Abstract 238
Primary Results of ROSE, A Randomized Placebo
Controlled Phase III Trial Evaluating the Addition
of Ramucirumab to First-Line Docetaxel
Chemotherapy in Metastatic Breast Cancer
( TRIO-012 )
JR Mackey,1 M Ramos-Vazquez,2 O Lipatov,3 N McCarthy,4 D Kranhozhon,5
V Semiglazov,6 A Manikhas,7 K Gelmon,8 G Konecny,9 M Webster,10 R Hegg,11
S Verma,12 V Gorbunova,13 DA Gerges,14 F Thireau,15 H Fung,16
L Simms17, M Buyse18, A Ibrahim19, M Martin20
1Cross
Center Institute, Edmonton, Canada; 2Centro Oncológico de Galicia "José Antonio Quiroga y Piñeiro",
Coruña, Spain; 3Republican Clinical Oncology Dispensary of Ministry of Health of Bashkortostan Republic, Ufa,
Russia; 4Haematology and Oncology Clinic Australia Wesley Medical Center, Queensland, Australia; 5Leningrad
Regional Oncology Dispensary, Leningrad, Russia; 6Institute of Oncology N.N. Petrov, St. Petersburg, Russia;
7City Clinical Oncology Dispensary, St. Petersburg, Russia; 8British Columbia Cancer Agency, Vancouver,
Canada; 9University of California, Los Angeles; 10Tom Baker Cancer Centre, Calgary, Canada; 11Hospital Pérola
Byigton Centro de Referência da Saúde da Mulher, Sao Paulo, Brazil; 12Sunnybrook Health Sciences Center,
Toronto, Canada; 13N.N. Blokhin Russian Cancer Research Center of Russian Academy of Medical Sciences,
Moscow, Russia; 14Middle East Institute of Health, Bsalim, Lebanon; 15Translational Research in Oncology,
Paris, France; 16Translational Research in Oncology, Edmonton, Canada; 17Eli Lilly Canada Inc; 18 2International
Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium; 19ImClone Systems LLC, a wholly owned
subsidiary of Eli Lilly and Co.; 20Hospital General Universitario Gregorio Marañon, Madrid, Spain
On behalf of the ROSE/TRIO-012 Investigator Group
Disclosure
• Research support from ImClone a wholly owned subsidiary of
Eli Lilly and Company
Mackey et. al. SABCS 2013
2
Background
• Vascular endothelial growth factor receptor-2 (VEGFR2) and its ligands ( VEGF-A, -C, and -D ) are important
mediators of angiogenesis
• In human breast cancer, intensive neovascularization
and tumor angiogenesis correlate with metastases and
poor prognosis
• Clinical trials of antiangiogenic therapy for breast
cancer have not yet demonstrated improvements in
overall survival
Mackey et. al. SABCS 2013
3
Mechanism of ramucirumab action
 Ramucirumab (IMC-1121B; RAM) a recombinant human IgG1
monoclonal antibody that binds the extracellular domain of VEGF
Receptor-2
VEGF-C
VEGF-D
VEGF-A
VEGF-A
Ramucirumab
VEGF binds to
VEGFR2 receptor;
VEGF-C, -D compete
for binding to
VEGFR2
VEGF-C
VEGF-D
Ramucirumab binds to
VEGFR2, blocks VEGF
ligand binding
VEGFR2
Endothelial cell
Ligand binding
activates VEGFR2 and
p44/p42 MAP kinases
VEGFR2
No signaling
Angiogenesis
Tumor growth
Inhibit new blood vessel
formation and tumor growth
Study Design
Docetaxel 75mg/m² I.V. q3wks
Blinded Ram 10mg/kg I.V. q3wks
RANDOMIZATION
2:1
N=1144
Docetaxel 75mg/m² I.V. q3wks
Progressive
Disease
Or
Unacceptable
Toxicity
Or
Consent
Withdraw
Follow-up for PD
and for OS
Blinded Placebo I.V. q3wks
•
•
•
•
Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial
Her2-Negative, unresectable, locally-recurrent or metastatic breast cancer
No prior chemotherapy or biologic therapy for advanced breast cancer
Stratification Factors: Prior taxane, Visceral metastasis, Hormone receptor
status, Geographic region
Mackey et. al. SABCS 2013
Study Endpoints and Analyses
• Primary Endpoint
– Investigator-Assessed Progression-free Survival (PFS)
• 796 events from 1113 patients; 86% power to detect a difference
of 2 mos in median PFS (6 mos in the control group vs. 8 mos),
HR=0.75
• Primary analysis is a stratified log-rank test with 2-sided α=0.05
• Survival Interim Analysis
– To occur at time of final PFS analysis or 375 deaths,
whichever is later.
• Secondary Endpoints
– Overall Survival (OS)
• 792 events; 85% power to detect a difference of 6 mos in
median survival (24 mos for the control group vs 30 mos),
HR=0.8
– TTP, ORR, safety and QOL
Mackey et. al. SABCS 2013
6
Key Eligibility Criteria
• Women with HER2-negative metastatic or locally-recurrent and
inoperable breast cancer
• No prior chemotherapy or biologic therapy for metastatic /
recurrent breast cancer
• Completed (neo) adjuvant taxane therapy ≥ 6 mos, (neo)
adjuvant biologic therapy ≥ 6 wks, and radiotherapy with
curative intent ≥ 3 wks prior to randomization
• Adequate hematologic, hepatic, and renal function
• ECOG Performance Status of 0-1
• No uncontrolled hypertension, symptomatic congestive heart
failure, unstable angina pectoris, or symptomatic or poorly
controlled cardiac arrhythmia
Mackey et. al. SABCS 2013
7
ROSE: Patient Disposition
Patients screened (n=1455)
Not eligible (n=311)
Patients randomized (n=1144)
(2:1 randomization)
Ramucirumab Arm
n=759
Did not receive
treatment (n=8)
Ramucirumab-treated
n=752*
Intent- totreat
population
(n=1144)
Safety
population
(n=1134)
Placebo Arm
n=385
Did not receive
treatment (n=2)
Placebo-treated
n=382*
*One PBO+DOC randomized patient , received RAM + DOC in Cycle 1 only therefore is included in the RAM + DOC safety population
•
1144 patients were randomized (Aug 2008 to Dec 2011)
•
Data cut-off on 31 Mar 2013 after observation of at least 796 PFS events
and > 375 OS events; database lock 29 Aug 2013 with 819 PFS and 471
OS events
Baseline Characteristics (ITT)
Median Age, years (range)
ECOG PS, %
0
1
RAM + DOC
(N=759)
PBO + DOC
(N=385)
54(24 – 82)
54(29 – 81)
58
42
62
37
48
52
52
48
71
72
26
74
27
73
24
64
12
24
64
13
Number of Metastatic Sites, %
<3
≥3
Disease Site
Visceral
Prior taxane therapy, %
Yes
No
Geographical Region, %
North & South America
Europe/Australia/New Zealand
Asia/Middle East/Africa
Mackey et. al. SABCS 2013
9
Baseline Characteristics (ITT)
RAM + DOC
(N=759)
PBO + DOC
(N=385)
76
24
77
23
ER Positive
Negative
72
27
75
25
PR Positive
Negative
53
47
61
39
Hormone Receptor Status, %
Positive
Negative
ER, PR, HER2 Status, %
HER2 Negative (IHC 0-1+ or ISH neg)
100
99.7
Triple Negative, %
Yes
No
25
75
22
78
Mackey et. al. SABCS 2013
10
Investigator-Assessed
Progression-Free Survival
Probability for Progression-free Survival
1.0
0.9
0.8
Number of Events (%)
Median PFS, months (95% CI)
0.7
RAM + DOC
(n = 759)
PBO + DOC
(n = 385)
528 (69.6)
291 (75.6)
9.5 (8.3, 9.8)
8.2 (7.1, 8.5)
Hazard Ratio (95% CI)
0.6
0.88 (0.75, 1.01)
P value
0.077
0.5
0.4
0.3
0.2
RAM + DOC
0.1
PBO + DOC
0.0
0
Number patients at risk
RAM + DOC
759
PBO + DOC
385
6
12
18
24
30
36
42
48
Months
591
284
439
219
313
140
211
96
151
61
86
39
47
27
21
16
12
11
6
6
4
1
3
1
3
0
1
0
1
0
Mackey et. al. SABCS 2013
0
0
11
Independent Review
Progression-Free Survival
Probability for Progression-free Survival
1.0
0.9
Number of Events (%)
0.8
Median PFS, months (95% CI)
0.7
RAM + DOC
(n = 759)
PBO + DOC
(n = 385)
378 (49.8)
224 (58.1)
11.1 (9.9, 11.8)
8.5 (7.9, 9.8)
Hazard Ratio (95% CI)
0.79 (0.67, 0.94)
P value
0.6
0.008
0.5
0.4
0.3
0.2
RAM + DOC
0.1
PBO + DOC
0.0
0
6
12
18
759
385
30
36
42
48
Months
Number of patients at risk
RAM +DOC
PBO + DOC
24
593
275
440
202
296
127
198
84
140
57
75
36
46
26
23
14
12
11
6
4
4
2
2
1
2
0
0
0
Mackey et. al. SABCS 2013
12
Overall Survival – Interim Analysis
PBO + DOC
(n = 385)
311 (41)
160 (41.6)
27.3 (23.6, 29.1)
27.2 (24.3, 32.2)
Number of Events (%)
1.0
Median OS, months (95% CI)
0.9
Probability for Overall Survival
RAM + DOC
(n = 759)
Hazard Ratio (95% CI)
0.8
1.01 (0.83, 1.23)
P value
0.915
0.7
0.6
0.5
0.4
0.3
RAM + DOC
0.2
PBO + DOC
0.1
0.0
0
Number patients at risk
RAM + DOC
759
PBO + DOC
385
6
12
18
24
30
36
42
48
Months
730
371
686
354
636
327
561
296
485
249
354
182
233
126
148
94
98
60
60
38
35
18
22
10
14
5
8
2
3
0
1
0
0
0
Mackey et. al. SABCS 2013
13
ROSE: PFS (Inv) by Subgroup (ITT)
Subgroups
Overall
Age Group
< 65
≥ 65
Race
White
Non-White
ECOG PS
0
≥1
Prior Taxane (IWRS)
Yes
No
Sites of Metastases (IWRS)
Visceral
Non-visceral
Hormone Receptor Status (IWRS)
Positive
Negative/Unknown
Geographic Region
North and South America
Europe/Australia/New Zealand
Asia/Africa/Middle East
RAM + DOC PBO + DOC
RAM + DOC PBO + DOC
 better better 
N
N
HR (95% CI)
759
385
0.88 (0.75, 1.01)
629
130
325
60
0.90 (0.77, 1.06)
0.85 (0.57, 1.28)
676
83
341
44
0.87 (0.75, 1.02)
1.27 (0.74, 2.18)
439
320
240
145
0.87 (0.72, 1.06)
0.85 (0.67, 1.08)
197
562
103
282
0.90 (0.68, 1.21)
0.86 (0.73, 1.03)
541
218
276
109
0.92 (0.78, 1.09)
0.75 (0.56, 1.01)
580
179
295
90
0.86 (0.72, 1.02)
0.93 (0.69, 1.25)
183
484
92
91
246
48
0.82 (0.59, 1.13)
0.87 (0.73, 1.04)
1.02 (0.65, 1.61)
0.5
N = Total number of patients
1
2
Hazard Ratio (95% CI)
Mackey et. al. SABCS 2013
4
Best Overall Response and Time to Progression
Investigator Review Assessment
RAM + DOC
(N=759)
PBO + DOC
(N=385)
%
%
Best Overall Response
CR
PR
SD
PD
Inevaluable
2.4
42.3
41.8
7.6
5.9
1.8
36.1
43.4
13.0
5.7
Objective Response Rate (CR + PR)
44.7
37.9
0.027
Disease Control Rate (CR + PR + SD)
86.4
81.3
0.022
65.3
73.0
9.7 (8.5, 10.3)
8.2 (7.1, 9.0)
Best Overall Response
P-value
Time to Progression
Number of patients with progression (%)
Median time to progression months (95% CI)
Hazard Ratio, (95% CI)
0.78 (0.65, 0.93)
0.034*
*Log-rank p-value stratified by prior use of taxane therapy, visceral metastasis, hormone receptor status, and geographic region.
Mackey et. al. SABCS 2013
15
Treatment Administration
Ramucirumab/Placebo
Docetaxel
RAM + DOC
(N = 752)
PBO + DOC
(N = 382)
RAM + DOC
(N = 752)
PBO + DOC
(N = 382)
28
(3 – 181.4)
27.2
(3.0 – 169.9)
24.0
(3.0 – 137.1)
24.0
(3.0 – 169.9)
9
(0 – 58)
9
(1 – 52)
8
(1 – 40)
8
(1 – 52)
Duration of Treatment (wks)
Median
Range
Median Number of Cycles*
Median
Range
Relative Dose Intensity (%)
Median
Range
97.2
(30 – 114)
97.3
96.7
98.1
(73.8 – 106.7) (54.6 – 106.7) (61.3 – 103.2)
* Cycle consists of 21 days
Mackey et. al. SABCS 2013
16
Treatment Emergent Adverse Events
(≥10% of patients and higher incidence on RAM + Docetaxel Arm)
RAM + DOC
(N = 752)
PBO + DOC
(N = 382)
Any Grade %
Grade ≥ 3 %
Any Grade %
Grade ≥ 3 %
Any AE
98.7
61.7*
98.2
52.4
Fatigue†
68.4
16.4*
66.0
9.7
Stomatitis
50.7*
6.1*
30.6
1.0
Epistaxis
39.9*
0.1
16.8
0
Lacrimation increased
31.1*
0.8
17.0
0.5
Hypertension
27.0*
6.8*
11.5
1.8
Weight decreased
21.9*
1.3
10.5
0.5
Decreased appetite
21.7*
0.7
16.2
0
Palmar-Plantar
Erythrodysaesthesia Syndrome
14.2*
3.9*
8.6
1.0
Insomnia
13.0*
0
8.4
0
MedDRA Version 16.0; CTCAE version 3.0 are used.
*p-value <0.05 using Fisher’s exact test comparing RAM to PBO
† Consolidated AE category comprising synonymous MEdDRA preferred terms.
Mackey et. al. SABCS 2013
17
Most Common Hematologic AEs
RAM + DOC
(N = 752)
PBO + DOC
(N = 382)
Any Grade
%
Grade ≥ 3
%
Any Grade
%
Grade ≥ 3
%
Neutropenia†
17.6
15.2
16.0
13.1
Anemia†
10.1
2.3
7.3
1.8
Febrile Neutropenia
8.1*
7.8*
4.2
3.9
Thrombocytopenia
2.8
0.8
1.6
0.5
Leukopenia†
1.9
1.2
3.1
1.8
MedDRA Version 16.0; CTCAE version 3.0 are used.
*p-value <0.05 using Fisher’s exact test comparing RAM to PBO
† Consolidated AE category comprising synonymous MEdDRA preferred terms.
Mackey et. al. SABCS 2013
18
Adverse Events of Special Interest
RAM + DOC
(N = 752)
PBO + DOC
(N = 382)
Any Grade
%
Grade ≥ 3
%
Any Grade
%
Grade ≥ 3
%
Bleeding / Hemorrhage Events
48.0*
0.9
22.3
1.8
Hypertension
27.0*
6.8*
11.5
1.8
Infusion Related Reaction
11.4
1.9
11.5
1.8
Proteinuria
5.1*
0.4
1.3
0
Venous Thromboembolic Events
2.4
1.3
4.2*
3.1
GI Perforation
1.3*
1.2
0
0
Arterial Thromboembolic Events
1.1
0.7
1.3
0.3
Congestive Heart Failure
1.1
0.3
0.8
0.3
MedDRA Version 16.0; CTCAE version 3.0 are used.
*p-value <0.05 using Fisher’s exact test comparing RAM to PBO
Mackey et. al. SABCS 2013
19
Treatment Emergent Adverse Events
with an Outcome of Death
(Any TEAE with a fatal outcome in 2 or more patients on either treatment arm)
RAM + DOC
(N = 752)
PBO + DOC
(N = 382)
n
%
n
%
Number of patients with any TEAE
29
3.9
9
2.4
Disease progression†
10
1.3
4
1.0
Death
2
0.3
0
0
Hepatic Failure
2
0.3
1
0.3
Renal Failure*
2
0.3
0
0
Sepsis
2
0.3
0
0
Sudden Death
2
0.3
0
0
*Terms listed under Consolidated AE Category are composite terms comprising synonymous MedDRA preferred terms.
† Includes Disease and Neoplasm progression reported as adverse events
Mackey et. al. SABCS 2013
Conclusions
• Ramucirumab + docetaxel did not significantly prolong the
primary endpoint of investigator assessed Progression Free
Survival over placebo + docetaxel (HR 0.88, p=0.077)
• IRC assessed PFS was slightly longer on the RAM arm (HR
0.79, p=0.008)
• No difference observed in this interim overall survival analysis
• ORR, DCR, and TTP were higher on the Ramucirumab arm
• Efficacy results did not differ in clinical subgroups
• Ramucirumab + docetaxel therapy had higher rates of adverse
events including fatigue, hypertension, bleeding, febrile
neutropenia, and stomatitis
Mackey et. al. SABCS 2013
21
Acknowledgments
We thank the study participants and their families, the members of
the Independent Data Monitoring Committee, and the TRIO network of
investigators and study staff.
Mackey et. al. SABCS 2013
22
Investigators
AUSTRALIA
N. McCarthy
R. Snyder
A. Bonaventura
E. Abdi
G. Kannourakis
A. Redfern
J. Chirgwin
D. Dalley
M. White
G. Beadle
R. Lowenthal
S. Ng
M. Cronk
R. Jennens
J. Thomson
F. Boyle
BELGIUM
J. Canon
G. Jerusalem
M. Graas
M. Huizing
V. Cocquyt
P. Vuylsteke
L. D'Hondt
M. Borms
D. Verhoeven
BRAZIL
R. Hegg
M. Mano
F. Franke
P. Santi
S. Sanches
J. Vinholes
C. Barrios
A. Morelle
GERMANY
B. Ataseven
H. Eidtmann
J. Ettl
M. Clemens
B. Luhn
V. Mueller
P. Krabisch
IRELAND
G. Gullo
CANADA
M. Keane
J. Mackey
C. Murphy
K. Gelmon
J. Kennedy
M. Webster
J. McCaffrey
S. Verma
L. Coate
C. Prady
L. Provencher S. O´Reilly
ISRAEL
J. Wilson
N. Efrat
CZECH
S. Stemmer
REPUBLIC:
M. Tokar
P. Klepetko
T. Ryvo
J. Vanasek
B. Uziely
V. Stahalova
LEBANON
O. Bednarik
D. Abi Gerges
J. Kattan
EGYPT
F. Farhat
N. Allahloubi
G. Chahine
A. El Said
H. El Zawahry A. Mugharbil
N. Kassem
G. Nsouli
NEW ZEALAND
D. Porter
R. Isaacs
PERU
M. Philco
H. Morón
W. Rodriguez
C. Lozada
POLAND
A. Piktel
Z. Rusinowska
W. Rogowski
REPUBLIC of
KOREA
S. Lee
Y. Park
S. Im
RUSSIA
O. Lipatov
D. Krasnozhon
V. Semiglazov
A. Manikhas
V. Gorbunova
I. Kiselev
R. Khasanov
I. Litvinov
M. Kopp
V. Merkulov
RUSSIA
S. Averyanova
A. Khorinko
A. Makhson
V. Shirinkin
V. Borisov
N. Chekha
V. Milovanov
SERBIA
S. Filipovic
SLOVAKIA
S. Spanik
R. Hruby
SOUTH AFRICA
G. Cohen
K. Maart
D. Vorobiof
M. CocciaPortugal
G. Demetriou
L. Dreosti
J. Jordaan
SPAIN
M. Martin
J. Garcia-Saenz
S. Morales
A. Gonzalez
SPAIN
N. Batista
M. Ruiz Borrego
M. Muñoz
A. Ruiz
S. Del Barco
A. Marquez
M. Margeli
B. Bermejo
R. Cubedo
S. Servitja
I. Alvarez
A. Anton
C. Rodriguez
P. Sanchez
J. Chacon
J. Ponce
J. Alarcon
UNITED KINGDOM
J. Joffe
T. Hickish
M. Lind
UNITED STATES
A. Thummala
M. Saleh
S. Sundaram
M. Shtivelband
S. Limentani
I. Oliff
P. Klein
S. Chui
R. Patel
E. Hu
G. Konecny
R. Dichmann
W. Walsh
G. Harker
M. Metcalfe
TAIWAN
R. Ansari
Y. Chang
J. Reeves
C. Huang
F. Kass
S. Chen
S. Beck
UNITED KINGDOMP. Acs
B. Bowers
A. Bowman
L. Siegel
S. Chan
G. Srkalovic
A. Wardley
I. Shalaby
Mackey et. al. SABCS 2013
23
Additional
Slides
Mackey et. al. SABCS 2013
Treatment Discontinuations (ITT)
RAM + DOC
(N = 759)
Ongoing, n (%)
53 ( 7.0)
PBO + DOC
(N = 385)
25 ( 6.5)
Discontinuations, n (%)
Progressive Disease†
398
(51.0)
251 (65.2)
Adverse Event
126
(17.0)
45 (12.0)
Death
12
( 1.6)
4 ( 1.0)
Consent Withdrawn††
87
(11.4)
30 ( 7.8)
Other
70
( 9.2)
23 ( 6.2)
Protocol Non-Compliance
7
( 0.9)
4
( 1.0)
Lost to Follow-up
6
( 0.7)
3
( 0.7)
†Including
† † Including
clinical progression.
consent withdrawn from protocol medication and consent withdrawn from overall study participation.
Mackey et. al. SABCS 2013
25
Post-discontinuation Treatment
RAM + DOC (N=759)
Patients with any
PDT*
Chemotherapy
Anthracycline
Taxane
Hormonal
Radiotherapy
Antiangiogenic
Biologic therapy†
Surgery (any)
PBO + DOC (N=385)
n
(%)
n
%
480
(63)
266
(69)
361
133
73
211
100
18
7
33
(48)
(18)
(10)
(28)
(13)
(2)
(0.9)
(4.3)
218
73
44
115
69
15
1
14
(57)
(19)
(11)
(30)
(18)
(4)
(0.3)
(3.6)
*PDT = Post-discontinuation Treatment; each patient may have received more than one regimen.
†Other than Antiangiogenic therapy.
Mackey et. al. SABCS 2013
ROSE: OS by Subgroup (ITT)
Subgroups
Overall
Age Group
< 65
≥ 65
Race
White
Non-White
ECOG PS
0
≥1
Prior Taxane (IWRS)
Yes
No
Sites of Metastases (IWRS)
Visceral
Non-visceral
Hormone Receptor Status (IWRS)
Positive
Negative/Unknown
Geographic Region
North and South America
Europe/Australia/New Zealand
Asia/Africa/Middle East
RAM + DOC PBO + DOC
RAM + DOC PBO + DOC
 better better 
N
N
HR (95% CI)
759
385
1.01 (0.83, 1.23)
629
130
325
60
0.99 (0.80, 1.23)
1.01 (0.61, 1.67)
676
83
341
44
0.99 (0.80, 1.21)
1.62 (0.78, 3.37)
439
320
240
145
0.98 (0.75, 1.27)
0.98 (0.73, 1.32)
197
562
103
282
1.00 (0.70, 1.41)
1.02 (0.81, 1.28)
541
218
276
109
1.07 (0.86, 1.33)
0.83 (0.56, 1.25)
580
179
295
90
0.95 (0.76, 1.20)
1.16 (0.81, 1.66)
183
484
92
91
246
48
0.82 (0.57, 1.18)
1.10 (0.86, 1.41)
1.04 (0.57, 1.89)
0.5
N = Total number of patients
1
2
Hazard Ratio (95% CI)
4