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 V Semiglazov, 6 M Ramos-Vazquez, 2 A Manikhas, 7 O Lipatov, 3 K Gelmon, 8 N McCarthy, 4 D Kranhozhon, 5 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 Simms 17 , M Buyse 18 , A Ibrahim 19 , M Martin 20

1

Cross Center Institute, Edmonton, Canada;

2

Centro Oncológico de Galicia "José Antonio Quiroga y Piñeiro", Coruña, Spain; 3 Republican Clinical Oncology Dispensary of Ministry of Health of Bashkortostan Republic, Ufa, Russia; 4 Haematology and Oncology Clinic Australia Wesley Medical Center, Queensland, Australia;

5

Leningrad Regional Oncology Dispensary, Leningrad, Russia;

6

Institute of Oncology N.N. Petrov, St. Petersburg, Russia;

7

City Clinical Oncology Dispensary, St. Petersburg, Russia;

8

British Columbia Cancer Agency, Vancouver, Canada;

9

University of California, Los Angeles;

10

Tom Baker Cancer Centre, Calgary, Canada;

11

Hospital Pérola Byigton Centro de Referência da Saúde da Mulher, Sao Paulo, Brazil;

12

Sunnybrook Health Sciences Center, Toronto, Canada;

13

N.N. Blokhin Russian Cancer Research Center of Russian Academy of Medical Sciences, Moscow, Russia;

14

Middle East Institute of Health, Bsalim, Lebanon; 15 Translational Research in Oncology, Paris, France;

16

Translational Research in Oncology, Edmonton, Canada;

17

Eli Lilly Canada Inc;

18 2

International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium;

19

ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Co.;

20

Hospital 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 (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

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 binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2 VEGF-A VEGFR2 Ramucirumab Endothelial cell Ligand binding activates VEGFR2 and p44/p42 MAP kinases Angiogenesis Tumor growth VEGFR2 VEGF-A VEGF-C VEGF-D Ramucirumab binds to VEGFR2, blocks VEGF ligand binding No signaling 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 Blinded Placebo I.V. q3wks Progressive Disease

Or

Unacceptable Toxicity

Or

Consent Withdraw Follow-up for PD and for OS

• • • •

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) Did not receive treatment (n=8) Ramucirumab Arm n=759 Ramucirumab-treated n=752* Intent- to treat population (n=1144) Safety population (n=1134) Placebo Arm n=385 Placebo-treated n=382* Did not receive treatment (n=2)

*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) RAM + DOC (N=759)

54(24 – 82)

PBO + DOC (N=385)

54(29 – 81)

ECOG PS, %

0 1

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 58 42 48 52 71 26 74 24 64 12 62 37 52 48 72 27 73 24 64 13

Mackey et. al. SABCS 2013 9

Baseline Characteristics (ITT)

RAM + DOC (N=759) PBO + DOC (N=385) Hormone Receptor Status, %

Positive Negative

ER, PR, HER2 Status, %

ER Positive Negative 76 24 72 27 77 23 75 25 PR Positive Negative 53 47 61 39 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

1,0

Progression-Free Survival

0,9 0,8 0,7 0,6 0,5 0,4 Number of Events (%) Median PFS, months (95% CI) Hazard Ratio (95% CI) P value RAM + DOC (n = 759) 0.077

PBO + DOC (n = 385) 528 (69.6) 9.5 (8.3, 9.8) 291 (75.6) 8.2 (7.1, 8.5) 0.88 (0.75, 1.01) 0,3 0,2 0,1 RAM + DOC PBO + DOC 0,0 0 Number patients at risk RAM + DOC PBO + DOC 759 385 591 284 6 439 219 313 140 12 211 96 151 61 18 86 39 24 47 27 Months 21 16 12 11 30 6 6 4 1 36 3 1 3 0 42 1 0 1 0 48 0 0

Mackey et. al. SABCS 2013 11

1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0

Independent Review Progression-Free Survival

RAM + DOC PBO + DOC 6 12 18 30 RAM + DOC (n = 759) 378 (49.8) PBO + DOC (n = 385) 224 (58.1) 11.1 (9.9, 11.8) 8.5 (7.9, 9.8) 0.79 (0.67, 0.94) 0.008

36 Number of patients at risk RAM +DOC PBO + DOC

759 385 593 275 440 202 296 127 198 84 140 57

24 Months

75 36 46 26 23 14 12 11 6 4 4 2

42

2 1 2 0

48

0 0 Mackey et. al. SABCS 2013 12

Overall Survival – Interim Analysis

1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 RAM + DOC PBO + DOC Number of Events (%) Median OS, months (95% CI) Hazard Ratio (95% CI) P value 6 Number patients at risk RAM + DOC PBO + DOC 759 385 730 371 686 354 636 327 12 561 296 485 249 18 354 182 24 233 126 Months 148 94 98 60 60 38 30 35 18 RAM + DOC (n = 759) 311 (41) 27.3 (23.6, 29.1) PBO + DOC (n = 385) 160 (41.6) 27.2 (24.3, 32.2) 1.01 (0.83, 1.23) 0.915

36 22 10 14 5 8 2 42 3 0 48 1 0 0 0

Mackey et. al. SABCS 2013 13

ROSE: PFS (Inv) by Subgroup (ITT)

RAM + DOC



better PBO + DOC better



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 N 759 PBO + DOC N 385 629 130 676 83 439 320 197 562 541 218 580 179 183 484 92 325 60 341 44 240 145 103 282 276 109 295 90 91 246 48 HR (95% CI) 0.88 (0.75, 1.01) 0.90 (0.77, 1.06) 0.85 (0.57, 1.28) 0.87 (0.75, 1.02) 1.27 (0.74, 2.18) 0.87 (0.72, 1.06) 0.85 (0.67, 1.08) 0.90 (0.68, 1.21) 0.86 (0.73, 1.03) 0.92 (0.78, 1.09) 0.75 (0.56, 1.01) 0.86 (0.72, 1.02) 0.93 (0.69, 1.25) 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

Best Overall Response Best Overall Response CR PR SD PD Inevaluable Objective Response Rate (CR + PR) Disease Control Rate (CR + PR + SD) Time to Progression Number of patients with progression (%) Median time to progression months (95% CI) Hazard Ratio, (95% CI) RAM + DOC (N=759) % 2.4

42.3

41.8

7.6

5.9

44.7

86.4

PBO + DOC (N=385) % 1.8

36.1

43.4

13.0

5.7

37.9

81.3

65.3

73.0

9.7 (8.5, 10.3) 8.2 (7.1, 9.0) 0.78 (0.65, 0.93) P-value 0.027

0.022

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 RAM + DOC (N = 752) PBO + DOC (N = 382) Docetaxel RAM + DOC (N = 752) PBO + DOC (N = 382)

Duration of Treatment (wks) Median Range Median Number of Cycles* Median Range Relative Dose Intensity (%) Median Range 28 (3 – 181.4) (0 (30 9 – 58) 97.2

– 114) 27.2

(3.0 – 169.9) 24.0

(3.0 – 137.1) 24.0

(3.0 – 169.9) 9 (1 – 52) 8 (1 – 40) 8 (1 – 52) 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 2013 16

Treatment Emergent Adverse Events

(≥10% of patients and higher incidence on RAM + Docetaxel Arm) Any AE Fatigue † Stomatitis Epistaxis Lacrimation increased Hypertension Weight decreased Decreased appetite Palmar-Plantar Erythrodysaesthesia Syndrome Insomnia RAM + DOC (N = 752) Any Grade % Grade ≥ 3 % 98.7

68.4

50.7* 39.9* 31.1* 27.0* 21.9* 21.7* 14.2* 13.0* 61.7* 16.4* 6.1* 0.1

0.8

6.8* 1.3

0.7

3.9*

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.

0 PBO + DOC (N = 382) Any Grade % Grade ≥ 3 % 98.2

66.0

52.4

9.7

30.6

16.8

17.0

1.0

0 0.5

11.5

10.5

16.2

1.8

0.5

0 8.6

8.4

1.0

0

Mackey et. al. SABCS 2013 17

Most Common Hematologic AEs

Neutropenia

†

Anemia

†

Febrile Neutropenia Thrombocytopenia Leukopenia

†

Any Grade %

RAM + DOC (N = 752)

Grade ≥ 3 % 17.6

10.1

8.1* 2.8

1.9

15.2

2.3

7.8* 0.8

1.2

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.

Any Grade %

PBO + DOC (N = 382)

Grade ≥ 3 % 16.0

7.3

13.1

1.8

4.2

1.6

3.1

3.9

0.5

1.8

Mackey et. al. SABCS 2013 18

Adverse Events of Special Interest

Bleeding / Hemorrhage Events Hypertension Infusion Related Reaction Proteinuria Venous Thromboembolic Events GI Perforation Arterial Thromboembolic Events Congestive Heart Failure Any Grade % RAM + DOC (N = 752) Grade ≥ 3 % 48.0* 27.0* 0.9

6.8* 11.4

5.1* 2.4

1.3* 1.1

1.1

1.9

0.4

1.3

1.2

0.7

0.3

Any Grade % PBO + DOC (N = 382) Grade ≥ 3 % 22.3

11.5

1.8

1.8

11.5

1.3

4.2* 0 1.3

0.8

1.8

0 3.1

0 0.3

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) Number of patients with any TEAE Disease progression † Death Hepatic Failure Renal Failure* Sepsis Sudden Death RAM + DOC (N = 752) n 29 10 2 2 2 2 2 % 3.9

1.3

0.3

0.3

0.3

0.3

0.3

*

Terms listed under Consolidated AE Category are composite terms comprising synonymous MedDRA preferred terms.

† Includes Disease and Neoplasm progression reported as adverse events PBO + DOC (N = 382) n 9 4 0 1 0 0 0 % 2.4

1.0

0 0.3

0 0 0

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

CANADA

J. Mackey K. Gelmon M. Webster S. Verma C. Prady L. Provencher J. Wilson

CZECH REPUBLIC:

P. Klepetko J. Vanasek V. Stahalova O. Bednarik

EGYPT

N. Allahloubi A. El Said H. El Zawahry

IRELAND

G. Gullo M. Keane C. Murphy J. Kennedy J. McCaffrey L. Coate S. O ´Reilly

ISRAEL

N. Efrat S. Stemmer M. Tokar T. Ryvo B. Uziely

LEBANON

D. Abi Gerges J. Kattan F. Farhat G. Chahine 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. Coccia Portugal 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

UNITED KINGDOM

J. Joffe T. Hickish M. Lind S. Del Barco A. Marquez M. Margeli

UNITED STATES

A. Thummala M. Saleh B. Bermejo R. Cubedo S. Servitja I. Alvarez A. Anton C. Rodriguez P. Sanchez J. Chacon J. Ponce J. Alarcon S. Sundaram M. Shtivelband S. Limentani I. Oliff P. Klein S. Chui R. Patel E. Hu G. Konecny R. Dichmann W. Walsh

TAIWAN

Y. Chang C. Huang S. Chen A. Bowman S. Chan R. Ansari J. Reeves F. Kass S. Beck P. Acs B. Bowers L. Siegel A. Wardley G. Harker M. Metcalfe G. Srkalovic I. Shalaby Mackey et. al. SABCS 2013 23

Additional Slides

Mackey et. al. SABCS 2013

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 25

Post-discontinuation Treatment

RAM + DOC (N=759)

n (%)

PBO + DOC (N=385)

n % Patients with any PDT* Chemotherapy Anthracycline Taxane Hormonal Radiotherapy Antiangiogenic Biologic therapy

†

Surgery (any) 480 361 133 73 211 100 18 7 33 (63) (48) (18) (10) (28) (13) (2) (0.9) (4.3) 266 218 73 44 115 69 15 1 14 (69) (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 N 759 PBO + DOC N 385 629 130 676 83 439 320 197 562 541 218 580 179 183 484 92 325 60 341 44 240 145 103 282 276 109 295 90 91 246 48 HR (95% CI) 1.01 (0.83, 1.23) 0.99 (0.80, 1.23) 1.01 (0.61, 1.67) 0.99 (0.80, 1.21) 1.62 (0.78, 3.37) 0.98 (0.75, 1.27) 0.98 (0.73, 1.32) 1.00 (0.70, 1.41) 1.02 (0.81, 1.28) 1.07 (0.86, 1.33) 0.83 (0.56, 1.25) 0.95 (0.76, 1.20) 1.16 (0.81, 1.66) 0.82 (0.57, 1.18) 1.10 (0.86, 1.41) 1.04 (0.57, 1.89) RAM + DOC



better PBO + DOC better



N = Total number of patients 0,5 1 2 Hazard Ratio (95% CI) 4