RIBBON-1: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy

with or without Bevacizumab for First-Line Treatment of HER2-Negative Locally Recurrent

or Metastatic Breast Cancer

Fairfax Northern Virginia Hematology Oncology, U.S. Oncology, Fairfax, VA; Institut Curie, Paris, France; UCLA TORI, Los Angeles, CA;

Univ. of Pittsburgh, Pittsburgh, PA; State Medical Academy, Dnepropetrovsk, Ukraine; Bashkirian Republican Clinical Oncology,

Ufa, Russia; Mayo Clinic, Jacksonville, FL; Sarah Cannon Cancer Center, Nashville, TN; Baylor-Sammons Cancer Center, Texas Oncology, U.S. Oncology, Dallas, TX; Genentech, South San Francisco, CA

N. Robert, V. Dieras, J. Glaspy, A. Brufsky, I. Bondarenko, O. Lipatov, E. Perez, D. Yardley,

J. O’Shaughnessy, X. Zhou, S. Phan

Introduction

• Bevacizumab (BV), a monoclonal antibody, directly inhibits vascular endothelial growth factor (VEGF), a central mediator of angiogenesis.

• Two previous Phase III trials demonstrated that BV + 1st line taxanes (paclitaxel and docetaxel) improved progression-free survival (PFS) for metastatic breast cancer (MBC) patients.

• RIBBON-1 was designed to demonstrate the clinical benefit of combining BV with other chemotherapies used for MBC.

Study Design

• Capecitabine (1000 mg/m2 BID x 14d)

• Taxane (docetaxel q3w or protein-bound paclitaxel q3w)

• Anthracycline-based chemotherapy (AC, EC, FAC, FEC)

• Placebo or bevacizumab (15 mg/kg q3w)

CHOICE OF CHEMO

BY INVESTIGATOR

Capecitabineor

Taxaneor

Anthracycline

Previously untreated MBC

(n=1237)

Stratification Factors:

• Disease-free interval

• Previous adjuvant chemotherapy

• Number of metastatic sites

• Cape, T or Anthra

Chemo +bevacizumab

q3w

Chemo +placebo

q3w

Optional2nd-line Chemo

+bevacizumab

Treat untilPD

RA

ND

OM

IZE

2:

1

Key Eligibility Criteria

• Age ≥18 years

• ECOG performance status 0 or 1

• Histologically confirmed, locally recurrent or MBC

• No prior chemotherapy for locally recurrent or MBC

• HER2-negative MBC

• ≥12 months since any prior adjuvant chemotherapy

Study Endpoints

• Primary endpoint:

- PFS, as assessed by investigator

• Secondary endpoints:

- PFS, by independent review committee (IRC)

- Objective response rate (ORR)

- Overall survival (OS) & 1-year survival rate

- Safety

Statistical Design and Analyses

HR Power Sample Size

Capecitabine 0.75 80% 600

Taxane/Anthracycline 0.70 90% 600*

CHOICE OF CHEMO

BY INVESTIGATOR

Capecitabineor

Taxaneor

Anthracycline

Cape + bevacizumab

Cape + placebo

T/Anthra + bevacizumab

T/Anthra + placebo

EFFICACYANALYSIS

RA

ND

OM

IZE

n=409

n=206

n=415

n=207

* 300 pts treated with taxane, 300 pts with anthracycline

Study Conduct

• Conducted at >200 sites in 22 countries

• Accrued 1237 patients from Dec 2005 to Aug 2007

• Data cutoff date: July 31, 2008

• Median follow-up

- Capecitabine: 15.6 months

- Taxane and anthracycline: 19.2 months

Cape T/Anthra

PL

(n=206)

BV

(n=409)

PL

(n=207)

BV

(n=415)

Median age, yr 57 56 55 55ECOG PS 0 53 53 53 53

HR positive 74 77 77 76Triple negative 25 22 23 24

Disease-free ≤12 months 22 27 41 37Adjuvant chemotherapy 76 70 47 45 Taxane 41 39 15 15 Anthracycline 69 60 30 30

≥ 3 metastatic sites 45 43 45 45Measurable dx 79 80 86 83

Patient Characteristics

All data as %, unless otherwise noted.

RESULTS

Capecitabine: PFS by Investigator

Median, mo 5.7 8.6

HR (95% CI) 0.69 (0.56–0.84)

p-value p=0.0002

Median, mo 6.2 9.8

HR (95% CI) 0.68 (0.54–0.86)

p-value p=0.0011

PL(n=206)

BV(n=409)

IRC

INV

Taxane/Anthra: PFS by Investigator

Median, mo 8.0 9.2

HR (95% CI) 0.64 (0.52–0.80)

p-value p<0.0001

Median, mo 8.3 10.7

HR (95% CI) 0.77 (0.60–0.99)

p-value p=0.040

PL(n=207)

BV(n=415)

IRC

INV

Taxane AnthraPL

(n=104)BV

(n=203)PL

(n=103)BV

(n=212)

Median PFS, mo 8.2 9.2 7.9 9.2

HR (95% CI) 0.75 (0.56–1.01) 0.55 (0.40–0.74)

p-value 0.0547 <0.0001

Exploratory Endpoint:PFS by Chemotherapy Subgroups

PFS = PFS by investigator

Analysis of PFS by stratification factors:

Cape and T/Anthra Cohorts

+ BVbetter

+ PLbetterBaseline Factor

Totaln

HazardRatio

All Patients 615 0.67

Disease-free interval (mo) ≤12 154 0.81 >12 461 0.63

Number of metastatic sites <3 345 0.63 ≥3 270 0.74

Prior adjuvant chemotherapy Yes 444 0.64 No 171 0.80

+ BVbetter

+ PLbetter

Totaln

HazardRatio

Cape T/Anthra

622 0.66

239 0.62383 0.69

341 0.65281 0.64

283 0.67339 0.64

Objective Response Rate

Measurabledisease (n) 161 325 177 345

Includes only patients with measurable disease at baseline.

23.6

35.4 37.9

51.3

Capep=0.0097

T/Anthrap=0.0054

%

BVPLBVPL

Cape T/Anthra

PL

(n=206)

BV

(n=409)

PL

(n=207)

BV

(n=415)

% of deaths 35 30 35 34

Median OS, mo 21.2 29.0 23.8 25.2

HR (95% CI) 0.85 (0.63–1.14) 1.03 (0.77–1.38)

p-value 0.27 0.83

1-yr survival rate (%) 74 81 83 81

p-value 0.076 0.44

Overall Survival

Safety Summary

Cape Taxane Anthra

Event (%)PL

(n201)BV

(n404)PL

(n102)BV

(n203)PL

(n100)BV

(n210)

Selected AEs* 9.0 21.8 22.5 43.8 16.0 28.1

SAEs 18.9 24.3 26.5 41.4 16.0 22.4

AEs leading to study drug (PL or BV) discontinuation

11.9 11.9 7.8 24.1 4.0 14.3

AEs leading to death** 2.5 1.5 3.0 2.5 3.0 1.4

* AEs previously shown to be associated with BV** Excludes AEs related to MBC progression

Event, %

Cape Taxane Anthra

PL (n=201)

BV (n=404)

PL (n=102)

BV (n=203)

PL (n=100)

BV (n=210)

Bleeding events 0.5 0.2 0 5.4 0 0

Febrile neutropenia 0 0 2.0 7.9 5.0 3.8

GI perforation 0 0 1.0 2.0 0 0

Hypertension 1.0 9.4 2.0 8.9 0 10.0

LV systolic dysfunction 0.5 1.0 0 2.0 0 2.9

Neutropenia 1.0 1.2 4.9 9.4 4.0 4.3

Proteinuria 0 2.2 0 3.4 0 1.9

Sensory neuropathy 0.5 3.0 8.8 8.4 0 0.5

VTE 3.5 4.8 4.9 2.0 1.0 2.9

Selected Grade ≥3 AEs

VTE=venous thromboembolism

Summary

• For the pre-specified Cape and T/Anthra cohorts, the addition of bevacizumab led to a statistically significant improvement in:

- PFS (by investigator)

- PFS (by IRC)

- ORR

• No difference was noted in OS

• Safety:

- Incidence of bevacizumab-related adverse events consistent with prior studies

- No new bevacizumab-related safety signals in each of the chemotherapy groups

Conclusions

• RIBBON-1 provides a third randomized Phase III trial demonstrating the efficacy and safety of combining bevacizumab, a direct VEGF inhibitor, with first-line chemotherapy for MBC.

• RIBBON-1 establishes the efficacy of combining bevacizumab with non-taxane chemotherapies used for first-line treatment of MBC.

• The safety profile of bevacizumab in combination with these chemotherapies was consistent with that reported from prior Phase III trials.

Acknowledgments

• 1237 patients and the RIBBON-1 investigators from:

Australia Peru

Brazil Philippines

Canada Russia

France Singapore

Greece Spain

Guatemala Sweden

Korea Taiwan

Mexico Ukraine

Netherlands United Kingdom

Norway USA

Panama Uruguay

Back-ups

Chemotherapy Regimens

• Investigator chose from the following protocol specified chemotherapy regimens prior to randomization:

- Capecitabine:• Capecitabine 1000 mg/m2 BID x 14d started q21d

- Taxanes:• Docetaxel 75 or 100 mg/m2 q21d

• Protein-bound paclitaxel 260 mg/m2 q21d

- Anthracyclines:• AC (doxorubicin 50 or 60 mg/m2, cyclophosphamide 500 or 600 mg/m2) q21d

• FAC (5-FU 500 or 600 mg/m2, doxorubicin 50 or 60 mg/m2, cyclophosphamide 500 or 600 mg/m2) q21d

• EC (epirubicin 90 or 100 mg/m2, cyclosphosphamide 500 or 600 mg/m2) q21d

• FEC (5-FU 500 or 600 mg/m2, epirubicin 90 or 100 mg/m2, cyclophosphamide 500 or 600 mg/m2) q21d

Second-line Usage of Bevacizumab

• Per protocol, at the time of disease progression, all patients were offered option of receiving bevacizumab with a 2nd line chemotherapy chosen by the investigator

Cape T/Anthra

PL BV PL BV

% of patients receiving 2nd line BV

69 52 55 50

Analysis of PFS by stratification factors:

Cape and T/Anthra Cohorts

+ BVbetter

+ PLbetterBaseline Factor

Totaln

HazardRatio

All Patients 615 0.67

Hormone receptor status Positive 458 0.69 Negative 143 0.70

Time from diagnosis of primary cancerto diagnosis of locally recurrent ormetastatic disease (months) ≤ 24 205 0.76 > 24 408 0.63

+ BVbetter

+ PLbetter

Totaln

HazardRatio

Cape T/Anthra

622 0.66

459 0.61142 0.78

262 0.65358 0.67

0.2 0.5 1 2 0.2 0.5 1 2

Subgroup Analyses of PFS T/Anthra Cohorts

+ BVbetter

+ PLbetterBaseline Factor

Totaln

HazardRatio

All Patients 622 0.66

TaxaneDocetaxel 181 0.78Abraxane 124 0.65

Anthracycline-based ChemotherapyDoxorubicin-based 236 0.63Epirubicin-based 74 0.46

T/Anthra

Clinical Summary of Cardiac Toxicity: Anthracycline Cohort

Anthra+PLn=100N (%)

Anthra+BVn=210N (%)

Left Ventricular Systolic Dysfunction

Any Grade 6 (6.0) 13 (6.2)

Grade 4 0 (0.0) 1 (0.5)

Grade 3 0 (0.0) 5 (2.4)

Grade 2 5 (5.0) 7 (3.3)

Grade 1 1 (1.0) 0 (0.0)

Grade 3 and 4 Events• Two patients with clinical CHF (Grade 3, Grade 4)• One patient with non-specific symptoms• Two patients with measurement error• One patient with progressive disease