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Challenges in the Treatment of Breast Cancer Overcoming .ppt

VIEWS: 81 PAGES: 37

									      Expert Review of Breast Cancer Treatment


Clinical Application of Evolving Treatment
 Paradigms in Advanced Breast Cancer

                 Clifford A. Hudis, MD
          Chief, Breast Cancer Medicine Service
          Memorial Sloan Kettering Cancer Center
                  Professor of Medicine
               Weill Cornell Medical College
                      New York, NY
                          Case 1

• 47 year-old woman, BRCA1 (+) with h/o stage IIa
  breast cancer (3-years ago) at age 44
   ─ ER weakly positive
   ─ PR negative
   ─ HER2 negative
   ─ Treatment: dose-dense AC→T and on tamoxifen for 2+ years


• Presents now with RUQ pain, 4kg weight loss, and
  fatigue
   ─ LFTs normal
   ─ CT with multiple hepatic metastases confirmed by biopsy c/w
     original tumor
                       Case 1
Which treatment option would you recommend:
    Hormone therapy
    Chemotherapy
    Bevacizumab
                           Case 1
Which treatment option would you recommend:
    Hormone therapy
    Chemotherapy
    Bevacizumab


Recommended Approach:
      Clinical considerations for selection of appropriate treatment
       will be discussed
Management of Metastatic Breast Cancer
            Diagnosis of Metastatic Breast Cancer
         Determination of sites and extent of disease. Assessment of HER2,
     hormonal receptor status, disease-free interval, age, and menopausal status


          No life-threatening disease             Hormone-unresponsive, or
            Hormone-responsive                     Life-threatening disease

           1st-line hormonal therapy                1st-line chemotherapy

        Response                                           Progression
                               No
                             Response                2nd-line chemotherapy
        Progression

2nd-line hormonal therapy       No                         Progression
                             Response
        Response                                     3rd-line chemotherapy
       Progression
                               No
3rd-line hormonal therapy    Response                   Supportive care
            Many Chemotherapy Options
   • Spindle toxins                           • Platinums
         – paclitaxel (Pac)                   • Antifolates
         – docetaxel (Doc)                        – methotrexate (MTX)
         – vinorelbine (Vin)                      – pemetrexed (PTX)
         – nab-Pac* (ABI-007)                 • Unique delivery
         – Ixabepilone (Ixa)                      – liposomal doxorubicin (LD)
   • Nucleoside analogues                     • Targeted therapy
         – gemcitabine (Gem)                      – HER2: trastuzumab (Trastuzumab)
         – capecitabine (Cap)                       and lapatinib (Lap)

         – 5-fluorouracil (5-FU_                  – VEGF: BVM and small-molecule TKIs
                                                    (investigational)
   • Topoisomerase inhibitors
                                                  – farnesyltransferase inhibitors
         – CPT-11 (Topo)
                                                  – EGFR inhibitors (investigational)
         – doxorubicin (Dox)

*Albumin-bound paclitaxel.
CPT = camptothecin; VEGF = vascular endothelial growth factor; BVM = bevacizumab;
mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor.
Approval is Different from Common Usage
     Adjuvant                                                  Metastatic1
 Anthracyclines (A)                  1st Line                    2nd Line                     3rd Line
                                Taxanes (after A)           Taxanes (after A)              Cap (after A+T)
                                Cap (after A + T)           Cap (after A + T)              Ixa (after A+T+Cap)
 Taxanes (T)
                                                            Ixa (after A + T +Cap)         Cap (after A + T)
                                Combination
                                Cap+taxane
                                   (after A)
                                Gem + taxane
                                   (after A)
                                Cap + Ixa
                                   (after A + T)

 • Despite treatment, most advanced tumors become resistant and progress2
 • Chemoresistance is the major cause of treatment failure3

 1. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer
                                                              V.2.2007. http://www.nccn.org. Accessed April 30, 2007;
                                                             2. Bernard-Marty C et al. Oncologist. 2004;9(6):617-632;
                                                         3. Longley DB, Johnson PG. J Pathol. 2005;205(2):275-292.
Rationale for Combination Therapy
    in the Treatment of MBC
Principles of Treatment With Multiple Agents
• MBC-inherent drug resistance = barrier to response (cure)
  – There are many subpopulations of cancer cells with
    different types of resistance
  – Combination CT should reduce the different sensitive subpopulations of
    cancer cells, leading to an improved
    disease response
• Improved disease response will translate into an improvement in
  outcome
  – Meta-analysis (2005): standard CT vs intensified CT
    (10 trials, 2126 patients)
  – Intensified CT associated with OR=0.60 for response
  – Tumor response was predictive of survival (P<0.001)
       • Median OS: CR=29 mon; PR=21 mon; NR=15 mon

   OR = odds ratio; OS = overall survival; CR = complete response;
   PR = partial response; NR = no response.
                                                      Bruzzi P et al. J Clin Oncol. 2005;23(22):5117-5125.
    Single-agent vs Combination
       Front-line CT in MBC

 • Response rate  favors combination
 • TTP  favors combination
 • Survival  ?
 • Toxicity  favors single agent
 • Quality of life  ?

Very few combination trials using investigational drugs truly tested
the hypothesis of combination vs sequential single-agent therapy



                                                  TTP = time to progression.
      Single-agent vs Combination Trials

                                                     Overall               Grade IV
                              Median TTP
           Clinical Trial*                           Survival             Neutropenia
                                (mon)
                                                      (mon)                  (%)
Albain et al (N=529)
  Pac                             2.9                   15.8                      7
  Pac + Gem                       5.2                   18.5                      17

O’Shaughnessy et al (N=511)
  Docetaxel (Doc)                 4.2                   11.5                      11
  Doc + Cap                       6.1                   14.5                      12




                                     Albain KS et al. J Clin Oncol. 2004;22(14) Abstract 810.
                                O'Shaughnessy J et al. J Clin Oncol. 2002;20(12):2812-2823.
                       E1193 Phase III Trial
 Dox vs Pac vs Dox + Pac Combination in MBC
                           Results: Efficacy and Tolerability

            Outcome                     Dox       Pac           Dox + Pac             P Value
                                                                                       0.007*
Response rate (%)                       36         34                 47
                                                                                       0.004†

Median survival (mon)                   18.9      22.2               22.0                NS

                                                                                      0.0022*
TTP (mo)                                6.0        6.3                8.2
                                                                                      0.0567†

Gr III/IV leukopenia (%)                47         60                 55                  —

Gr III/IV infection (%)                 4.1        8.3               12.7                 —

Gr III/IV neurologic
                                        1.6        3.7               10.7                 —
complications (%)

*Dox vs Dox + Pac; †Pac vs Dox + Pac.            *Sledge GW et al. J Clin Oncol. 2003;21(4):588-592.
             CALGB 9840: Design
    1998–2000 (N=171)                           2000–2003 (N=406)
    (HER2 status unknown)                       (HER2 status known)

        Pac q 3 wks
                                                                   

         Pac q wk
                                 

                                            Pac q 3 wks + Trastuzumab
                                                                      
Pac 80       q wk –or–
         mg/m2
        2 q 3 wks                          
175 mg/m

Tras 4-mg/kg load,                           Pac q wk + Trastuzumab
then 2 mg/kg/wk                            
                                           


                            Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
                                              CALGB 9840
                                            Results (All Patients)
                              Tumor Response                                         Time to Progression
                    50                                                    10
                                                                                                           9
                         HR=1.61; P=0.017                                      Adjusted HR=1.45;
                                               40
                    40                                                     8   P=0.0008
Response Rate (%)




                                                             Time (mon)
                    30        28                                           6
                                                                                     5

                    20                                                     4


                    10                                                     2


                     0                                                     0
                         Pac q 3 Wks        Pac Weekly                          Pac q 3 Wks         Pac Weekly
                           (N=373)           (N=344)                              (N=373)            (N=344)
                                                                   Events/patients:       221/350        324/385

                                                         Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
                     CALGB 9840
                       Conclusions

• Pac once weekly is superior to Pac q 3 wks for the
  treatment of MBC (with respect to response rate and TTP)
• Pac once weekly is associated with slightly less frequent
  myelosuppression but more frequent neurotoxicity than
  Pac q 3 wks
• Trastuzumab does not improve outcome when added to
  Pac in HER2-neutral MBC




                           Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.
 TAX-31: Docetaxel vs Paclitaxel
   s/p anthracycline / 0-1 prior chemo for MBC

                            Docetaxel 100q3w   Paclitaxel 175q3w
*P ≤ 0.05                       (N=225)              (N=224)
               ORR (ITT)           32%               25%
                    TTP            5.7*               3.6
                     OS           15.4*              12.7
       Severe AE (>5%)          (3 deaths)         (0 deaths)
            Neutropenia*          93%                55%
      Feb Neutropenia*            15%                 2%
                Infection         10%                 2%
                Anemia*           10%                 7%
            Neurosensory           7%                 4%
             Neuromotor            5%                 2%
               Asthenia*          21%                 5%
    Peripheral oedema*             7%                 1%
               Stomatitis         11%                 0%
               Diarrhea*           5%                 1%

                                                      Jones et al. JCO 2005.
New Formulations
        Nab-Pac Transport & Tumor Targeting
        Tapping Into Biology of Albumin and Rapid Cell Growth


                                                        Tumor
                 Leaky junction
                                                        interstitium               Tumor cell


       (A) Albumin,
    the body’s natural
        transporter
    of water-insoluble             Lumen of
          nutrients                  tumor              (C) High tumor uptake
                                  microvessel            (SPARC binding of
                                                          albumin complexes)

                                                        Albumin-receptor (gp60, albondin)


                                                       Caveolae (vesicles)
Tumor
 cell
                                                      (B) Receptor-mediated
                                                transcytosis of albumin complexes
                                                    (gp60/caveolin-1 pathway)

                                                SPARC = secreted protein and rich in cysteine.
                                Phase III Trial
         Albumin-Bound (Nab) Pac vs Pac in MBC

             Albumin-bound Pac: 260 mg/m2 q3w; Pac: 175 mg/m2 q3w

                                        Albumin-Bound
                                          (Nab) Pac                      Pac               P Value
                                           (N=229)                    (N=225)

                           ORR (%)           33                           19                 0.001

                           TTP (wk)         23.0                         16.9                0.006

             Gr IV neutropenia (%)            9                           22                 <0.001

     Gr III sensory neuropathy (%)           10*                           2                 <0.001


*Median time to improvement: 22 days.

                                             Gradishar WJ et al. J Clin Oncol. 2005;23(31):7794-7803.
 Phase II Study of Weekly or q3wk Nab-Pac
 vs q3wk Doc as First-line Therapy in MBC

                                   R
                                            Arm A:    nab-Pac 300 mg/m2 q3wk
                                   A
    Eligibility criteria:          N        Arm B:    nab-Pac 100 mg/m2
    • Stage IV                     D                  weekly, 3 out of 4
      adenocarcinoma               O
                                            Arm C:    nab-Pac 150 mg/m2
    • No prior CT for              M                  weekly, 3 out of 4
      metastatic disease           I
                                   Z        Arm D:    Doc 100 mg/m2 q3wk
                                   E


Primary endpoint Antitumor response (q 8 wks) and toxicity
                     nab-Pac vs Doc (A, B, C vs D) weekly vs q3wk nab-Pac (B, C vs A)
   Comparisons low- vs high-dose weekly nab-Pac (B vs C)


                                                     Gradishar W et al. SABCS 2006. Abstract 46.
Where Exactly Are We?




                        Hudis JCO 2005.
            Novel Microtubule Inhibitors

     Need for change in                   Novel microtubule inhibitors

Toxicity profile                    Albumin-bound Pac (nab-Pac)

Therapeutic Efficacy                Halicrobdrin analogue (E7389)

  – Improve effect at target site   Epothilones (Ixa, patupilone)

  – Overcome resistance             Polyglutamic acid conjugated Pac (CT 2103)

  – Cross blood-brain barrier       Vinflunine (novel vinca alkaloid)




                                        Lee JJ, Swain SM. Semin Oncol. 2005;23(2 suppl 7):S22-26.
                                                Cortes J, Baselga J. Oncologist. 2007;12(3):271-280.
    Epothilones in Clinical Development
             for Breast Cancer
   Agent                                        Phase in
                     Epothilone Analog                                       Clinical Toxicities
(Manufacturer)                                 Development

                         Epothilone B
EPO-906/patupilone                                      III                          Diarrhea
                       (natural product)

                          Epothilone B
     ZK-EPO                                             II                Neuropathy, nausea, ataxia
                        (fully synthetic)


                         Epothilone D
    KOS-1584                                            II              Myelosuppression, neuropathy
                     (desoxyepothilone B)


                                                                           Hypersensitivity reactions,
                         Epothilone B
   BMS-310705                                          I / II              pancytopenia, neuropathy,
                       (semi-synthetic)
                                                                              arthralgia/myalgia


                                                    Goodin S et al. J Clin Oncol. 2004;22(10):2015-2025.
                                                 Kolman A. Curr Opin Investig Drugs. 2005;6(6):616-622.
                                            Schmid P et al. J Clin Oncol. 2005;23(16 suppl): Abstract 2051.
                         Ixabepilone (Ixa)
         First in the New Class of Epothilones

                                                          • Naturally occurring epothilone B
                 O                                          chemically modified to improve
                                                            metabolic activity, protein
S                                                           binding, and antitumor activity1
                                            OH
    N                                                     • Tubulin-binding mode distinct
            HN                                              from other microtubule-
                                                            stabilizing agents1
                 O       OH       O                       • Active against multiple tumor
                                                            xeno grafts, including drug-
            Ixabepilone                                     resistant types that overexpress
        Semi-synthetic analog                               P-gP, MRP-1, and b-III tubulin
          of epothilone B                                   isoforms1
                                                          • Active in taxane-resistant
                                                            disease2,3
           1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
                                                             2. Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.
                                                           3. Thomas E et al. J Clin Oncol. 2007;25(23):3399 3406.
                   Ixa: Mechanism of Action
Extracellular
                                                          • Poor substrate for efflux pumps, eg,
                                     Ixa                    P-gP and MRP-11
                                     MRP-1
                                                                – P-gP and MRP-1 are involved in drug
                                     P-gP                         resistance2



Intracellular
                                                          • Binds multiple ß-tubulin isoforms,
                                                            including ßIII-tubulin to inhibit
                                                            microtubule dynamics1
                                      Ixa
                                      Tubulin                   – Overexpression of ßIII is associated
                                      ß-tubulin                   with in vivo and clinical resistance to
                                      ßIII-tubulin                taxanes3,4



                1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
                                                       2. Lee JJ, Swain SM. Semin Oncol. 2005;32(6 suppl 7):S22-S26.
                                                            3. Kamath K et al. J Biol Chem. 2005;280(13):12902-12907.
                                                                  4. Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.
Phase II Trial Ixa in Anthracycline-, Taxane-,
    and Capecitabine-Resistant MBC
                               Efficacy

                   Efficacy (N=113 Evaluable Patients)
              ORR                                     11.5%
              SD                                      50.0%
              Median PFS                              3.1 mo
              Grade III/IV Toxicities                     %
              Neutropenia                                54
              Peripheral neuropathy                      14
              Fatigue                                    10
              Myalgia                                     7
              Stomatitis                                  7

    Single-agent Ixa 40 mg/m2 IV over 3 hrs q3w until disease progression

                                        Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.
                                        Ixa Study 046
                                                    Design
   Ixa in Combination With Cap in Patients Resistant to an Anthracycline and a Taxane

          MBC                   Combination therapy:
                                Ixa 40 mg/m2 IV over 3 h q 21 days +
      Demonstrated                                                                                   Primary
                                Cap 2000 mg/m2/d PO Days 1–14
      resistance to                                                                                  Endpoint
      anthracycline
       and taxane                Monotherapy:                                                        PFS (IRR)
         N=752                   Cap 2500 mg/m2/d PO Days 1–14

        Strict resistance criteria prospectively defined as
        • Disease progression = 3 mon of the last anthracycline dose in the metastatic
          setting –OR– recurrence = 6 mon in the adjuvant or neoadjuvant setting
          –AND–
        • Disease progression = 4 mon of the last taxane dose in the metastatic setting –OR–
          recurrence = 12 mon in the adjuvant or neoadjuvant setting

*Pts who received a minimum cumulative dose of 240 mg/m2 of Dox or 360 mg/m2 of epirubicin were also eligible.
RR = independent radiologic review.

                      Imprexa (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
                                                                 Thomas ES et al. J Clin Oncol. 2007; 25(33):5210-5217.
                                              Ixabepilone Study 046
                                  Significant Improvement in Median PFS*
                                1.0
                                0.9
                                                                                                     Median PFS
                                0.8                               Ixa + Cap
    Proportion not Progressed




                                0.7                               Cap                                5.8 mos
                                                                                                        vs
                                0.6                                                                  4.2 mos
                                                                                                 (95% CI, 3.8–4.5)
                                0.5
                                                             P=0.0003†
                                0.4                                                                HR = 0.75
                                0.3
                                                                                               (95% CI, 0.64–0.88)

                                0.2
                                0.1
                                0.0

                                      0   4     8       12      16       20      24      28       32      36       40
                                                                     Months
*Based on IRR of ITT population; †Stratified by visceral metastasis in liver/lung, prior CT in metastatic
setting, and anthracycline resistance..

                                                    Thomas ES et al. J Clin Oncol. 2007; Early online release; 0: JCO.2007.12.6557v1.
                Grade 3/4 Non-hematologic Toxicities
                80
                                                            Ixabepilone + Capecitabine (N=369)
                                                            Capecitabine (N=368)
                60
% of Patients




                40

                     23
                              18 17
                20
                                      9       8              9
                                                        6         4
                                          3                           2   3   2    3   2   3
                          0                       0.3                                          0
                0
What About Anti-angiogenics?
                                 E2100
                               Study Design

                                 R
Stratify:                        A
 • DFI ≤24 mon                   N
   vs >24 mon                                        Pac + Bev
 • <3 vs ≥3                      D
   metastatic sites              O
 • Adjuvant CT:
                                 M                        Pac
   yes vs no                                         28-day cycle
 • ER(+) vs ER(–)                I                  Pac 90 mg/m2
   vs ER unknown                                    D1, 8, and 15
                                 Z                  BVM 10 mg/kg
                                 E                    D1 and 15



DFI = disease-free interval.


                                              Miller KD et a. SABCS 2005. Abstract 3.
First-line Therapy of Metastatic Breast Cancer with
 Bevacizumab Added to Paclitaxel Improved PFS
                                                            Pac. + Bev. 11.4 mos
                    1.0
                                                            Paclitaxel   6.11 mos

                    0.8
                                                              HR = 0.51 (0.43-0.62)
  PFS Probability




                    0.6                                     Log Rank Test P < 0.0001

                    0.4


                    0.2


                    0.0

                           0              6   12             18           24               30
                                                   Months
                    484 events reported
                                                                               Miller K, NEJM 2007.
                                         AVADO
                 Double-blind, Placebo-controlled Trial

  1st line locally recurrent or         Docetaxel* 100mg/m2
     mBC (N=705)                           + placebo q3w
                                                                                        All patients
  Stratification factors:                                               Treat with      given option
  • region                            Docetaxel* + bevacizumab           placebo/        to receive
  • prior taxoid/time to                   7.5mg/kg q3w               bevacizumab      bevacizumab
    relapse since adjuvant                                              to disease           with
    chemo                                                              progression         2 nd line

  • measurable disease                                                                 chemotherapy
  • hormone receptor                  Docetaxel* + bevacizumab
    status                                  15mg/kg q3w


*Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted

  • Primary endpoint:             Progression-free survival
  • Secondary endpoints:          Overall response rate, duration of response, time to
                                  treatment failure, overall survival, safety, quality of life
                                     Progression-free Survival
                                                         (ITT population)
                                       Placebo +           Bev 7.5† +                                             Placebo +              Bev 15† +
                                    docetaxel (n=241)   docetaxel (n=248)                                      docetaxel (n=241)      docetaxel (n=247)


                       HR + 95% CI (unstratified)        0.79 (0.63–0.98)                          HR + 95% CI (unstratified)         0.72 (0.57–0.90)
                                                            P = 0.0318                                                                   P = 0.0036
                       HR + 95% CI (stratified*)         0.69 (0.54–0.89)                          HR + 95% CI (stratified*)           0.61 (0.48–0.78)
                                                            P = 0.0035                                                                    P < 0.0001
                       Median              8.0                 8.7                                 Median              8.0                   8.8
               1.0                                                                         1.0

               0.8                                                                         0.8
PFS estimate




                                                                            PFS estimate
               0.6                                                                         0.6

               0.4                                                                         0.4

               0.2                                                                         0.2

               0.0 0                 6              12               18                    0.0 0                6                12                18
                                         Months                                                                     Months
                     †mg/kg   q3w                                                                    *Data censored for non-protocol therapy prior to PD
     Sorafenib Targets Both Tumor-cell
      Proliferation and Angiogenesis
                     Tumour cell                                       Endothelial cell or pericyte
                                                                                               VEGF
                                    Autocrine loop
                                                                             PDGF-b
                                                   Paracrine stimulation
   EGF/IGF
                                                                     PDGFR-b                          VEGFR-2
                               Apoptosis
                                                                                       RAS
                RAS
     RAF
             Mcl-1                                                                     RAF

                                       Mitochondria                                              Angiogenesis:
     MEK
                       HIF-2                                      Mitochondria         MEK       Differentiation
                                                                                                 Proliferation
     ERK                           EGF/TGF-a                                                     Migration
                                                                   Apoptosis           ERK
                                   PDGF                                                          Tubule formation
                                   VEGF
             Nucleus               Proliferation                             Nucleus
                                   Survival



                                                         Sorafenib
PDGF =       platelet-derived growth factor
EGF =        epidermal growth factor
VEGF =       vascular endothelial growth factor
TGF-a =      transforming growth factor-alpha
Mcl-1 =      myeloid cell leukemia-1                                   Wilhelm SM, et al. Cancer Res 2004;64:7099–109.
                       Sorafenib in Breast Cancer
    Six Randomized, Double-blind, Placebo-controlled Phase 2b Trials


                                       Paclitaxel   Capecitabine*
                                   Dr. GRADISHAR Dr. BASELGA
                                    (Northwestern,     (SOLTI)
                                       ACORN)      Started Aug 07
                                   Started Jun 07
                                                       TRIALS
                                                   INVESTIGATING     Gemcitabine*3
                           Triplet  2
                                                    THE EFFECTS      Drs. HUDIS &
                        Dr. SLEDGE                                  SCHWARTZBERG
                           (HOG)                                       (MSKCC/
                          Planned                  OF SORAFENIB
                                                    IN BREAST
                                                                       ACORN)
                                                      CANCER         Started Jun 07

                                           Aromatase       Docetaxel or
                                           Inhibitors*1      Letrozole
                                           Dr. PEREZ        Dr. GIANNI
                                            (MCCRC)       (Michelangelo)
                                             Planned         Planned        *includes 2nd line patients
1. Letrozole, anastrozole, or exemestane
2. Paclitaxel/bevacizumab +/- sorafenib
3. Bevacizumab-progressors
                        Conclusions
• Newly approved and other novel agents for the treatment of
  patients with MBC continue to improve outcomes
   – The addition of biologics may make a substantial impact

• There is a clear and immediate need for larger, better
  designed clinical trials to assess the role of these
  new agents
   – As monotherapy
   – As combination therapy
   – As additions to therapies employing a growing number
     of biologics

								
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