1. 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

2. 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 + 1 st 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.

3. Study Design Capecitabine (1000 mg/m 2 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 Capecitabine or Taxane or 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 Optional 2 nd -line Chemo + bevacizumab Treat until PD RANDOMIZE 2:1

4. 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

5. 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

6. Statistical Design and Analyses HRPowerSample Size Capecitabine0.7580%600 Taxane/Anthracycline0.7090% 600* CHOICE OF CHEMO BY INVESTIGATOR Capecitabine or Taxane or Anthracycline Cape + bevacizumab Cape + placebo T/Anthra + bevacizumab T/Anthra + placebo EFFICACY ANALYSIS RANDOMIZE n=409 n=206 n=415 n=207 * 300 pts treated with taxane, 300 pts with anthracycline

7. 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

8. CapeT/Anthra PL (n=206) BV (n=409) PL (n=207) BV (n=415) Median age, yr 575655 ECOG PS 053 HR positive7477 76 Triple negative25222324 Disease-free ≤12 months22274137 Adjuvant chemotherapy76704745 Taxane413915 Anthracycline 696030 ≥ 3 metastatic sites454345 Measurable dx79808683 Patient Characteristics All data as %, unless otherwise noted.

9. RESULTS

10. Capecitabine: PFS by Investigator Median, mo5.78.6 HR (95% CI)0.69 (0.56–0.84) p-valuep=0.0002 Median, mo6.29.8 HR (95% CI)0.68 (0.54–0.86) p-valuep=0.0011 PL (n=206) BV (n=409) IRC INV

11. Taxane/Anthra: PFS by Investigator Median, mo8.09.2 HR (95% CI)0.64 (0.52–0.80) p-valuep<0.0001 Median, mo8.310.7 HR (95% CI)0.77 (0.60–0.99) p-valuep=0.040 PL (n=207) BV (n=415) IRC INV

12. TaxaneAnthra PL (n=104) BV (n=203) PL (n=103) BV (n=212) Median PFS, mo 8.29.27.99.2 HR (95% CI)0.75 (0.56–1.01)0.55 (0.40–0.74) p-value0.0547<0.0001 Exploratory Endpoint: PFS by Chemotherapy Subgroups PFS = PFS by investigator

13. Analysis of PFS by stratification factors: Cape and T/Anthra Cohorts + BV better + PL better Baseline Factor Total n Hazard Ratio All Patients6150.67 Disease-free interval (mo) ≤121540.81 >124610.63 Number of metastatic sites <33450.63 ≥32700.74 Prior adjuvant chemotherapy Yes4440.64 No1710.80 + BV better + PL better Total n Hazard Ratio CapeT/Anthra 622 0.66 239 0.62 383 0.69 341 0.65 281 0.64 283 0.67 339 0.64

14. Objective Response Rate Measurable disease (n) 161325 177 345 Includes only patients with measurable disease at baseline. 23.6 35.4 37.9 51.3 Cape p=0.0097 T/Anthra p=0.0054 % BVPLBVPL

15. Cape T/Anthra PL (n=206) BV (n=409) PL (n=207) BV (n=415) % of deaths35303534 Median OS, mo21.229.023.825.2 HR (95% CI)0.85 (0.63–1.14)1.03 (0.77–1.38) p-value0.270.83 1-yr survival rate (%)74818381 p-value0.0760.44 Overall Survival

16. Safety Summary CapeTaxaneAnthra Event (%) PL (n  201) BV (n  404) PL (n  102) BV (n  203) PL (n  100) BV (n  210) Selected AEs* 9.021.822.543.816.028.1 SAEs 18.924.326.541.4 16.022.4 AEs leading to study drug (PL or BV) discontinuation 11.9 7.824.1 4.014.3 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

17. Event, % CapeTaxaneAnthra PL (n=201) BV (n=404) PL (n=102) BV (n=203) PL (n=100) BV (n=210) Bleeding events 0.50.205.400 Febrile neutropenia 002.07.95.03.8 GI perforation 001.02.000 Hypertension 1.09.42.08.9010.0 LV systolic dysfunction 0.51.002.002.9 Neutropenia 1.01.24.99.44.04.3 Proteinuria 02.203.401.9 Sensory neuropathy 0.53.08.88.400.5 VTE 3.54.84.92.01.02.9 Selected Grade ≥3 AEs VTE=venous thromboembolism

18. 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

19. 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.

20. Acknowledgments 1237 patients and the RIBBON-1 investigators from: AustraliaPeru BrazilPhilippines CanadaRussia FranceSingapore GreeceSpain GuatemalaSweden KoreaTaiwan MexicoUkraine NetherlandsUnited Kingdom NorwayUSA PanamaUruguay

21. Back-ups

22. Chemotherapy Regimens Investigator chose from the following protocol specified chemotherapy regimens prior to randomization: -Capecitabine: Capecitabine 1000 mg/m 2 BID x 14d started q21d -Taxanes: Docetaxel 75 or 100 mg/m 2 q21d Protein-bound paclitaxel 260 mg/m 2 q21d -Anthracyclines: AC (doxorubicin 50 or 60 mg/m 2, cyclophosphamide 500 or 600 mg/m 2 ) q21d FAC (5-FU 500 or 600 mg/m 2, doxorubicin 50 or 60 mg/m 2, cyclophosphamide 500 or 600 mg/m 2 ) q21d EC (epirubicin 90 or 100 mg/m 2, cyclosphosphamide 500 or 600 mg/m 2 ) q21d FEC (5-FU 500 or 600 mg/m 2, epirubicin 90 or 100 mg/m 2, cyclophosphamide 500 or 600 mg/m 2 ) q21d

23. Second-line Usage of Bevacizumab Per protocol, at the time of disease progression, all patients were offered option of receiving bevacizumab with a 2 nd line chemotherapy chosen by the investigator CapeT/Anthra PLBVPLBV % of patients receiving 2 nd line BV 69525550

24. Analysis of PFS by stratification factors: Cape and T/Anthra Cohorts + BV better + PL better Baseline Factor Total n Hazard Ratio All Patients6150.67 Hormone receptor status Positive4580.69 Negative1430.70 Time from diagnosis of primary cancer to diagnosis of locally recurrent or metastatic disease (months) ≤ 242050.76 > 244080.63 + BV better + PL better Total n Hazard Ratio CapeT/Anthra 622 0.66 459 0.61 142 0.78 262 0.65 358 0.67 0.20.5120.20.512

25. Subgroup Analyses of PFS T/Anthra Cohorts + BV better + PL better Baseline Factor Total n Hazard Ratio All Patients 622 0.66 Taxane Docetaxel 181 0.78 Abraxane 124 0.65 Anthracycline-based Chemotherapy Doxorubicin-based 236 0.63 Epirubicin-based 74 0.46 T/Anthra

26. Clinical Summary of Cardiac Toxicity: Anthracycline Cohort Anthra+PL n=100 N (%) Anthra+BV n=210 N (%) Left Ventricular Systolic Dysfunction Any Grade6 (6.0)13 (6.2) Grade 40 (0.0)1 (0.5) Grade 30 (0.0)5 (2.4) Grade 25 (5.0)7 (3.3) Grade 11 (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