
0.2
0.0
0
CPP
CPB
CPB15
153
165
165
12
144
149
154
Randall, et al. SGO 2013: Abstract 80
Randall, et al. SGO 2013: Abstract 80
129
142
144
24
113
117
130
95
104
117
36
Time (months)
72
73
83
42
44
57
28
30
37
48
15
15
21
60
5
10
10
3
3
3
72
0
1
0
0
0
0
ICON 7 Schema
•
•
FIGO stage I–IIA
(clear cell or grade 3)
or FIGO stage IIB–IV
Surgically debulked
histologically
confirmed OC
n=1528
30
Carboplatin AUC 5 or 6
1:1
Paclitaxel 175 mg/m2
R
Carboplatin AUC 5 or 6
Paclitaxel 175 mg/m2
Dec 2006 to Feb 2009
Bevacizumab 7.5 mg/kg q3w
18 cycles (12 months)
Stratification variables:
• Stage & extent of debulking (I–III debulked ≤1cm vs I–III debulked >1 cm vs IV and
inoperable stage III)
• Timing of intended treatment start (≤4 vs >4 weeks after surgery)
• GCIG group
OC = epithelial ovarian, primary peritoneal or fallopian tube cancer
31
PFS (2013 update):
High-risk (n=502)
Stage III suboptimally debulked , any stage IV or no debulking surgery
1.00
Proportion alive without progression
Non-proportionality test: p<0.0001
0.75
Events (%)
Restricted mean,
months
Median, months
Log-rank test
0.50
Control
Research
Total
∆
228
223
451 (90)
15.9
20.0
+4.1
10.5
16.0
p=0.001
+5.5
0.73 (0.61–0.88)
HR (95% CI)
0.25
10.5
16.0
BEV exposure
0
0
Number at risk
Control
254
Research
248
6
12
109
175
18
24
30
36
Time (months)
43
53
24
32
42
48
18
23
54
60
6
5
32
Final OS: High-risk
(n=502)
Stage III suboptimally debulked , any stage IV or no debulking surgery
Total
Control Research ∆
332 (66)
174
158
Deaths (%)
Non-proportionality test:
p=0.0072 Restricted
34.5
39.3
+4.8
mean, months
30.3
39.7
+9.4
Median, months
p=0.03
Log-rank test
0.78 (0.63–0.97)
HR (95% CI)
1.00
Proportion alive
0.75
0.50
0.25
9.4
30.3
BEV exposure
0
0
Number at risk
Control
254
Research
248
6
12
208
224
18
24
39.7
30
36
Time (months)
156
180
101
135
42
48
82
95
54
60
21
27
Avastin RCP Dicembre 2011:
Avastin, in combinazione con carboplatino e paclitaxel è indicato per il
trattamento in prima linea del carcinoma ovarico epiteliale, del carcinoma
alle tube di Falloppio o del carcinoma peritoneale primario in stadio
avanzato (stadio III B, III C e IV, secondo la classificazione FIGO).
Avastin è somministrato in aggiunta a carboplatino e a paclitaxel fino a 6 cicli di
trattamento, seguiti dalla somministrazione di Avastin in monoterapia da proseguire
fino alla progressione della malattia o per un massimo di 15 mesi o fino a che non compare
tossicità inaccettabile, qualsiasi si manifesti prima.
La dose raccomandata di Avastin è di 15 mg/kg di peso corporeo, da somministrarsi
una volta ogni 3 settimane mediante infusione endovenosa
‘Boost Trial’
Bevacizumab in ovarian cancer:
four pivotal trials
Trial
Chemotherapy
Bevacizumab
PFS HR
(n=1873)
Paclitaxel
Carboplatin
Concurrent and
maintenance
15 mg/kg q3w
(3-arm placebo)
0.72
ICON72
(n=1528)
Paclitaxel
Carboplatin
Concurrently only
7.5 mg/kg q3w
(2 arm)
0.81
Platinum resistant
Aurelia3
(n=361)
Caelyx
Topotecan
Paclitaxel
Concurrent
10 mg/kg q2w
(2 arm)
0.48
Platinum sensitive
OCEANS4
(n=484)
Gemcitabine
Carboplatin
Concurrent
15 mg/kg q3w
(2 arm)
0.48
First line
GOG-02181
Second line
1. Burger et al. N Engl J Med 2011
2. Perren et al. N Engl J Med 2011
3. Pujade-Laurain et al. J Clin Oncol 2012
4. Aghajanian et al. J Clin Oncol 2012
36
PFS (2013 update)
Restricted mean
Subgroup
Median, months
Control Research Control Research
All patients
27.7
29.2
17.5
19.9
Non-high riska
33.8
33.7
26.0
25.0
High riskb
15.9
20.0
10.5
16.0
Stage I, II, III (0 cm)
37.9
39.3
45.5
38.8
Stage III >0, ≤1 cm
22.7
21.3
13.7
17.7
Stage III >1 cm
17.0
20.8
11.1
17.0
Stage IV
15.5
19.4
10.2
14.9
Inoperable
10.4
15.8
8.4
12.4
aAll
bNo
stage I and II, stage III ≤1 cm
debulking surgery, stage III >1 cm, any stage IV
HR
(95% CI)
0.93
(0.83–1.05)
1.03
(0.88–1.21)
0.73
(0.61–0.88)
0.97
(0.79–1.18)
1.07
(0.83–1.38)
0.75
(0.59–0.96)
0.75
(0.55–1.02)
0.58
(0.26–1.29)
Research
Events/n
better
Control
better
1080/1528
629/1026
Interaction
p=0.005
451/502
378/725
251/301
260/290
Trend
interaction
p=0.014
163/182
28/30
0.2
0.5
1
2
HR (95% CI)
5
DISCREPANCY BETWEEN SURGEON AND POST
OPERATIVE CT SCAN EVALUATION IN RESIDUAL
TUMOR DETECTION
Author
No patients
% discrepancy
Site of failure
Chi D 2007
78
48%
Perihepatic
region, small
bowel peritoneum
Lakhman Y 2011
63
49%
Perihepatic
Region, Upper
abdominal
lymphnodes
Lorusso D 2013
(submitted)
64
20.3%
Perihepatic
region, small
bowel peritoneum
AURELIA (GINECO)
Platinumresistant
OC, PP, FTC,
(PFI <6 months)
Prior
bevacizumab
allowed
Chemotherapy
to progression
Chemotherapy
to progression
n=360
(4/2011)
Stratification variables:
• Chemotherapy regimen
• Previous anti-angiogenic
therapy
• PFI <3 vs 3–6 months
Bevacizumab 10 mg/kg
q2w* to progression
P
R
O
G
R
E
S
S
I
O
N
Physician’s
choice: SOC or
bevacizumab 15
mg/kg q3w
SOC (Optional
bevacizumab)
Primary endpoint:
PFS
Secondary
endpoints:
ORR, PFIbio, OS, QoL,
safety
Chemotherapy options (physician’s choice):
• Weekly paclitaxel 80 mg/m2
• Topotecan (4 mg/m2 d1, 8, 15 OR 1.25
mg/m2 d1–5 q3w)
• Pegylated liposomal doxorubicin 40 mg/m2
d1 q4w
*15 mg/kg q3w if combined with topotecan q3w
Paclitaxel cohort: OS
CT
(N=55)
41 (75)
13.2
(8.2‒19.7)
BEV + CT
(N=60)
36 (60)
22.4
(16.7‒26.7)
0.65
(0.42‒1.02)
Overall survival (%)
100
Events, n (%)
Median OS,
months (95% CI)
HR (unadjusted)
(95% CI)
75
50
25
0
No. at risk:
CT
BEV + CT
0
6
12
55
60
40
52
32
43
18
24
Time (months)
22
34
13
19
30
36
3
4
0
1
42
OCEANS, a phase III, multicenter, randomized, blinded, placebocontrolled trial of carboplatin and gemcitabine plus bevacizumab in
patients with platinum-sensitive recurrent ovarian, primary
peritoneal, or fallopian tube cancer
Platinum-sensitive
recurrent OCa
CG + PL
C AUC 4
G 1000 mg/m2, d1 & 8
•Measurable disease
•ECOG 0/1
•No prior chemo for
recurrent OC
•No prior BV
PL q3w until progression
C AUC 4
(n=484)
G 1000 mg/m2, d1 & 8
CG + BV
BV 15 mg/kg q3w until progression
Stratification variables:
• Platinum-free interval
(6–12 vs >12 months)
• Cytoreductive surgery for
recurrent disease (yes vs no)
CG for 6 (up to 10) cycles
OCEANS: Primary analysis of PFS
Proportion progression free
1.0
0.8
CG + BV
(n=242)
Events, n (%)
187 (77)
151 (62)
Median PFS,
months (95% CI)
8.4
(8.3–9.7)
12.4
(11.4–12.7)
Stratified analysis
HR (95% CI)
Log-rank p-value
0.6
0.484
(0.388–0.605)
<0.0001
0.4
0.2
0
0
No. at risk
CG + PL
CG + BV
CG + PL
(n=242)
6
12
18
24
30
11
33
3
11
0
0
Months
242
242
177
203
45
92
MITO-16/MaNGO OV-2: Avastin plus chemotherapy at progression after
front-line Avastin plus chemotherapy in platinum sensitive
Carboplatin
PLD or gemcitabine or paclitaxel
1:1
Carboplatin
PLD or gemcitabine or paclitaxel
Avastin15mg/kg q3w
until PD
• Primary endpoint: PFS
• Secondary endpoint: OS
• 60 Italian centres involved and involvement of others European groups (ENGOT –
Italy, Germany, France, Greece, Switzerland) (sponsor: INT Napoli)
Principal investigators: Sandro Pignata, Nicoletta Colombo
x 6 – 8 cycles
Stage IIIB–IV EOC, FT or PPC
progressing or recurring at least
6 months after
front-line chemotherapy
plus Avastin
(n≈400)
Target therapies in Ovarian Cancer
 Bevacizumab
 Pazopanib
 Nintedanib
 Trebananib
 Cediranib
Study Design
• Phase III randomized, placebo-controlled, double-blind, multicenter
• N=940 patients randomized (1:1) from June 2009 to August 2010
• Pazopanib administered at 800 mg daily for up to 24 months*
First-line
surgery and
chemotherapy
(allowed: dosedense, IP,
neoadjuvant)
If not PD
+ tumor
< 2 cm
R
A
N
D
O
M
I
Z
E
Pazopanib
24 months
Placebo
24 months
Observation
(to PD)
Survival
follow-up
(post-PD)
Median 7 months from
ICF
diagnosis to randomization
*Original design was for 12 months and later amended to 24 month
Pazopanib trial: 1st Endpoint: Progressionfree Survival (RECIST)
1
Median time from
Diagnosis: 7 months
Pazopanib: 472 pts. / 237 events
median 17.9 (15.9 - 21.8) mos
Placebo: 468 pts. / 273 events
median 12.3 (11.8 - 17.7) mos
Δ= 5.6 months
0,5
HR = 0.766 (95% CI: 0.643-0.911)
Stratified log-rank test: P = 0.0021
0
0
Patients
at risk
472
468
6
12
18
24
30
36 (months)
332
318
234
208
171
164
91
88
19
20
1
Adverse Events Grade 3-4 per Patient
occurring in at least 1% in the Pazopanib Arm
Grade 3/4 adverse events
Placebo
(N=461)
Pazopanib
(N=477)
Δ
Hypertension
26 (6%)
147 (31%)
121 (25%)
• Hypertension (including Grade 2)
80 (17%)
248 (52%)
168 (35%)
Liver-related toxicity
3 (<1%)
45 (9%)
42 (9%)
Neutropenia
7 (2%)
47 (10%)
40 (8%)
Diarrhea
5 (1%)
39 (8%)
34 (7%)
Asthenia / Fatigue
1 (<1%)
13 (3%)
12 (3%)
Thrombocytopenia
3 (<1%)
12 (3%)
9 (2%)
Palmar-plantar erythrodysesthesia
1 (<1%)
9 (2%)
8 (2%)
Headache
3 (<1%)
8 (2%)
5 (1%)
Abdominal pain
5 (1%)
8 (2%)
3 (<1%)
Proteinuria
2 (<1%)
6 (1%)
4 (<1%)
Arthralgia
3 (<1%)
5 (1%)
2 (<1%)
Drug Exposure: Mean Daily Dose
weeks
Patient Daily Dose (mg)
Mean
Median
Patients with any dose reduction
Placebo
Pazopanib
(N=461)
761.0
800.0
63 (14%)
(N=477)
585.6
607.4
277 (58%)
AGO-OVAR12
Multicenter, randomised, double-blind, Phase III trial to investigate the
efficacy and safety of Vargatef (BIBF 1120) in combination with standard
treatment of carboplatin and paclitaxel compared to placebo plus carboplatin
and paclitaxelin patients with advanced ovarian cancer
S
U
R
G
E
R
Y
C
C
C
C
C
C
T
T
T
T
T
T
= Vargatef 2 x 200 mg po qd
2
R
C
= Carboplatin AUC 5-6
d1
T
= Paclitaxel 175 mg/m2 (3h)
d1
q21d / 6 courses
1
n=1300
C
C
C
C
C
C
T
T
T
T
T
T
Vargatef / Placebo :
- no intake on days of chemotherapy
- dose: 200 mg po bid (combi + mono)
- dose adaptation in case of undue toxicity
- max. duration of 120 weeks in non-progressing pts
= Placebo
 120 weeks
Nintedanib: Primary Endpoint:
Progression-Free Survival
RECIST 1.1 and CA-125 in conjunction with Clinical MBO Criteria
All patients (N=1366) – Cut-off date: 29 April 2013
1
TC +
Nintedanib
(n=911)
TC +
Placebo
(n=455)
486 (53.3)
266 (58.5)
17.3
16.6
Events, n (%)
Median, months
HR* (95% CI)
0.84 (0.72, 0.98)
p value
0.0239
0,5
0
0
6
12
18
24
30
36
42
Time from randomization (months)
911
761
542
352
160
17
1
0
455
381
257
168
76
3
0
0
*Stratified for macroscopic residual postoperative tumour, FIGO stage and carboplatin dose
Exploratory Subgroup Analysis
“ICON 7 defined low-risk patients subgroup”
(FIGO II or FIGO III and ≤ 1cm residual postoperative tumor)
Estimated percentage alive
and progression-free
1
TC +
Nintedanib
(n=556)
TC +
Placebo
(n=283)
234(42.1)
149(52.7)
27.1
20.8
Events, n (%)
Median, months
HR (95% CI)
0.74 (0.61, 0.91)
0,5
Time from randomization (months)
0
0
6
Nintedanib
556
Placebo
283
Patients at risk
12
18
24
30
36
478
380
270
124
9
0
248
186
123
52
2
0
median PFS difference: + 6.3 months (similar to OVAR 16)
42
Nintedanib trial: non-haematological AEs
(>15%), all CTCAE Grades
Placebo + chemo
Nintedanib + chemo
Dose intensity – Drug exposure
Chemo dose reductions, number of pts
Placebo + chemo
n (%)
Nintedanib + chemo
n (%)
450
902
50 (11.1)
190 (21.1)
6 ( 1.3)
40 ( 4.4)
Carboplatin (regardless of Paclitaxel)
24 ( 5.3)
90 ( 9.9)
Paclitaxel (regardless of Carboplatin)
32 ( 7.1)
140 (15.5)
450
902
5.8
5.5
414 (92.0%)
778 (86.3%)
445
890
407 (91.5)
430 (48.3)
32 ( 7.2)
297 (33.4)
6 ( 1.3)
163 (18.3)
any dose reduction of chemotherapy
Carboplatin and Paclitaxel
Chemo courses, number of patients
mean n courses
reaching 6 courses
Nintedanib or placebo, number of pts
Patients without any dose reductions
One dose reduction
Two dose reductions
TRINOVA-1
Weekly paclitaxel
Recurrent partially
platinum sensitive or
12 June
Placebo 2013
IV qw
resistant OC, PP,
to progression
FTC,
(PFI <12 months,
Press release
>6months after the
beginning of the firstline platinum-based
Weeklybenefit
paclitaxel of
chemotherapy)
AMGEN announces PFS
Radiographically
2 months in favour
of trebananib
evaluable disease,
AMG-386 IV 15 mg/kg qw to
documented PD
progression
arm
Prev Chemo <3
(HR 0.66)
Toxicity <G3
n=900
Primary endpoint: PFS
Secondary endpoints: OS, ORR, DOR, CA125 response
rate, safety and tolerbality of AMG386, PK of AMG386
ClinicalTrials.gov. Identifier NCT01204749
Progression-free Survival
(Primary Analysis)
Events, n (%)
Median PFS, months
Pac + Placebo
(n = 458)
Pac + Trebananib
(n = 461)
361 (79)
310 (67)
5.4
7.2
HR = 0.66 (95% CI, 0.57–0.77)
P (stratified log rank) < 0.001
Presented by Monk BJ at European Cancer Congress
European Journal of Cancer 49; suppl 3, Sept 2013 LBA 41
Treatment-emergent AEs in
≥ 25%Paclitaxel
of Patients
+
Paclitaxel +
Patient Incidence, n (%)
Placebo
N = 458
All Grades
Trebananib
N = 461
Grade ≥ 3
All Grades
Grade ≥ 3
Any
434 (96)
244 (54)
446 (97)
258 (56)
Localized edema
116 (26)
4 (1)
264 (57)
24 (5)
Nausea
171 (38)
6 (1)
187 (41)
8 (2)
Alopecia
163 (36)
2 (<1)
154 (33)
0
Diarrhea
122 (27)
13 (3)
136 (30)
11 (2)
Abdominal pain
131 (29)
21 (5)
132 (29)
22 (5)
Asthenia
119 (26)
15 (3)
129 (28)
13 (3)
Fatigue
137 (30)
17 (4)
127 (28)
15 (3)
Vomiting
101 (22)
12 (3)
122 (26)
14 (3)
Constipation
128 (28)
4 (1)
105 (23)
3 (1)
Neutropenia
125 (28)
40 (9)
99 (21)
26 (6)
Presented by Monk BJ at European Cancer Congress
OV6 TRINOVA-2
Pegylated Liposomal Doxorubicin
50 mg/m² IV Q4W
Recurrent partially
platinum sensitive or
resistant OC, PP,
FTC,
(PFI <12 months,
>6months after the
beginning of the firstline platinum-based
chemotherapy)
Radiographically
evaluable disease,
documented PD
Prev Chemo <3
Toxicity <G3
n=380
Placebo IV qw
to progression
Pegylated Liposomal Doxorubicin
50 mg/m² IV Q4W
AMG-386 IV 15 mg/kg qw to
progression
Primary endpoint: PFS
Secondary endpoints: OS, ORR, DOR, CA125 response
rate, safety and tolerbality of AMG386, PK of AMG386
ClinicalTrials.gov Identifier: NCT01281254
TRINOVA-3/ENGOT-ov2/ BGOG-ov7
TC ± AMG 386 as first-line therapy of stage III–IV
ovarian cancer
ARM A:
AMG 386*
Paclitaxel**
Carboplatin**
AMG 386
monotherapy
until progression or
18 months
ARM B:
AMG 386/Placebo*
Paclitaxel**
Carboplatin**
AMG 386 Placebo
monotherapy
Until progression or
18 months
RANDOMIZATION
N = 1000
Neoadjuvant chemo +
Interval Debulking
allowed in both arms
After 3 courses
Up to 7 days from
randomization to 1st dose
Treatment phase
(Progressive disease or unacceptable toxicity or
withdrawal of consent or death
Maintenance phase
END OF TREATMENT
Concurrent treatment
Paclitaxel 175 mg/m2 IV Q3W
Carboplatin AUC 5 or 6 IV Q3W
for
maximum of 6 cycles
Plus
AMG 386 15 mg/kg IV QW or
AMG 386 placebo IV QW
Randomised double-blind phase III
trial of cediranib (AZD 2171) in
relapsed platinum sensitive ovarian
cancer: Results of the ICON6 trial.
Ledermann JA, Perren T, Raja FA, Embleton AC, Rustin GJS,
Jayson G, Kaye SB, Swart AM, Vaughan M, Hirte H
on behalf of the ICON 6 Collaborators
(NCRN, NCIC-CTG, ANZGOG, GEICO)
An academic sponsored GCIG trial
Chronology and Statistical Design – Summary
 Dec 2007: Trial opened in seven centres in UK and Canada. Cediranib 30 mg
reduced to 20 mg after 30 patients enrolled
 Nov 2009: Completed new Stage I (toxicity phase) recruitment at 20 mg dose.
Stage II (efficacy phase) trial expanded
 Sept 2011: AZ ceased development of cediranib.
•
•
•
•
•
•

Trial size reduced
PFS instead of OS as primary endpoint
Trial re-designed without Interim Analysis
Primary comparison: Arm A (Chemo only) vs. Arm C (Maintenance)
Secondary: OS and Chemo only vs. Concurrent vs. Maintenance, Toxicity, QoL
80% power, at 5% alpha, to detect a HR=0.65 would require 176 PFS events (470
patients)
Dec 2011: Trial closed 486 patients (456 at 20 mg dose)
•
176 PFS events occurred around Q4 2012. Analysis delay until ~5% remained on trial
drug
CEDIRANIB IN RECURRENT PLATINUM SENSITIVE
OC: Progression-free survival – arms A vs. C
1.00
Maintenance
PFS events, n (%)
Chemo.
Maint.
112 (94.9)
139 (84.8)
8.7
11.1
Median, months
Chemotherapy
0.75
Log-rank test
p=0.00001
HR (95% CI)
0.57 (0.45 – 0.74)
Test for non-proportionality p=0.024
Restricted means, months
0.50
9.4
12.5
Restricted mean survival time increases by
3.1 months with maintenance treatment
0.25
0.00
0
3
6
9
12
Months
15
18
21
24
.
Chemo. 118
Maint. 164
90
148
24
65
8
21
3
7
CEDIRANIB IN RECURRENT PLATINUM SENSITIVE
OC : Overall survival
Maintenance
1.00
Restricted mean survival time increases
by 2.7 months with maintenance
treatment (over two years)
Chemotherapy
0.75
Chemo.
Maint.
OS events, n (%)
63 (53.3)
75 (45.7)
Median, months
20.3
26.3
0.50
0.25
Log-rank test
p=0.042
HR (95% CI)
0.70 (0.51 – 0.99)
Test for non-proportionality p=0.0042
0.00
Restricted means, months
0
6
17.6
20.3
12
18
24
30
46
89
27
48
11
22
Months
.
Chemo. 118
Maint. 164
106
159
89
139
CONCLUSIONS
• Treatment according to histotype is the future
• Angiogenesis is the driving pathway
in
ovarian
cancer
carcinogenesis
- 4 positive phase III trials in first line treatment
- 2 positive second line trials in platinum resitant disease
- 3 positive second line trials in platinum sensitive disease
…..The pitfalls:
• NO predictive factors of response
• NO idea which phase of disease
• NO idea what schedule and for how long
• NO idea which type of therapy
• NO clear mechanism of resistance that may conditionate the most
appropriate sequence of treatment, if any.
• NO comparison data between drugs
……many trials to do, MANY LESSONS TO LEARN……