Letrozole (CGS 20267) Femara� Protocol CGS 2026701025 Double by WV05FP

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									Anti-HER2 Epitope Map

Extracellular Domain



                           CRD-1



                 CRD-2               Herceptin (4D5)
                                      (aa 529-625)

888888888888888888888888888888888888888888888888888


Intracellular Domain

               TK




                                 CB11

                                              data from L. Bald & B. Fendly
    FISH/Clinical Outcome Analysis
               H0648g
Response Rate

                C alone     C+H
   FISH-          38%        38%
                (25-50%)     (24-52%)

   FISH+          31%        54%
                (24-38%)    (47-61%)




                                        n=451
    FISH/Clinical Outcome Analysis
        H0649g-Response Rate
IHC 2+/3+ combined
                               Number of Patients
                             FISH+             FISH-
 Total patients evaluable     173                36
 CR                            8                  0
 PR                           25                  0
 CR + PR                    33 (19%)           0 (0%)
                       (95% CI: 14%–26%)   (95% CI: 0%–10%)

 CR + PR + SD > 6 mo        41 (24%)           0 (0%)
    FISH/Clinical Outcome Analysis
        H0650g-Response Rate
IHC 2+/3+ combined
                               Number of Patients
                             FISH+             FISH-
 Total patients evaluable     82                 29
 CR                            7                  0
 PR                           22                  1
 CR + PR                    29 (35%)           1 (3%)
                       (95% CI: 25%–47%)   (95% CI: 0%–20%)

 CR + PR + SD > 6 mo        41 (50%)           1 (3%)
                                      ®
                     Use Herceptin upfront
                                    RR      TTP     Survival
Initial therapy                     (%)   (months) (months)

Paclitaxel*                         17      3.0      18.4

Herceptin + paclitaxel
               ®
                                    49      7.1      25.0

Herceptin monotherapy
               ®
                                    35      3.5      24.4

Other  Herceptin salvage       ®
                                    18      3.2      16.4
                            ®
*2/3 subsequent Herceptin
         FISH versus IHC 0/1+ in the
                            ®
     Herceptin plus weekly paclitaxel trial

                                                    Response/clinical
IHC score 0/1+                    FISH positive (%)    benefit (%)
                  ®
HercepTest (n=33)                         3/33 (9)                        2/3 (67)
CB11 (n=42)                              6/42 (14)                       6/6* (100)
*3 partial responses; 3 stable disease 6 months




                                                                Fornier, personal communication
                                                   Seidman A, et al. J Clin Oncol 2001;19:2587–95
             Intergroup
    Real World IHC vs Central Test

                          % False (+)
   (3+) OUT vs Central       27

   (3+) OUT vs FISH           31

   (3+) Central vs FISH       7

OUT = Outside Lab
         NSABP B-31 Central Review
                (104 cases)
     ICH Test   Type of Lab Central Lab               Central Lab
                            IHC Neg #                 IHC Neg %
                            of cases                  of cases
     HercepTest Non-ref     10/52                     19%
         3+
     (n=80)     Ref         1/28                      4%
     Other IHC Non-ref      11/23                     48%
     assay
     (n=24)     Ref         0/1                       0%
* cases whose eligibility was determined by FISH were excluded from analysis
                     Summary
   Clinical outcomes data in patients with prospective
    FISH and IHC testing
    - IHC 3+/FISH+
    - IHC 2+/FISH+
    - IHC 3+/FISH-
    - IHC 0 and 1+/FISH+

   Cardiac incidence in 1000 patients

   Exploratory comparison of Herceptin plus Taxol vs
    Herceptin plus Taxotere

                 Gabriel N. Hortobagi, MD, FACP and Pamela N. Klein, MD
                                                              HER-First
                Recent Cardiac Data

                Seldman et al Burstein et al Vogel et al
                 Taxol + H Navelbine + H H monotherapy
                   (n=95)       (n=40)        (n=113)

  Any cardiac
  dysfunction     10%          28%             3%
  Cardiac
  toxicity
   CTC            3%           0%             3%
  grade 3


H = Herceptin                               Pamela M. Klein, MD
                                             Cardiac Dysfunction
          Herceptin and Chemotherapy:
                In-vitro Activity
Synergistic (CI < 1)              Additive (CI = 1)
Vinorelbine                0.34   Doxorubicin     0.82 - 1.16
Docetaxel / Carboplatin    0.34   Paclitaxel      0.91
Docetaxel                  0.41   Epirubicin      0.99
Etoposide                  0.54   Vinblastine     1.09
Cyclophosphamide           0.57   Antagonistic (CI > 1)
Paclitaxel / Carboplatin   0.64   Methotrexate 1.36
Thiotepa                   0.67   Gemcitabine 1.25 - 5.34
Cisplatin                  0.67   Fluorouracil 2.87
Liposomal doxorubicin      0.70
           Pegram et al. Oncogene. 1999; 18:2241-51.
           Pietras et al. Oncogene. 1998; 17:2235-49.
    Taxotere + Herceptin
         Abstracts
Site        Sched.   No. RR%
Kuzur       3 wk.    16 62
Nicholson   Wkly     21 63
Germany     Wkly     12 50
Italy       Wkly     23 70
         Weekly Docetaxel* + Herceptin
          MDACC ( First or 2nd Line)
                   (30 pts)

                        63% RR
                      67% FISH (+)
                      76% ECD (+)
                     9 mo Med. TTP

* 35 mg/m2/wk x 3/course (med D.I. = 24 mg/m2/wk)
JCO 20: 1800, 2002
                  Toxicity
         Weekly Docetaxel + Herceptin
                  (30 pts)

      Dexamethasone 4 mg x 3 doses
      23% DCd Tox
        5 pleural effusion
        1 fatigue
        1 fungal infection
        1 bleeding ulcer

JCO 20: 1800, 2002
                  Toxicity
         Weekly Docetaxel + Herceptin
              MDACC - 30 pts

      93% Epiphora - Stenosis
      12 Pts Cannalicular Intubation
      10% Gr 1  LVEF
      16% Gr 2  LVEF
      1 case CHF (LVEF = 48%)


JCO 20: 1800, 2002
Clinical Activity of Trastuzumab and
 Vinorelbine in Women with Her2-
 Overexpressing Metastatic Breast
Cancer: JCO May 2001: Burstein et.
                   Al
              Response Rates: Overall

      Response                     N                 RR (%)
      CR                           3                       8
      PR                          27                      68
      CR + PR                     30                      75*
      SD > 6 m                     2                       5
      PD                           8                      20



*Conditional corrected 95% confidence interval 57%-89%.
 Phase II Trial of Weekly Vinorelbine
and Trastuzumab as First-Line Therapy
   in Patients With HER2-Positive
Metastatic Breast Cancer: SABCS 2001;
            Jahanzeb et. Al.
             Navelbine + Herceptin
                    20 Pts.



              RR = 60%
Jahanzeb - Asco 2001 - Abst 1986
TRastuzumab And VInorelbine Or Taxane
            (TRAVIOTA)
Eligibility:
1st line chemo                    HER2 + MBC
HER2+                   First-line Chemo & Trastumuzab
RECIST
                   Trastuzumab &           Trastuzumab &
                    Vinorelbine            Weekly Taxane
Multicenter
                                       (paclitaxel or docetaxel)
n=250

Endpoints:       Progressive Disease     Progressive Disease
RR, TTP
X-over RR, TTP
                                       ®                                 ®
                     Xeloda plus Herceptin : activity
                  against BT474 breast cancer xenografts
                                                                                     Control
               1,000                                                                 Xeloda
                                                                                     Herceptin
                       800                                                           Xeloda + Herceptin
 Tumour volume (mm3)




                       600

                       400



                       200
                                                                                       ***

                       100
                             20   25       30     35      40       45        50       55
                                            Days after inoculation
*p<0.05                                            Ouchi KF et al. Cancer Chemother Pharmacol (in press)
                     ®                                  ®
           Xeloda plus Herceptin :
           the German experience
• 18 patients with anthracycline and taxane-pretreated
  HER2+ MBC received 21-day cycle of
   • standard-dose Herceptin, weekly
   • Xeloda 1,125mg/m twice daily, days 1–14
                         2




• 47% ORR in 13 patients

• Median response duration of 10 months (range 7–18)

• Minimal side effects
                         Bangemann N et al. Ann Oncol 2000; 11:143 (Abst 653P)
             Gemzar + Herceptin
             3 + Overexpression

   Population = Heavily
                Pretreated (64 Pts.)
   R.R. = 45%
   T.T.P (medium) = 5.8 mo.
San Antonio 2001 (Abst 523)
           Coley (CpG 7909)
            (+) Herceptin
• Herceptin acts by modulating signal
   transduction pathways and through ADCC
• CpG stimulates ADCC
• In a mouse model
   • CpG as active as Herceptin
   • Markedly synergistic
• Clin. Trial in Herceptin Resistant Pts.
        Schema of Administration

                            Taxotere
                                            Every 3 weeks
                            Platinum Salt   At least 6 cycles




Herceptin weekly until PD

Premedication
•Standard Taxotere premed
•Standard CDDP hydration
         TCH - Response Rates
             First Line Patients

                            FISH       FISH
               Overall    positive** negative**

UCLA ORR    31/55 (56%) 23/36 (64%) 7/17 (41%)
carbo 95% CI [40-69]       [46-79]    [19-67]

BCIRG ORR 49/62 (79%) 27/35 (77%) 16/19 (84%)
  cis 95% CI [66-88]     [59-90]     [60-96]
   TCarboH – Time to Progression
   First Line Patients by FISH Result*                                                                              FISH +       FISH -
                                                                                              Patients                38           19
                                                                                              Median TTP (mos)       17.0          7.4
                                                                                              95% CI               [9.1-NE*]    [6.7-12.0]
                                  1.0
                                                                                              Events                  15           15
                                                                                              Censored                23               4
                                                                                              •Still responding       15               1
                                  0.8
    Proportion Progression Free




                                                                                              •Further Therapy         8               1
                                                                                              •Lost to Follow-up       0               2
                                                                                                                           NE* = Not
                                  0.6                                                                                      Estimable



                                  0.4


                                  0.2            FISH Positive
                                                 FISH Negative

                                  0.0

                                        0   2     4      6       8      10      12      14         16         18      20
                                                       Time to Disease Progression (months)
Number at Risk
          38                                37   32      26      19     15      12      10             8       4       0
          19                                17   15      13       8      6       5       3             1       1       0

   * 3 patients were treated in second line, 2 patients did not have tumor samples available for FISH testing
            Dana - Farber
    Preoperative Trastuzumab &
  Paclitaxel: Tumor Response Rates
        No.     cPR    cCR     pCR
                 17     12      7
Total    40     43%    30%     18%
                 16     11      6
3+       32     50%    34%     19%
                  1      1      1
2+        8
                13%    13%     13%
         Continue Weekly
         Herceptin for 8
         addt’l weeks    Reevaluate    Begin weekly
         (weeks 9-16)                  Herceptin /
                         (Week 17)     Pac / Carbo ---
     CR, PR, MR                        Continue 8-wk
                                       courses until
Herceptin                              progression or
Weekly      Reevaluate     Stable      total 12 mos.
x8                                     treatment

        Progression
                                         Continue
                                         8-week
                   Stop Herceptin        courses
                   Begin Pac / Carbo     until PD
    Schema                               or 12
                                         months
      Herceptin / Paclitaxel /
           Carboplatin

• Response to Herceptin induction (58 pts.)
  ¬ ORR 19%; SD or better 60%
• Response to H / P / C (34 pts.)
  ¬ ORR 68%; SD or better 73%
• Response to P/C (18 pts. with PD on Herceptin)
  ¬ ORR 50%
               Neoadjuvant
      Cisplat + Taxotere + Herceptin
           U of Miami (16 Pts.)
                          PRE
                   Herceptin Std. Dose
                 T/C 70 mg/m2 each q 21 d

                         POST
100% RR                  AC x 4
25 % pCR
Asco 2001 - Abst. 1871
                Herceptin Q 3 Wks.
 • 8 mg./kg. Loading -> 6 mg. /kg. Q 3 wk.
   Taxol 175 mg./m2 Q 3 wk. x 8
 • 1/2 Life > 3 Wks.
 • AUC and Peak (? More Tox ?)
 • Trough Levels Therapeutic ( > 20 ng./ml )
                  After 2 Doses
 • Reanalysis Pivotal Trials - T1/2 = 25 Days
   Time to Steady State = 18 Wks.
Proc Asco 2001 - Abst. 271
                                               Trough levels - weekly vs q3w
                              Weekly Administration                                   Q-3 Weekly Administration
                    140                                                               140
                    120                                                               120




                                                                  Herceptin (ug/mL)
Herceptin (ug/mL)




                    100                                                               100
                    80                                                                80
                    60                                                                60
                    40                                                                40
                    20                                                                20
                     0                                                                 0
                          1    4   7 10 13 16 19 22 25 28 31 34                            1   4   7 10 13 16 19 22 25 28 31 34

                                        Week Number                                                       Week Number
                  Summary
• Herceptin administered q3w is safe with no
  unexpected toxicity.
• No interaction of Taxol and Herceptin
  pharmacokinetics was observed.
• Trough levels for q3w Herceptin were similar to
  those seen with weekly dosing.
• Peak and average serum concentrations were
  higher than those seen with weekly Herceptin.
• Half-life of Herceptin was 21 days.
• This suggests that it could take approximately 18
  weeks after discontinuing Herceptin to clear the
  drug from the body.            Karen A. Gelmon, MD, FRCPC
                                          Herceptin + Taxol q3w
   Adjuvant Herceptin
      Q3 Wk 2001

Hera
Intergroup
BCIRG - Maintenance
Should Herceptin be continued in patients
 with disease progression on Herceptin?
     Limited clinical data

   Depends     on mechanism of action of Herceptin
        - ? Alters sensitivity of breast cancer cells to
            cytotoxic therapy
        - ? Interferes with anti-apoptotic pathways

     Clinical anecdotes suggest some activity
           Herceptin + Vinorelbine
           Study Design (MDACC)
                          Vinorelbine
Progressive
                         (Single Agent)
disease after
Herceptin +
Taxane-based
Therapy
                          Vinorelbine
                              +
(HER2 +)
                           Herceptin
                      Adjuvant Taxol® + Herceptin® (T+H) 
                         AC, Then Continued Herceptin
                        (Trial E-2198): Schema
Hypothesis: T + H  AC is less cardiotoxic than AC  T + H
Patients: node+, HER2 positive (IHC 2+/3+*); no prior CHF or recent MI; LVEF > 50%
(n = 234)
                      (q3w x 4)                          (q3w x 4)



                                                (3-wk
                      (qw x 10)                 break)




                      (qw x 10)                                      (qw x 52)


                                                                    
               LVEF testing


                                                                                 6 mo
  Taxol 175   mg/m2   q3w                                                        1y
  Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w
  Herceptin 4 mg/kg first wk, then 2 mg/kg qw
         Adjuvant Taxol + Herceptin (T + H)
           AC, Then Continued Herceptin
               (E-2198): Cardiotoxicity
   • Primary end point: rate of clinical CHF
   • Secondary end point: > 10% absolute decrease
     in LVEF from baseline
     - Patients to go off Herceptin for LVEF drop of > 20%,
       LVEF drop below LLN, or CHF
   • Results through immediate post-AC evaluation
     - CHF in 4 patients (< 2%), 3 post-AC
     - LVEF below LLN: 2.8% post-T + H, 6% post-AC
     - LVEF drop of > 10%: 9% post-T + H, 13.2% post-AC
Update of Sledge et al. Breast Cancer Res Treat. 2001;69:209. Abstract 4.
           Adjuvant Therapy With Herceptin®
               in the NSABP B-31 Trial
  Patient characteristics: node+, HER2 positive (IHC 3+* or FISH+†)
    Activation: March 2000
    (n = 2700)


                                                                       (q3w x 4)


                    (q3w x 4)




                                                                       (qw x 52)
     Doxorubicin 60   mg/m2     + cyclophosphamide 600   mg/m2   q3w
     Taxol® 175 mg/m2 q3w
     Herceptin 4 mg/kg first wk, then 2 mg/kg qw

* HercepTestTM.
† PathVysionTM or INFORM® (>5 copies/cell).

  Adjuvant tamoxifen for ER+ or PR+ patients.

 Romond. Protocol NSABP-B-31.
           Adjuvant Therapy With Herceptin®
            in the Intergroup Trial (N9831):
                         Schema
• Patient characteristics: node+, HER2 IHC 3+ or FISH+ (> 5 copies/cell)
 (n = 3000)                                      (qw x 12)




                                                                                    (qw x 52)

      (q3w x 4)



                                                 (qw x 52)
    Doxorubicin 60 mg/m2 +
    cyclophosphamide 600 mg/m2 q3w
    Taxol® 80 mg/m2 qw
    Herceptin 4 mg/kg first wk, then 2 mg/kg qw

 Radiotherapy for all pts  5 wks after Taxol, with tamoxifen for all ER+ pts at initiation of therapy.
 Perez. Protocol NCCTG-N9831.
 Horton. Cancer Control. 2001;8:103.
      Adjuvant Therapy With Herceptin®:
      Breast Cancer International Research
           Group Trial (BCIRG 006)
 (n = 3150)

                            (q3w x 4)                (q3w x 4)
    Node+/
    High Risk
    Node–/
    FISH+
                                                     (qw x 12)                (q3w x 14)
                           (q3w x 6)




                           (qw x 18)                             (q3w x 12)

  A 60 mg/m2 + C 600 mg/m2 q3w
  Taxotere® 100 mg/m2 q3w
  Carboplatin AUC 6 + Taxotere 75 mg/m2 q3w
 Herceptin 4 mg/kg first wk, then 2 mg/kg qw    Herceptin 6 mg/kg q3w
                HER2 Adjuvant (HERA) Trial:
                         Schema
 Patients HER2 IHC 3+/FISH+
                        Surgery

                                 Primary Management
                         (chemotherapy, local or locoregional radiation)


                                           Stratify

                                         Randomize

       Herceptin®                         Herceptin                Observation
        q3w x 12 mo                       q3w x 24 mo                  N=1100
          N=1100                            N=1100

Courtesy of Clifford Hudis.
   Number of Patients in Adjuvant
        Herceptin Trials

              Accrual       Target
              (~June ’02)
NSABP         720 (27%)      2700
Intergroup    781 (26%)      3000
BCIRG 006     679 (22%)      3150
HERA           50 (2%)       3300
Total        2230 (18%)     12150

								
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