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XXVIII RIUNIONE NAZIONALE MITO
Il Lato Oscuro di Venere
Mesagne 20/01/2017
Domenica Lorusso
Gynecologic Oncologic Unit
National Cancer Institute-Milan
STATO DELL’ARTE DEL CARCINOMA OVARICO:
5°OVARIAN CANCER CONSENSUS CONFERENCE: DALLA
SCELTA TERAPEUTICA ALLA QUALITA’ DI VITA
TOKYO 7-9/11/2015
29 INTERNATIONAL COOPERATIVE GROUPS
90 ATTENDEES
TOKYO CONSENSUS CONFERENCE
THE QUESTIONS: 4 TOPIC AREA
Individualized therapy and patients factors:
What are the most important factors to be evaluated prior initial therapy?
Are there specific considerations for special populations?
Initial treatment:
what defines groups that should be evaluated for comparators?
What different control arms could be considered for trial in first line therapy?
What should be the end point?
Recurrent disease:
wha are the subgroup for clinical trial in recurrent disease?
What different control arms could be considered ?
What should be the end points?
Rare tumors:
Unique nedd for research in rare tumors
Are randomized trial possible?
What are the unmet needs in rare epithelial OC, germ cell tumors and sex-cord stromal
ovarian tumors?
Ovarian cancer is not a single disease
70 %
5%
2%
Romero I et al. Endocrinology 2012; 153: 1593-1602
15%
5%
Ovarian Cancer - not one disease<br />Outcome depends on histiotype
© Colombo, IEO 2015
© Colombo, IEO 2015
Long-term overall survival of patients treated with intravenous (IV)
versus intraperitoneal (IP) chemotherapy (P = .04).
GOG 172: 42% completed treatment
8% never started
34% received only one or two cycles
NOT feasible in the majority of patients
Devansu Tewari et al. JCO doi:10.1200/JCO.2014.55.9898
© Colombo, IEO 2015
© Colombo, IEO 2015
BRCA1 expression and improved survival in ovarian cancer
patients treated with intraperitoneal cisplatin and paclitaxel:
a Gynecologic Oncology Group Study
Lesnock et al. British Journal of Cancer (2013) 108, 1231–1237
Presented by:
First line Dose dense in ovarian cancer
JGOG-3016
PFS
Overall survival
Median PFS
28.2 months vs 17.5 months
(HR 0.76, 95% CI 0.62–0.91; p=0.0037).
Median overall survival was
100.5 vs 62.2 months
(HR 0.79, 95% CI 0.63–0.99; p=0.039).
Noriyuki Katsumata et al .Lancet Oncol 2013; 14: 1020–26
© Colombo, IEO 2015
First line Dose dense in ovarian cancer
MITO 7
1.0
OS
0.8
0.6
0.0
0.2
0.2
0.4
403
Probability of survival
0.8
0.6
Every 3week
405
0.4
Weekly
0.0
Probability of progression-free survival
1.0
PFS
0
6
12
18
24
30
36
42
Median PFS 18.8 vs 16.5
Log-rank test p = 0.18
Unadjusted HR: 0.88 (0.72 – 1.06)
Presented by: S.Pignata
48
0
6
12
18
24
30
36
42
Months
Months
Median OS n.a. vs 47.9
Log-rank test p = 0.24
Unadjusted HR: 1.20 (0.88 – 1.63)
Pignata et al. Lancet Oncol. 2014 Apr;15(4):396-405
48
GOG 262
Two positive trials with bevacizumab
in front line
Overall Survival
Deaths
1-Year Survival
Arm I
CP
(n = 625)
Arm II
CP + Bev
(n = 625)
Arm III
CP + Bev  Bev
(n = 623)
156 (25.0%)
150 (24.0%)
138 (22.2%)
90.6%
90.4%
91.3%
Events were observed in ~ 24% of patients at the time of database lock.
Burger RA et al. Proc ASCO 2010;Abstract LBA1.
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
A GiNECO study:Therapy-free
Recurrent
Ovarian
Cancer:
Population
Interval and Efficacy
Characteristics
Survival
Response
P
Rate6 (%)
R (days)
3
0
12
100
1000
I
M
A Refractory
80
800
R
Y
LA SENSIBILITA’ AL PLATINO E’
T
H
E
R
A
P
Y
Overall
Survival
UNA VARIABILE CONTINUA!!!
Resistant 60
600
400
40Partially Sensitive
217
200
366
PFS
Fully Sensitive
166
90
0-3/Pr
Response
Rate
32
20
9
0
24 months
18
0-3
3-6
6-9
9-12 12-18 ≥18
Pisano et al. Ther Clin Risk Manag. 2009;5:421-426; Gadducci et al. Anticancer Res. 2001;21:3525-3533.
Therapy-free interval (months)
© Colombo, IEO 2015
Recurrent Ovarian Cancer (ROC):
Population Characteristics
Response to Platinum
Time to
Recurrence
Response to
Further
Platinum
12 mo
30-60%
Platinum-partially sensitive
6-12 mo
25-30%
Platinum-resistant
< 6 mo
< 10%
Platinum-refractory
No initial
response
N/A
Platinum-sensitive
© Colombo, IEO 2015
Recurrent Ovarian Cancer (ROC):
Population Characteristics
Response to Platinum
Time to
Recurrence
Response to
Further
Platinum
12 mo
30-60%
Platinum-partially sensitive
6-12 mo
25-30%
Platinum-resistant
< 6 mo
< 10%
Platinum-refractory
No initial
response
N/A
Platinum-sensitive
© Colombo, IEO 2015
Hypersensitivity, incidence and development
• Incidence seems to be correlated with increased number of cycles of
carboplatin administered occurring in less than 1% of the patients
during primary treatment but in 8–44% of patients during 2nd or 3rd
line.1-2
• The risk of hypersensitivity reactions rises with a longer platinum-free
interval.3
• Particular caution is advised in patients receiving:4
– eighth course of carboplatin
– second platinum dose after reintroduction in second-line
chemotherapy.
1. Sliesoraitis S, Chikhale PJ. Int J Gynecol Cancer. 2005;15:13-8; 2. Gaducci et al. Int J Gynecol
Cancer. 2008;18(4):615-20; 3. O´Cearbhaill R, et al. Gynecol Oncol. 2011;116(3):326-31; 4. Markman
M, et al. J Clin Oncol.1999;17(4):1141-5
© Colombo, IEO 2015
Active Single-Agents in Recurrent Ovarian Cancer
Response Rates
Agent
PlatinumSensitive
PlatinumResistant
Patient Tolerance/QoL Issues
28%
12-16%
HFS, mucositis
Paclitaxel
20-45%
7-17%
Alopecia, peripheral neuropathy,
arthralgias/myalgias
Etoposide
34%
27%
Gemcitabine
34%
13-19%
Flu-like constitutional symptoms,
hepatic dysfunction, dyspnea
Yondelis
36%
7-16%
Transaminases elevation, Asthenia, GI
toxicity
Vinorelbine
29%
15-19%
Constipation, nausea, peripheral
neuropathy
Topotecan
33%
12-19%
Asthenia, alopecia, schedule
PLD
Alopecia, GI toxicity
Armstrong et al. The Oncologist. 2002;7:20-28; Herzog. Clin Cancer Res. 2004;10:7439-7449.
© Colombo, IEO 2015
Clinical Activity of the Poly(ADP-Ribose) Polymerase (PARP) Inhibitor Rucaparib in Patients
with High-Grade Ovarian Carcinoma
and a BRCA Mutation: Analysis of Pooled Data
from Study 10 (Parts 1, 2a, and 3) and ARIEL2 (Parts 1 and 2)
Rebecca S. Kristeleit,1 Ronnie Shapira-Frommer,2 Ana Oaknin,3 Judith Balmaña,3
Isabelle Ray-Coquard,4 Susan Domchek,5 Anna V. Tinker,6 Cesar Castro,7
Stephen Welch,8 Andres Poveda,9 Kathy Bell-McGuinn,10 Gottfried Konecny,11
Heidi Giordano,12 Lara Maloney,12 Sandra Goble,12 Lindsey Rolfe,12 Amit M. Oza13
1University
College London, Cancer Institute, London, UK; 2Sheba Medical Center, Ramat Gan, Israel;
d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain;
4GINECO, Centre Léon Bérard and University Claude Bernard, Lyon, France; 5University of Pennsylvania,
Philadelphia, PA, USA; 6British Columbia Cancer Agency, Vancouver, BC, Canada; 7Gynecological Oncology, Massachusetts General
Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA; 8Division of Medical Oncology, London Regional
Cancer Program, London, ON, Canada; 9Clinical Area of Gynecologic Oncology,
Valencian Institute of Oncology, Valencia, Spain; 10Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 11University of
California Los Angeles, Los Angeles, CA, USA; 12Clovis Oncology, Inc., Boulder, CO, USA;
13Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
3Vall
Investigator-Assessed ORR in the
Efficacy Population
Study 10
n=42
Efficacy population
n=106
n (%)
[95% CI]
Parameter
Investigator-assessed RECIST
ORR
(confirmed CR+PR)
ARIEL2
n=64
25 (59.5)
[43.3–74.4]
32 (50.0)
[37.2–62.8]
57 (53.8)
[43.8–63.5]
CR
4 (9.5)
5 (7.8)
9 (8.5)
PR
21 (50.0)
27 (42.2)
48 (45.3)
SD
12 (28.6)
24 (37.5)
36 (34.0)
PD
2 (4.8)
7 (10.9)
9 (8.5)
NE
3 (7.1)
1 (1.6)
4 (3.8)
Investigator-assessed
RECIST/GCIG CA-125 ORR
Data cutoff dates: 30 Nov 2015 (Study 10); 29 Feb 2016 (ARIEL2).
CI, confidence interval; CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate;
response; RECIST, Response Evaluation Criteria In Solid Tumors.
75 (70.8)
[61.1–79.2]
PR, partial
Progression-Free Survival in the
Efficacy Population
Progression-free at 6 months:
79%
Median (months)
10.0
95% CI
7.3–12.5
Range
0.0–22.1+
+ Censored; Censoring rate: 47%
Progression-free at 12 months:
41%
At risk (events)
106 (0)
93 (9)
85 (14)
69 (19)
43 (37)
31 (40)
21 (43)
• 32 patients had not progressed as of the cutoff dates
Data cutoff dates: 30 Nov 2015 (Study 10); 29 Feb 2016 (ARIEL2).
14 (49)
8 (54)
3 (55)
3 (55)
2 (56)
0 (56)
Randomized phase III trials of chemotherapy
combinations vs single agent in platinum
refractory/resistant ovarian cancer
Author
N pts
Drugs
RR (%)
PFS
(median)
OS (median)
Note
Buda 2004
212
PTX vs
PTX+EPI
46.9
37.4
6.0 m
6.0 m
14.0 m
12.0 m
Increased toxicity
in the
combination arm
Bolis 1999
81
PTX vs
PTX+EPI
17.1
34.2
NR
NR
18
10
(2-year OS)
Increased toxicity
in the
combination arm
TPT vs
TPT+ VP 16 vs
TPT +GEM
27.8
36.1
31.6
7.0 m
7.8 m
5.3 m
17.2 m
17.8 m
15.2 m
Increased toxicity
in the
combination arm
Vergote 2010 125
PLD vs
CAN+PLD
12.3
8.3
3.7 m
5.6 m
NR
NR
Increased toxicity
in the
combination arm
Monk 2010
242
PLD vs
PLD + ET743
12.2
13.4
4.0 m
3.7 m
12.4 m
14.2 m
Increased toxicity
in the
combination arm
Lortholary
2012
165
PTX w vs
CBDA + PTX w vs
TPT w
35
37
39
3.7 m
4.8 m
5.4 m
19.9 m
15.2 m
18.6 m
Increased toxicity
in the
combination arm
Sehouli 2008
502
© Colombo, IEO 2015
STUDIO AURELIA
ASCO 2012
Sopravvivenza globale: popolazione generale
Sopravvivenza globale: w paclitaxel
100
75
Overall survival (%)
Overall survival (%)
Events, n (%)
75
50
25
0
0
12
Time (months)
18
24
Median OS,
months (95% CI)
HR (unadjusted)
(95% CI)
50
CT
(N=55)
BEV + CT
(N=60)
41 (75)
36 (60)
13.2
(8.2‒19.7)
22.4
(16.7‒26.7)
0.65
(0.42‒1.02)
25
0
0
6
12
18
24
30
36
ESMO 2013
PLD 50 mg/m2 q 28
R
A
N
D
O
M
672 patients
PLD 30 mg/m² + Trabectedin*
1.1 mg/m² q 21
PLD
PLD+ET743
Trabectedin-PLD PFS – Intermediate
Sensitivity (PFI 6-12 mo)
PFS events= 124
HR=0.65 (0.45-0.92)
p=0.0152
# Censored: 84
Trabectedin+PLD
7.4 mo
PLD
5.5 mo
Time from Randomisation (Months)
PFI = Platinum Free Interval
Role of Yondelis+PLD in PPS Ovarian
Cancer: OS data
Events/censored:177/37
Cox regression:
HR: 0.64 (0.47-0.86)
p=0.0027
Yondelis+PLD
Median=22.4 months
PLD
Median=16.4 months
Monk BJ et al. J Clin Oncol. 2011:29(suppl):abstr 5046.
Sehouli J, Gonzalez A. Ann Oncol 2011. Epub 2011 Jul 6. DOI: 10.1093/annonc/mdr321
© Colombo, IEO 2015
INOVATYON
Relapsed ovarian cancer
with platinum-free interval (PFI) of 6-12 months
Randomization
(strata: ECOG, Measurable disease, PFI)
PLD 30 mg/m2 1 hour i.v. +
Carboplatin AUC 5 q4weeks
PLD 30 mg/m2 1 hour i.v. +
Trabectedin 1.1 mg/m2 q3weeks
3rd line chemotherapy: at
investigator discretion
3rd line chemotherapy:
platinum rechallenge
Up to 6 cycles or progression
Up to 6 cycles or progression
The MITO8 – ENGOT OV1 phase 3 international multicenter randomized
study testing the effect on survival of prolonging platinum-free interval
(PFI) in patients with ovarian cancer (OC) recurring between 6 and 12
months after previous platinum based chemotherapy.
A collaboration of MITO, MaNGO, AGO, BGOG, ENGOT, and GCIG
Pignata Sandro1, Scambia Giovanni2, Raspagliesi Francesco3, Murgia Viviana4, Pisano Carmela1, Salutari
Vanda2, Bologna Alessandra5, Sorio Roberto6, Ferrandina Gabriella7, Sacco Cosimo8, Vergote Ignace9,
Cormio Gennaro10, Breda Enrico11, Cinieri Saverio12, Cecere Sabrina Chiara 1, Wagner Uwe13, Daniele
Gennaro14 , Gallo Ciro15, Perrone Francesco14, Piccirillo Maria Carmela14
1
S.C. Oncologia Medica Ginecologica, Istituto Nazionale Tumori, Napoli 2 U.O. Ginecologia Oncologica, Fondazione Policlinico Universitario Gemelli Università Cattolica del Sacro
Cuore, Roma 3 Divisione Ginecologia Oncologica, Istituto Nazionale Tumori, Milano 4 U.O. Oncologia Medica, Ospedale S. Chiara , Trento 5 Oncologia Medica, IRCCS-Arcispedale
S. Maria Nuova, Reggio Emilia 6 Oncologia Medica C, Centro di Riferimento Oncologico, Aviano (PN) 7 U.O. Ginecologia Oncologica, Centro di Ricerca e Formazione ad Alta
Tecnologia nelle Scienze Biomediche, Università Cattolica del Sacro Cuore, Campobasso 8 Dipartimento Interaziendale di Oncologia, A.O. S. Maria della Misericordia, Udine
9 UZ Leuven-Gynecological Oncology, Leuven (Belgium) 10 Divisione Ginecologia ed Ostetricia, Policlinico Universitario, Bari 11 Oncologia Medica, Ospedale S. Giovanni CalibitaFatebenefratelli , Roma 12 Oncologia Medica, Ospedale Senatore Antonio Perrino , Brindisi 13 Gynaegoligy, Frauenklinik - Marburg (Germany) 14 Unità Sperimentazioni Cliniche,
Istituto Nazionale Tumori, Napoli 15 Statistica Medica, Seconda Università di Napoli
Study Design
R
A
N
D
O
M
Standard
PBC: Platinum-Based
Chemotherapy*
PD
NPBC: Non-Platinum
Based
Chemotherapy**
PD
PBC: Platinum-Based
Chemotherapy*
1:1
NPBC: Non-Platinum
Experimental Based
Chemotherapy**
*Pt-based Chemotherapy:
• Carboplatin + Paclitaxel or
• Carboplatin + Gemcitabine
(in case of neurotoxicity at
baseline)
**Non-Pt-Based Chemotherapy:
• PLD or other approved single
agents
Platinum Free Interval
• Platinum free interval was effectively prolonged in the
experimental arm
Arm
Median
Time from previous platinum to
randomization
IQRange
PBC->NPBC
8 months
7-9
NPBC->PBC
8 months
6-9
Time from randomization to platinum
95%CI
PBC->NPBC
0.01 months
0.01-0.15
NPBC->PBC
7.8 months
3.7-13.3
1.00
Overall Survival (primary end-point)
Arm
Median
95%CI
0.50
0.75
PBC24.5
22.4-33.6
>NPBC
months
NPBC21.8
16.3-29.3
>PBC
months
Adjusted* HR 1.38; 95%CI 0.991.94 p=0.06
0.00
0.25
* By line of treatment, residual disease
and size of centre
0
6
12
18
24
30
36
42
48
54
60
66
72
10
6
5
5
3
5
3
1
3
1
Months
Number at risk
PBC->NPBC
NPBC->PBC
108
107
102
90
92
71
70
52
45
34
31
23
21
13
16
10
STUDI RANDOMIZZATI DI FASE III SULLE
COMBINAZIONI A BASE DI PLATINO NELLA
RECIDIVA PLATINO SENSIBILE DI
CARCINOMA DELL’OVAIO
Autore
Trattamento
PFS HR
OS HR
Tossicita’
Parmar 2003
CBDA vs
CBDA+TAX
0.76
0.82
Neurotossicita
Alopecia
Reazioni
allergiche
Pfisterer
2006
CBDA vs
CBDA+GEM
0.72
0.96
Mielotossicita
Reazioni
allergiche
Pujade 2010
CBDA+TAX vs
CBDA+PLD
0.82
0.99
Piastrinopenia
PPE
Proportion surviving progression-free
GOG-0213: primary analysis of PFS
0.8
Carboplatin +
Paclitaxel
(n=337)
Carboplatin +
Paclitaxel +
Avastin
(n=337)
Events, n (Total)
304
296
Median (months)
10.4
13.8
HR, adj. (95% CI)
0.614 (0.522–0.722)
p-value
0.6
0.4
p<0.0001*
39% reduction
in risk of PD or death
0.2
0.0
0
•
12
Coleman, et al. SGO 2015 (Abstract 3)
24
36
48
60
GOG-0213: primary analysis of OS
Carboplatin +
Paclitaxel
(n=337)
Carboplatin +
Paclitaxel +
Avastin
(n=337)
Events, n
214
201
Median (months)
37.3
42.2
1.0
Proportion surviving
0.8
HR, adj. (95% CI)
2 tailed p-value
0.6
0.4
0.829 (0.683–1.005)
p=0.056
17% reduction in risk of death
5-month difference in median overall
survival, favouring Avastin arm
0.2
0.0
0
•
12
Coleman, et al. SGO 2015 (Abstract 3)
24
36
Time (months on study)
48
60
Proportion of patients progressionfree
OLAPARIB: 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
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Olaparib BRCAm
Placebo BRCAm
0.2
Astra Zeneca Press Release 26/10/2016
0.1
0
0
Number at risk
Olaparib BRCAm
Placebo BRCAm
3
6
9
12
15
4
0
0
0
Time from randomization (months)
74
62
59
35
33
13
14
2
• 82% reduction in risk of disease progression or death with olaparib
© Colombo, IEO 2015
Phase III trials with PARP inhibitors
Recruiting:
• SOLO 1 and 2 (olaparib)
– Randomised maintenance trials in
first line and platinum-sensitive recurrent BRCAm ovarian cancer
• NOVA (niraparib)
– Randomised maintenance trial following platinum-based
chemotherapy in BRCAm and BRCAwt high-grade serous cancer
• ARIEL 3 (rucaparib)
– Randomised maintenance trial following platinum-based
chemotherapy in BRCAm and BRCAwt high-grade serous cancer
with companion diagnostic
© Colombo, IEO 2015
ENGOT-OV16/NOVA Trial
Niraparib Maintenance Therapy in Patients with
Recurrent Ovarian Cancer
Mansoor R. Mirza1, B.J. Monk2, A. M. Oza3, S. Mahner4, A. Redondo5, M. Fabbro6, J. Ledermann7,
D. Lorusso8, I.B. Vergote9, O. Rosengarten10, J. Berek11, J. Herrstedt12, A.V. Tinker13, A. du Bois14,
A. González Martín15, P. Follana16, B. Benigno17, B.J. Rimel18, S. Agarwal19, U. Matulonis20
1NSGO
& Rigshospitalet, Copenhagen, Denmark, 2University of Arizona Cancer Center-Phoenix, US, 3Princess Margaret Cancer Centre, Toronto, Canada, 4AGO &
University of Munich, Germany, 5GEICO & Hospital Universitario, Madrid, Spain, 6GINECO & Institut du Cancer de Montpellier, France,
7NCRI & University College London, UK, 8MITO/MaNGO & Fondazione IRCCS National Cancer Institute, Milano, Italy, 9BGOG & University of Leuven, Belgium,
10ISGO & Sha’are Zedek Medical Center, Jerusalem, Israel, 11Stanford Comprehensive Cancer Institute, US, 12NSGO & Odense University Hospital, Denmark,
13British Columbia Cancer Agency, Vancouver, Canada, 14AGO & Kliniken Essen Mitte, Germany, 15GEICO & MD Anderson Cancer Center Madrid, Spain,
16GINECO & Centre Antoine Lacassagne, Nice, France, 17University Gynecologic Oncology, Atlanta, US, 18Cedars-Sinai Medical Center, West Hollywood, US,
19Tesaro Inc, Waltham, US, 20Dana-Farber Cancer Institute, Boston, US
Progression-free Survival: gBRCAmut
PFS
Median
(95% CI)
Treatme (Month
nt
s)
Nirapar
ib
(N=138
)
Placeb
o
(N=65)
21.0
(12.9,
NR)
5.5
(3.8,
7.2)
Hazard
Ratio
(95% CI)
p-value
0.27
(0.173,
0.410)
p<0.000
1
% of
Patients
without
Progressio
n or Death
12
18
mo mo
62
%
50
%
16
%
16
%
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier
methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards
model, with the stratification factors used in randomization.
NR=not reached
Progression-free Survival: Non-gBRCAmut
PFS
Median
(95% CI)
Treatme (Month
nt
s)
Nirapar
ib
(N=234
)
Placeb
o
(N=116
)
9.3
(7.2,
11.2)
3.9
(3.7,
5.5)
Hazard
Ratio
(95% CI)
p-value
0.45
(0.338,
0.607)
p<0.000
1
% of
Patients
without
Progressio
n or Death
12
18
mo mo
41
%
30
%
14
%
12
%
PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier
methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards
model, with the stratification factors used in randomization.