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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
Mackey et. al. SABCS 2013 2
Disclosure
• Research support from ImClone a wholly owned subsidiary of Eli Lilly and Company
Mackey et. al. SABCS 2013 3
Background
• Vascular endothelial growth factor receptor-2 (VEGFR-2) 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
AngiogenesisTumor growth
VEGF-A
VEGFR2
VEGF-A
VEGFR2
Ligand binding activates VEGFR2 andp44/p42 MAP kinases
Ramucirumab
No signaling
Inhibit new blood vesselformation and tumor growth
Ramucirumab binds to VEGFR2, blocks VEGFligand binding
VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2
¨ Ramucirumab (IMC-1121B; RAM) a recombinant human IgG1 monoclonal antibody that binds the extracellular domain of VEGF Receptor-2
Mechanism of ramucirumab action
Endothelial cell
VEGF-CVEGF-D
VEGF-CVEGF-D
Mackey et. al. SABCS 2013
RANDOMIZATION2:1
Follow-up for PD and for OS
ProgressiveDisease
Or Unacceptable
ToxicityOr
Consent Withdraw
Docetaxel 75mg/m² I.V. q3wks
Blinded Ram 10mg/kg I.V. q3wks
Docetaxel 75mg/m² I.V. q3wks
Blinded Placebo I.V. q3wks
Study Design
• 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
N=1144
Mackey et. al. SABCS 2013 6
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 7
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
ROSE: Patient DispositionPatients screened (n=1455)
Patients randomized (n=1144)(2:1 randomization)
Not eligible (n=311)
Ramucirumab Armn=759
Placebo Armn=385
Ramucirumab-treatedn=752*
Placebo-treatedn=382*
Did not receive treatment (n=8)
Did not receive treatment (n=2)
Intent- to-treat
population
(n=1144)
Safety population
(n=1134)
• 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
*One PBO+DOC randomized patient , received RAM + DOC in Cycle 1 only therefore is included in the RAM + DOC safety population
Mackey et. al. SABCS 2013 9
Baseline Characteristics (ITT)RAM + DOC
(N=759)PBO + DOC
(N=385)Median Age, years (range) 54(24 – 82) 54(29 – 81)
ECOG PS, % 0 1
5842
6237
Number of Metastatic Sites, % <3 ≥3
4852
5248
Disease Site Visceral 71 72
Prior taxane therapy, % Yes No
2674
2773
Geographical Region, % North & South America Europe/Australia/New Zealand Asia/Middle East/Africa
246412
246413
Mackey et. al. SABCS 2013 10
Baseline Characteristics (ITT)RAM + DOC
(N=759)PBO + DOC
(N=385)
Hormone Receptor Status, % Positive Negative
76 24
7723
ER, PR, HER2 Status, %
ER Positive Negative
72 27
7525
PR Positive Negative
53 47
6139
HER2 Negative (IHC 0-1+ or ISH neg)
100
99.7
Triple Negative, % Yes No
25 75
2278
Mackey et. al. SABCS 2013 11
Investigator-AssessedProgression-Free Survival
RAM + DOC(n = 759)
PBO + DOC(n = 385)
Number of Events (%) 528 (69.6) 291 (75.6)
Median PFS, months (95% CI) 9.5 (8.3, 9.8) 8.2 (7.1, 8.5)
Hazard Ratio (95% CI) 0.88 (0.75, 1.01)
P value 0.077
759 591 439 313 211 151 86 47 21 12 6 4 3 3 1 1 0RAM + DOC
385 284 219 140 96 61 39 27 16 11 6 1 1 0 0 0 0PBO + DOC
Number patients at risk
0 6 12 18 24 30 36 42 480.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RAM + DOC
PBO + DOC
Months
Pro
ba
bili
ty f
or
Pro
gre
ss
ion
-fre
e S
urv
iva
l
Mackey et. al. SABCS 2013 12
RAM + DOC(n = 759)
PBO + DOC(n = 385)
Number of Events (%) 378 (49.8) 224 (58.1)
Median PFS, months (95% CI) 11.1 (9.9, 11.8) 8.5 (7.9, 9.8)
Hazard Ratio (95% CI) 0.79 (0.67, 0.94)
P value 0.008
Independent Review Progression-Free Survival
759 593 440 296 198 140 75 46 23 12 6 4 2 0RAM +DOC385 275 202 127 84 57 36 26 14 11 4 2 1 0PBO + DOC
Number of patients at risk
20
0 6 12 18 24 30 36 42 480.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RAM + DOC
PBO + DOC
Months
Pro
ba
bili
ty f
or
Pro
gre
ss
ion
-fre
e S
urv
iva
l
Mackey et. al. SABCS 2013 13
Overall Survival – Interim Analysis
759 730 686 636 561 485 354 233 148 98 60 35 22 14 8 3 1 0RAM + DOC
385 371 354 327 296 249 182 126 94 60 38 18 10 5 2 0 0 0PBO + DOC
Number patients at risk
0 6 12 18 24 30 36 42 480.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RAM + DOC
PBO + DOC
Months
Pro
ba
bil
ity
fo
r O
ve
rall
Su
rviv
al
RAM + DOC(n = 759)
PBO + DOC(n = 385)
Number of Events (%) 311 (41) 160 (41.6)
Median OS, months (95% CI) 27.3 (23.6, 29.1) 27.2 (24.3, 32.2)
Hazard Ratio (95% CI) 1.01 (0.83, 1.23)
P value 0.915
Mackey et. al. SABCS 2013
ROSE: PFS (Inv) by Subgroup (ITT)Subgroups
RAM + DOCN
PBO + DOCN HR (95% CI)
Overall 759 385 0.88 (0.75, 1.01)Age Group < 65 629 325 0.90 (0.77, 1.06) ≥ 65 130 60 0.85 (0.57, 1.28)Race White 676 341 0.87 (0.75, 1.02) Non-White 83 44 1.27 (0.74, 2.18)ECOG PS 0 439 240 0.87 (0.72, 1.06) ≥ 1 320 145 0.85 (0.67, 1.08)Prior Taxane (IWRS) Yes 197 103 0.90 (0.68, 1.21) No 562 282 0.86 (0.73, 1.03)Sites of Metastases (IWRS) Visceral 541 276 0.92 (0.78, 1.09) Non-visceral 218 109 0.75 (0.56, 1.01)Hormone Receptor Status (IWRS) Positive 580 295 0.86 (0.72, 1.02) Negative/Unknown 179 90 0.93 (0.69, 1.25)Geographic Region North and South America 183 91 0.82 (0.59, 1.13) Europe/Australia/New Zealand 484 246 0.87 (0.73, 1.04) Asia/Africa/Middle East 92 48 1.02 (0.65, 1.61)
0.5
Hazard Ratio (95% CI)N = Total number of patients
RAM + DOC better
PBO + DOCbetter
Mackey et. al. SABCS 2013 15
Best Overall Response and Time to Progression Investigator Review Assessment
RAM + DOC(N=759)
PBO + DOC(N=385)
P-value
Best Overall Response % %
Best Overall Response CR PR SD PD Inevaluable
2.442.341.8 7.6 5.9
1.836.143.413.0 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
Time to Progression
Number of patients with progression (%) 65.3 73.0
Median time to progression months (95% CI) 9.7 (8.5, 10.3) 8.2 (7.1, 9.0)
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 16
Treatment Administration
Ramucirumab/Placebo Docetaxel
RAM + DOC(N = 752)
PBO + DOC (N = 382)
RAM + DOC(N = 752)
PBO + DOC (N = 382)
Duration of Treatment (wks)
Median Range
28(3 – 181.4)
27.2(3.0 – 169.9)
24.0(3.0 – 137.1)
24.0(3.0 – 169.9)
Median Number of Cycles*
Median Range
9(0 – 58)
9(1 – 52)
8(1 – 40)
8(1 – 52)
Relative Dose Intensity (%)
Median Range
97.2(30 – 114)
97.3(73.8 – 106.7)
96.7(54.6 – 106.7)
98.1(61.3 – 103.2)
* Cycle consists of 21 days
Mackey et. al. SABCS 201317
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 18
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 19
Adverse Events of Special InterestRAM + 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
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 21
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 22
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 23
CANADAJ. MackeyK. GelmonM. WebsterS. VermaC. PradyL. ProvencherJ. Wilson
GERMANYB. AtasevenH. EidtmannJ. EttlM. ClemensB. LuhnV. MuellerP. Krabisch
REPUBLIC of KOREAS. LeeY. ParkS. Im
RUSSIAS. AveryanovaA. KhorinkoA. MakhsonV. ShirinkinV. BorisovN. ChekhaV. Milovanov
AUSTRALIA N. McCarthyR. SnyderA. BonaventuraE. AbdiG. KannourakisA. RedfernJ. ChirgwinD. DalleyM. WhiteG. BeadleR. LowenthalS. NgM. CronkR. JennensJ. ThomsonF. Boyle
BRAZILR. HeggM. ManoF. FrankeP. SantiS. SanchesJ. Vinholes C. Barrios A. Morelle
CZECHREPUBLIC: P. KlepetkoJ. Vanasek V. StahalovaO. Bednarik
EGYPTN. AllahloubiA. El SaidH. El Zawahry
IRELANDG. GulloM. KeaneC. MurphyJ. KennedyJ. McCaffreyL. CoateS. O´ReillyISRAEL N. EfratS. StemmerM. TokarT. RyvoB. Uziely
PERU M. PhilcoH. MorónW. RodriguezC. Lozada
NEW ZEALAND D. PorterR. Isaacs
LEBANOND. Abi GergesJ. KattanF. FarhatG. ChahineA. MugharbilN. KassemG. Nsouli
SPAINM. Martin J. Garcia-SaenzS. MoralesA. Gonzalez
SERBIA S. Filipovic
UNITED STATESA. ThummalaM. SalehS. SundaramM. ShtivelbandS. LimentaniI. OliffP. KleinS. ChuiR. PatelE. HuG. KonecnyR. DichmannW. WalshG. HarkerM. MetcalfeR. AnsariJ. ReevesF. KassS. BeckP. AcsB. BowersL. SiegelG. SrkalovicI. Shalaby
TAIWAN Y. ChangC. HuangS. Chen
POLANDA. PiktelZ. RusinowskaW. Rogowski
UNITED KINGDOM A. BowmanS. ChanA. Wardley
BELGIUMJ. CanonG. JerusalemM. GraasM. HuizingV. CocquytP. Vuylsteke L. D'HondtM. BormsD. Verhoeven
SOUTH AFRICA G. CohenK. MaartD. VorobiofM. Coccia-PortugalG. DemetriouL. DreostiJ. Jordaan
SLOVAKIA S. SpanikR. Hruby
RUSSIAO. LipatovD. KrasnozhonV. SemiglazovA. ManikhasV. GorbunovaI. KiselevR. KhasanovI. LitvinovM. KoppV. Merkulov
SPAINN. Batista M. Ruiz Borrego M. MuñozA. RuizS. Del BarcoA. MarquezM. MargeliB. BermejoR. Cubedo S. ServitjaI. AlvarezA. AntonC. Rodriguez P. SanchezJ. ChaconJ. PonceJ. Alarcon
UNITED KINGDOM J. JoffeT. HickishM. Lind
Investigators
Mackey et. al. SABCS 2013
AdditionalSlides
Mackey et. al. SABCS 2013 25
Treatment Discontinuations (ITT)
RAM + DOC(N = 759)
PBO + DOC (N = 385)
Ongoing, n (%) 53 ( 7.0) 25 ( 6.5)
Discontinuations, n (%)
Progressive Disease†
Adverse Event
Death
Consent Withdrawn††
Other
Protocol Non-Compliance
Lost to Follow-up
398
126
12
87
70
7
6
(51.0)
(17.0)
( 1.6)
(11.4)
( 9.2)
( 0.9)
( 0.7)
251
45
4
30
23
4
3
(65.2)
(12.0)
( 1.0)
( 7.8)
( 6.2)
( 1.0)
( 0.7)
†Including clinical progression.† † Including consent withdrawn from protocol medication and consent withdrawn from overall study participation.
Mackey et. al. SABCS 2013
Post-discontinuation Treatment
RAM + DOC (N=759) PBO + DOC (N=385)
n (%) n %
Patients with any PDT*
480 (63) 266 (69)
Chemotherapy 361 (48) 218 (57)
Anthracycline 133 (18) 73 (19)
Taxane 73 (10) 44 (11)
Hormonal 211 (28) 115 (30)
Radiotherapy 100 (13) 69 (18)
Antiangiogenic 18 (2) 15 (4)
Biologic therapy† 7 (0.9) 1 (0.3)
Surgery (any) 33 (4.3) 14 (3.6)
*PDT = Post-discontinuation Treatment; each patient may have received more than one regimen.†Other than Antiangiogenic therapy.
ROSE: OS by Subgroup (ITT)
SubgroupsRAM + DOC
NPBO + DOC
N HR (95% CI)Overall 759 385 1.01 (0.83, 1.23)Age Group < 65 629 325 0.99 (0.80, 1.23) ≥ 65 130 60 1.01 (0.61, 1.67)Race White 676 341 0.99 (0.80, 1.21) Non-White 83 44 1.62 (0.78, 3.37)ECOG PS 0 439 240 0.98 (0.75, 1.27) ≥ 1 320 145 0.98 (0.73, 1.32)Prior Taxane (IWRS) Yes 197 103 1.00 (0.70, 1.41) No 562 282 1.02 (0.81, 1.28)Sites of Metastases (IWRS) Visceral 541 276 1.07 (0.86, 1.33) Non-visceral 218 109 0.83 (0.56, 1.25)Hormone Receptor Status (IWRS) Positive 580 295 0.95 (0.76, 1.20) Negative/Unknown 179 90 1.16 (0.81, 1.66)Geographic Region North and South America 183 91 0.82 (0.57, 1.18) Europe/Australia/New Zealand 484 246 1.10 (0.86, 1.41) Asia/Africa/Middle East 92 48 1.04 (0.57, 1.89)
0.5
Hazard Ratio (95% CI)N = Total number of patients
RAM + DOC better
PBO + DOCbetter