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					    Update on Breast Cancer

           William J. Gradishar, MD
            Professor of Medicine
Robert H. Lurie Comprehensive Cancer Center
        Feinberg School of Medicine
           Northwestern University
Overview
 PARP Inhibitors
 Neoadjuvant Therapy in BRCA+ BC
 SLNB and Auxillary Recurrence
 Endocrine Therapy Studies
 Metastatic Breast Cancer Therapy
   – DM-1
   – Neratanib
   – RIBBON-1
PARP Inhibitors
PARP-1 is a key enzyme involved in repair of
single strand DNA breaks
                                                        DNA single strand
                                                        break (SSB)
                                                        damage
             •PNK 1
    •pol β                •XRCC1
                                                        Inhibition of
                                              •LigIII   PARP-1
                                                        prevents
                  •PARP                                 recruitment of
                                                        DNA repair
                                                        enzymes leads
                                                        to failure of
                                                        SSB repair
                            During S-phase,

                          replication fork              -accumulation
                           is arrested at
                                                        of SSBs
                          site of SSB

                                                        Degeneration into
                                                        double strand breaks
Selective effect of PARP-1 inhibition
on cancer cells with BRCA1 mutation


                                    •DSB in DNA

               •Normal cell                      •BRCA-deficient cancer cell
       Triggers
      activation                                                Deficient HR repair
        of HR                                                   Increases DSB that
     pathway to                                                  can’t be repaired
     repair DSB


       •Cell                                                       •Genomic
       survival                                                    instability
                                                                   and
                                                                   apoptosis
•HR – homologous recombination; DSB – double strand
break
 PARP Inhibitor Mechanism of Action
  1. PLATINUM CHEMOTHERAPY
     Inflicts DNA damage via
     adducts and DNA crosslinking

                                           CG
       CG
                                           CG
       CG                                                PARP1
                                            AT
        AT                                  T                BSI-201
        T            PARP1                                                    4. REPLICATION
                                                       3. INHIBITION OF          FORK COLLAPSE
                                           TA
       TA
                 2. PARP1                  C      PARP1 PARP1                    Double strand DNA
       CG                                                 Disables DNA           break
                    UPREGULATION            G             base-excision
        GC          Base-excision repair    A             repair
        A           of DNA damage


                                                              BRCA1
                                                              BRCA2


                                     Cell Survival                     Cell Death
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
 Triple Negative BC Shares Clinical and
 Pathologic Features with BRCA1-Related BC
 Characteristics                            Hereditary BRCA1                     Triple Negative/Basal-Like              1,2,3


 ER/PR/HER2 status                                 Negative                                     Negative
 TP53 status                                        Mutant                                        Mutant
 BRCA1 status                            Mutational inactivation*                     Diminished expression*
 Gene-expression pattern                          Basal-like                                    Basal-like
 Tumor histology                           Poorly differentiated                         Poorly differentiated
                                              (high grade)                                  (high grade)
 Chemosensitivity to                          Highly sensitive                              Highly sensitive
 DNA-damaging agents

 *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of
 HMG or ID44

1. Perou C, et al. Nature. 2000;408:747-752. 2. Cleator S, et al. Lancet Oncology. 2007;8:235-244. 3. Sorlie T, et al.
Proc Natl Acad Sci USA. 2001;98:10569-10674. 4. Miyoshi Y, et al. Int J Clin Oncol. 2008;13:395-400.

O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
 Phase II TNBC Study: Treatment Schema
 BSI-201:                                 Metastatic TNBC
 small molecule                               N = 120
 PARP inhibitor
                                               RANDOMIZE



                                                                BSI-201 (5.6 mg/kg, IV, d 1,4,8,11)
  Gemcitabine (1000      mg/m2,   IV, d 1,8)      21-Day
                                                   Cycle        Gemcitabine (1000 mg/m2, IV, d 1,8)
  Carboplatin (AUC 2, IV, d 1,8)
                                                                Carboplatin (AUC 2, IV, d 1,8)



                                                 Restaging
                                               Every 2 Cycles
 * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at
 disease progression
O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
 BSI-201: Preliminary Efficacy Results*
                                            Gem/Carbo BSI-201 +Gem/Carbo P-value
                                             (n = 44)       (n = 42)
 Objective Response Rate, n (%)                   7 (16)       20 (48)             .002
 **Clinical Benefit Rate, n (%)                   9 (21)       26 (62)            .0002

 * Includes patients enrolled before September 30, 2008 and patients who had a confirmed
 response or disease progression
 **Clinical Benefit Rate = CR + PR + SD ≥ 6 months




O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
 BSI-201: Conclusions
  PARP1 was upregulated in most evaluated TNBC patients
  BSI-201 + gemcitabine/carboplatin was well tolerated and did not
   potentiate chemotherapy-related toxicities
  BSI-201 improved patients’ clinical outcomes
      – Clinical Benefit Rate (62% vs. 21%; P = .0002)

      – ORR (48% vs 16%; P = 0.002)

      – Median PFS (6.9 months vs. 3.3 months; P < 0.0001)

      – Median OS (9.2 months vs. 5.7 months; P = 0.0005)

 Promising safety and efficacy data from this Phase II study justify further
    investigation of BSI-201 in a Phase III study

O’ Shaughnessy J, et al. ASCO 2009. Abstract 3.
 Phase II Study with Olaparib: Rationale
 and Design
    To assess the efficacy and tolerability of oral olaparib in BRCA1/BRCA2
     mutation carriers with breast cancer

    Multicenter proof-of-concept phase II study, single-arm sequential cohort
     design
                              Confirmed BRCA1 or BRCA2 mutation
                                 Advanced refractory breast cancer
                       (stage IIIB/IIIC/IV) after failure ≥1 prior chemotherapy
                                         for advanced disease

           Cohort 1 (enrolled first)                              Cohort 2*
       Olaparib 400 mg po BID (MTD)                       Olaparib 100 mg po BID
           28-day cycles; n = 27                           28-day cycles; n = 27

 *Following an interim review of the emerging efficacy of each cohort, patients ongoing in
 100 mg BID cohort were permitted to crossover to receive the 400 mg bid dose
 MTD: determined during Phase I evaluation
Tutt A, et al. ASCO 2009. Abstract 501.
 Olaparib: Efficacy Results
 ITT cohort                                      Olaparib 400 mg bid           Olaparib 100 mg bid
                                                       (n = 27)                      (n = 27)
 Overall Response Rate, n (%)                            11 (41)*                      6 (22)*
 Complete Response, n (%)                                  1 (4)                          0
 Partial Response, n (%)                                  10 (37)                      6 (22)
 *An additional 1 patient in the 400 mg cohort and 3 patients in the 100 mg cohort had unconfirmed
 responses

 Per protocol cohort                                   400 mg bid                   100 mg bid
                                                         (n = 26)                     (n = 24)
 Overall Response Rate, n (%)                            11 (42)                      6 (25)   †

 Complete Response, n (%)                                  1 (4)                          0
 Partial Response, n (%)                                 10 (39)                       6 (25)
 †An   additional 3 patients in the 100 mg cohort had unconfirmed responses

Tutt A, et al. ASCO 2009. Abstract 501.
Olaparib: Conclusions
 First report of a targeted therapy trial designed for BRCA1/BRCA2
  carriers with breast cancer
 Single agent oral olaparib 400 mg bid has substantial activity in
  heavily pre-treated BRCA1/BRCA2 carriers with advanced breast
  cancer
    – Objective response rate ITT (RECIST): 41%

    – Median PFS: 5.7 months

 Oral olaparib is well tolerated in BRCA1/BRCA2 carriers with a similar
  side effect profile to prior experience in non-carriers
 Clinical proof-of-concept for targeting BRCA1/BRCA2 mutations in
  both breast and ovarian1,2 cancer
Neoadjuvant Therapy in BRCA+
       Breast Cancer
 Neoadjuvant Study: Design

                                                         S
BRCA1 Mutation                     Cisplatin 75mg/m2     U
    Carriers                      q 3wks IV x 4 cycles   R   AC
 Primary Breast                                          G
     Cancer                                              E
                                                         R
                                   N = 10       25       Y

       Primary Endpoint: pCR (in breast and axilla, DCIS permitted)




Gronwald J, et al. ASCO 2009. Abstract 502.
              Neoadjuvant Study: Response to
                        Treatment
 Response                                          No.                 %
                                            Clinical response
 Complete response                                  18                 72
 Partial response                                    7                 28
 No change                                           0                  0
 Progressive disease                                 0                  0
                                          Pathologic response
 Complete pathologic response                       18                 72
 Partial response                                    7                 28
 No response                                         0                  0
                                        Residual disease in breast
 None                                               19                 76
 < 1 cm                                              0                  0
 1-5 cm                                              6                 24
 > 5 cm                                              0                  0
                                      Number of lymph nodes positive
 0                                                  21                 84
 1-3                                                 4                 16
 4-9                                                 0                  0
 >9                                                  0                  0




Gronwald J, et al. ASCO 2009. Abstract 502.
 Neoadjuvant Study: Conclusions
  Platinum-based chemotherapy is effective in a high
   proportion of patients with BRCA1-associated breast
   cancers
  Choice of breast cancer treatment may be better with
   BRCA1 testing




Gronwald J, et al. ASCO 2009. Abstract 502.
Sentinel Lymph Node Biopsy and
      Auxillary Recurrence
 Omission of Axillary Therapy in Patients with
  pN1mi or pN0i+ by Sentinel Node Biopsy:
             the MIRROR Study
                           •   Patients with favorable
                           •   primary tumor characteristics
                           •   No indication for adjuvant                           •N = 2680 after
                           •   systemic therapy                                    central pathology
                           •   Sentinel node procedure
                                                                                        review
                           •   pN0, pN0(i+) or pN1mi




   •Sentinel node biopsy             •Completion axillary                •Axillary radiotherapy
      •only (SN only)               •lymph node dissection                          •(axRT)
         N = 1218                      •(cALND) N = 1314
                                                                                    N = 148

• Patients selected from the Netherlands Cancer Registry (1998-2005) (N = 3205)
• Median follow-up: 4.7 years
                                        Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).
   Omission of Axillary Therapy in Patients with
    pN1mi or pN0i+ by Sentinel Node Biopsy:
               the MIRROR Study
         Results: Multivariate Analysis
Sentinel node      Axillary        N           5-yr axillary              HR
                                                                                            95 % CI
status             therapy                     recurrence
                   cALND          125               1.6%                  1.00            Reference
pN0
                   SN only        732               2.3%                  1.08            0.23 – 4.98
                 cALND/axRT       450               0.9%                  1.00             Reference
pN0 (i+)
                   SN only        345               2.0%                  2.39            0.67 – 8.48
                 cALND/axRT       887               1.0%                  1.00            Reference
pN1mi
                   SN only        141               5.0%                 4.39*           1.46 – 13.24


•HR corrected for age, tumor size, grade, hormone receptor status, adjuvant
systemic therapy and radiotherapy to the breast


•* Statistically significant compared to cALND/axRT
                                   Tjan-Heijnen et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA506).
   Omission of Axillary Therapy in Patients with
    pN1mi or pN0i+ by Sentinel Node Biopsy:
               the MIRROR Study
                   Conclusions
− Omission of axillary therapy appears feasible in pN0 disease
− Axillary therapy non-significantly decreased axillary
  recurrence in those with pN0(i+) disease
− Axillary therapy significantly decreased axillary recurrence in
  those with pN1mi disease
− Patients who received axRT showed no axillary recurrence,
  although number of events was too small for statistical
  analysis
− Tumor size, histological grade III, and negative ER/PgR status
  were significantly predictive of 5-year axillary recurrence by
  multivariate analysis
                                           Tjan-Heijnen et al. J Clin Oncol 2009; 27
                                                   (suppl): 18s (abstract CRA506).
Endocrine Therapy Studies:
    CYP2D6 Inhibition
                         Tamoxifen Metabolism
              TAMOXIFEN                               4-OH-TAM
                                                                CH2
                               CH2                             O
                           O                              O
                     O                                           CH2
                               CH2   CYP2D6
                                                                         SULT1A1
                                     CYP2B6                              UGT
                                     CYP2C9     H2O
        H2O
                                     CTYP2C19
                                     CYP3A                OH
                   CYP3A4/5                              CYP3A4/5
                   CYP1A2
                   CYP2C9
                   CTYP2C19                                        CH2
                   CYP2B5 CH                                   N
                          N 2                             O        H
                      O     H
                                                                         SULT1A1
                                     CYP2D6     H2O                      UGT
           H2O
                                                          OH
                                                      ENDOXIFEN
                 NDM-TAM
Aubert RE, et al. ASCO 2009. Abstract 508.
Risk of breast cancer recurrence in women initiating
          tamoxifen with CYP2D6 inhibitors
 Eligibility:                   •No CYP2D6 inhibitor therapy                             •(n = 945)
  Continuous eligibility 6
 mo prior to tamoxifen
 initiation                     •Weak CYP2D6 inhibitor therapy use                       •(n = 355)
 Tamoxifen naïve (6 mo          or without overlap with tamoxifen
 negative history)
 Tamoxifen duration ≥ 24        •Moderate-severe CYP2D6 inhibitor
 months                         use with tamoxifen                                       •(n = 359)
 Medication possession
        •(n = 1659)
 ratio of ≥ 0.7


   • Retrospective cohort analysis of medical and pharmacy claims from the
   Medco Health Solutions integrated database
   • Primary endpoint: hospitalization for breast cancer (event-free survival)
   • Median duration of overlap between CYP2D6 inhibitors and tamoxifen:
   287 days
                                     Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
Risk of breast cancer recurrence in women initiating
          tamoxifen with CYP2D6 inhibitors
                               N      Breast cancer                    HR*                   P value
                                       recurrence
 No CYP2D6 inhibitors          945            7.5%                 reference                reference
 Moderate/severe CYP2D6        407            14%              1.92 (1.36-2.73)                .0002
 inhibitors
 SSRIs
                      Weak     137            9%               1.07 (0.79-1.45)                .677
            Moderate/potent    213            16%              2.20 (1.46-3.31)                .0002
 * HR relative to no CYP2D6 inhibitor group


 • Concomitant use of tamoxifen with moderate-severe CYP2D6 inhibitors
   significantly increases the risk of breast cancer recurrence
 • Moderate-potent SSRIs double the risk of recurrence, while weak SSRIs
   were not associated with increased risk



                                         Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
Concomitant CYP2D6 inhibitor use and tamoxifen
    adherence in early stage breast cancer
         Inclusion criteria:                       Tamoxifen only
         breast cancer resection                               (n = 1749)
         Tamoxifen use ≥ 120 days
                                                   Tamoxifen + CYP2D6 inhibitor
         CYP2D6 inhibitor use ≥ 60
         days (n = 3147)                                         (n = 150)

• Retrospective pharmaco-epidemiologic study
• Databases: PHARMO, PALGA, Dutch Medical Register
• Univariate Cox regression of event-free time:

        CYP2D6 inhibitor             HR              95% CI               P value
        use
        No use                      1.00            reference            reference
        Use ≥ 60 days               0.95            0.60-1.50                0.73
• No difference when only strong CYP2D6 inhibitors included

                                     Dezentje et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA509).
Summary of concomitant CYP2D6 inhibitor use with
    tamoxifen in early stage breast cancer


 • Registry studies give conflicting results regarding the
   effect of concomitant use on breast cancer recurrence
 • CYP2D6 pharmacogenomics likely complicated;
   published data on CYP2D6 genotypes inconsistent
 • Possession of drug does not necessarily indicate
   compliance
 • Need further validation studies before
   recommendations for routine use can be made
Metastatic Breast Cancer
                         Trastuzumab-DM1
       •Target-dependent cytotoxic activity

• DM1-Derivative of maytansine:
   - Naturally occurring antitumor
     antibiotic
   - Significant preclinical activity,
     but significant clinical toxicity as
     free drug

• Trastuzumab-DM1 is designed to
  preferentially deliver DM1 to
  HER2+ tumor cells:
    - Improve therapeutic index of DM1
    - Maintain biological effect of
      trastuzumab
 Phase II T-DM1 Study Description
  A multi-institutional, open-label, single-arm Phase II US study in
   patients with locally confirmed HER2-positive MBC who
   progressed while receiving HER2-directed therapy
      – Patients had received a median of 3 prior chemotherapy agents for
        MBC (range 1-12)
      – 67/112 (60%) patients also received prior lapatinib
      – T-DM1 (3.6 mg/kg) was given by IV infusion over 30-90 minutes
        every 3 weeks (q3w) until progression

  Primary endpoint
      – Objective response rate (ORR) per RECIST by independent
        review facility (IRF)

Krop IE, et al. ASCO 2009. Abstract 1003.
Retrospective analysis of biomarkers for response
  to trastuzumab-DM1 in pretreated HER2+ MBC
• Study objective:
   − Identify biomarkers that will predict for response to T-DM1
• Study details:
   − Retrospective analysis of phase II study evaluating trastuzumab-
     DM1 in patients with HER2+ MBC with progression on prior HER2-
     targeted therapy
   − Examined HER2 (IHC, FISH, RT-PCR), HER2 extracellular
     domain (ECD), HER3, PI3K mutations, PTEN loss

                     Centrally       Centrally confirmed
  Efficacy       confirmed HER2+       HER2 normal                            P value
                      (n = 75)             (n = 21)
  ORR*
                   32% (22-43%)            5% (<1-22%)                            .01
  (95%CI)
  PFS*                7.4 mo                    2.6 mo                           NR

    •* By independent review
                                    Krop et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1003).
Retrospective analysis of biomarkers for response
  to trastuzumab-DM1 in pretreated HER2+ MBC

      •Centrally-confirmed HER2+ Patients
      PI3K mutation             Number with                   ORR (95% CI)
                       N
      or PTEN loss           objective response                   (%)
      Yes             15               3                          20 (6-45)
      No              16               7                         44 (20-70)
      Unknown         38              14                       37 (23-53.5)


• HER2-positivity by central testing was strongly correlated with
  response to trastuzumab-DM1
• In patients with HER2+ disease, numerically lower response rate
  in patients with either PI3K mutations or PTEN loss
• Response to trastuzumab-DM1 showed no correlation with levels
  of HER2 ECD, HER2 gene copy number, or HER3 levels

                                   Krop et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1003).
A Phase II Study of Trastuzumab-DM1 in
Patients With HER2+ Pretreated MBC: Efficacy
                                              IRF ORR                        IRF CBR*
Tumor response                  n
                                             % (95% CI)                      % (95% CI)
All evaluable patients         112         25 (17.5-33.6)                  35 (26.1-43.9)
Patients previously treated
with trastuzumab and            67         24 (14.3-35.4)                  36 (25.2-48.2)
lapatinib
Patients with centrally-
                                75         32 (22.1-43.0)                  44 (33.2-55.5)
confirmed HER2+ disease
•* CBR = CR+PR+SD ≥ 6 mo
•IRF = independent review facility; ORR = overall response rate




• Median PFS = 4.9 months

                                     Vogel et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1017).
  A Phase II Study of Trastuzumab-DM1 in
  Patients With HER2+ Pretreated MBC: Safety
                                             Cardiac safety (n = 108):
Adverse event (AE)   Grade 3   Grade 4
                                                    No grade 3 or 4 LVEF
(n = 112)              (%)       (%)
                                                      dysfunction reported
Thrombocytopenia       4.5       3
                                                    Only 2 patients had LVEF
Hypokalemia            8         0                    declines below 45%
Fatigue                4.5       0
Epistaxis              2         0
Musculoskeletal        2         0           Treatment discontinuation:
chest pain                                          83/112 discontinued (70 due to
Dyspnea                2         1                    disease progression and 1
                                                      death due to progression)
Pleural effusion       2         0
Confusional state      0         2                  5 patients discontinued due to
                                                       AE, 4 that were possibly
                                                       related to T-DM1


                                         Vogel et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1017).
 Phase II results of the pan-HER inhibitor neratinib (HKI-
 272) in patients with advanced breast cancer
240 mg/day in women with stage IIIB,C or IV HER2-positive BC.

Arm A: Prior (at least 6 weeks) trastuzumab treatment

Arm B: No prior trastuzumab

Most common grade 3/4 adverse event was diarrhea


                                      Prior             No Prior                      Total
                                  Trastuzumab         Trastuzumab                   (n = 127)
                                     (n = 61)            (n = 66)
ORR (95% CI)                      26% (16-39)          56% (43-68)               42% (33-51)
Clinical benefit rate* (95% CI)   36% (24-49)          68% (56-79)               53% (44-62)
16-week PFS rate (95% CI)         60% (46-72)          77% (64-86)                      NR
PFS (95% CI)                       23 weeks              40 weeks                       NR
                                    (16-39)               (32-55)

                                           Burstein et al. Cancer Res 2009; 69 (suppl): (abstract 37).
Phase I/II trial of neratinib (HKI-272) +
trastuzumab in advanced breast cancer
Stage IIIB, IIIC, or IV HER2+ BC with progression following ≥ 1 trastuzumab-
  containing regimen in any setting

    Part 1: Neratinib 160 mg qd (n = 4), 240 mg qd (n = 4) with trastuzumab 2
      mg/kg weekly (4 mg/kg loading dose)

    Part 2: Neratinib 240 mg qd (n = 37) with trastuzumab 2 mg/kg weekly (4
      mg/kg loading dose)

          Adverse events* N (%)                                      Efficacy
                 All grades   Grade 3/4                ORR                        29%
    Diarrhea       41 (91)       7 (16)                                   CR 7%
    Nausea         23 (51)       2 (4)                                     PR 21%
    Anorexia       18 (40)        NR                   CBR*                       36%
    Vomiting       17 (38)       2 (4)                 16 wk PFS rate 45%
    Asthenia       13 (29)        NR                   Median PFS                 16 wks
  * No significant changes in LVEF reported          * CR+PR+SD ≥24wks
                                          Swaby et al. J Clin Oncol 2009; 27 (suppl): 15s (abstract 1004).
 RIBBON-1: Study Design
       Previously
     untreated MBC
       (n = 1237)           CHOICE OF
                             CHEMO
                                                               Chemo +




                                             RANDOMIZE 2:1
 Stratification Factors:
                             Capecitabine                    bevacizumab             Optional
 Disease-free                    or                                       Treat      2nd-line
                                                                 q3w       until
 interval                       Taxane                                               chemo +
                                  or                                        PD     bevacizumab
 Previous adjuvant                                           Chemo +
                             Anthracycline                    placebo
 chemotherapy
                                                                q3w
 Number of
 metastatic sites
 Cape, T, or Anthra
     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 (15mg/kg q3w)
Robert N, et al. ASCO 2009. Abstract 1005.
 RIBBON-1: Exploratory Endpoint - PFS by
 Chemotherapy Subgroups
                                        Taxane                       Anthra
                               PL                   BV          PL             BV
                            (n = 104)            (n = 203)   (n = 103)      (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                                 .0547                       <.0001

 PFS = PFA by investigator




Robert N, et al. ASCO 2009. Abstract 1005.
 RIBBON-1: Objective Response Rates

                                 Cape              T/Anthra            CR
                    60         P = .0097           P = .0054
                                                                51.3   PR
                     50
                     40                             37.9
                                         35.4
                %




                     30      23.6
                     20
                     10
                      0
                              PL             BV      PL         BV
         Measurable
         disease, (n)         161        325        177         345

  Includes only patients with measurable disease at baseline.
Robert N, et al. ASCO 2009. Abstract 1005.
 RIBBON-1: Overall Survival
                                             Cape                       T/Anthra
                                  PL                  BV          PL                BV
                               (n = 206)           (n = 409)   (n = 207)         (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                                     .27                           .83
 1-yr survival rate (%)            74                 81         83                81
 P-value                                     .076                          .44




Robert N, et al. ASCO 2009. Abstract 1005.
 RIBBON-1: Safety Summary
                                    Cape                     Taxane                   Anthra
                             PL            BV          PL           BV          PL          BV
 Events (%)
                          (n = 201)     (n = 404)   (n = 102)    (n = 203)   (n = 100)   (n = 210)
 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           11.9            11.9     7.8          24.1        4.0         14.3
 BV) discontinuation
 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




Robert N, et al. ASCO 2009. Abstract 1005.
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.