Anti-HER2 Epitope MapAnti-HER2 Epitope Map

Herceptin (4D5) (aa 529-625)

TK

CRD-2

CRD-1

data from L. Bald & B. Fendly

888888888888888888888888888888888888888888888888888

Extracellular Domain

Intracellular Domain

CB11

C aloneC alone C + H C + H

FISH-FISH- 38%38% 38% 38%

FISH+FISH+ 31%31% 54% 54%

n=451

(25-50%) (24-52%)

(24-38%) (47-61%)

FISH/Clinical Outcome AnalysisH0648g

Response RateResponse Rate

Number of Patients

FISH+ FISH-

Total patients evaluable 173 36

CR 8 0

PR 25 0

CR + PRCR + PR 33 (19%)33 (19%) 0 (0%)0 (0%)

(95% CI: 14%–26%) (95% CI: 0%–10%)

CR + PR + SD > 6 mo 41 (24%) 0 (0%)CR + PR + SD > 6 mo 41 (24%) 0 (0%)

FISH/Clinical Outcome AnalysisH0649g-Response Rate

IHC 2+/3+ combined IHC 2+/3+ combined

Number of Patients

FISH+ FISH-

Total patients evaluable 82 29

CR 7 0

PR 22 1

CR + PRCR + PR 29 (35%)29 (35%) 1 (3%)1 (3%)

(95% CI: 25%–47%) (95% CI: 0%–20%)

CR + PR + SD > 6 mo 41 (50%) 1 (3%)CR + PR + SD > 6 mo 41 (50%) 1 (3%)

FISH/Clinical Outcome AnalysisH0650g-Response Rate

IHC 2+/3+ combined IHC 2+/3+ combined

Use Herceptin® upfront

*2/3 subsequent Herceptin®

Initial therapyRR(%)

TTP(months)

Survival(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

FISH versus IHC 0/1+ in the Herceptin® plus weekly paclitaxel trial

Fornier, personal communicationSeidman A, et al. J Clin Oncol 2001;19:2587–95

*3 partial responses; 3 stable disease 6 months

IHC score 0/1+ FISH positive (%)Response/clinical

benefit (%)

HercepTest® (n=33) 3/33 (9) 2/3 (67)

CB11 (n=42) 6/42 (14) 6/6* (100)

IntergroupReal World IHC vs Central Test

OUT = Outside Lab

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

(3+) OUT vs FISH 31

(3+) Central vs FISH 7

NSABP B-31 Central Review(104 cases)

* cases whose eligibility was determined by FISH were excluded from analysis

ICH Test Type of Lab Central LabIHC Neg #of cases

Central LabIHC Neg %of cases

HercepTest 3+(n=80)

Non-ref

Ref

10/52

1/28

19%

4%Other IHCassay(n=24)

Non-ref

Ref

11/23

0/1

48%

0%

SummaryClinical outcomes data in patients with prospective FISH and IHC testingIHC 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, MDHER-First

Recent Cardiac Data

H = Herceptin Pamela M. Klein, MDCardiac Dysfunction

Seldman et alTaxol + H

(n=95)

Burstein et alNavelbine + H

(n=40)

Vogel et alH monotherapy

(n=113)

Any cardiacdysfunction 10% 28% 3%Cardiactoxicity CTCgrade 3

3% 0% 3%

Doxorubicin 0.82 - 1.16Paclitaxel 0.91Epirubicin 0.99Vinblastine 1.09

Herceptin and Chemotherapy:In-vitro Activity

Pegram et al. Oncogene. 1999; 18:2241-51.Pietras et al. Oncogene. 1998; 17:2235-49.

Synergistic (CI < 1)

Vinorelbine 0.34Docetaxel / Carboplatin 0.34Docetaxel 0.41Etoposide 0.54Cyclophosphamide 0.57Paclitaxel / Carboplatin 0.64Thiotepa 0.67Cisplatin 0.67Liposomal doxorubicin 0.70

Additive (CI = 1)

Antagonistic (CI > 1)

Methotrexate 1.36Gemcitabine 1.25 - 5.34Fluorouracil 2.87

Taxotere + HerceptinAbstracts

Site Sched. No. RR% Kuzur 3 wk. 16 62 Nicholson Wkly 21 63 Germany Wkly 12 50 Italy Wkly 23 70

Weekly Docetaxel* + HerceptinMDACC ( First or 2nd Line)

(30 pts)

63% RR67% 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

ToxicityWeekly Docetaxel + Herceptin

(30 pts)

Dexamethasone 4 mg x 3 doses23% DCd Tox

5 pleural effusion1 fatigue1 fungal infection1 bleeding ulcer

JCO 20: 1800, 2002

ToxicityWeekly Docetaxel + Herceptin

MDACC - 30 pts

93% Epiphora - Stenosis12 Pts Cannalicular Intubation10% Gr 1 LVEF16% Gr 2 LVEF1 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 N RR (%)

CR 3 8PR 27 68CR + PR 30 75*SD > 6 m 2 5PD 8 20

*Conditional corrected 95% confidence interval 57%-89%.

Response Rates: Overall

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 + Herceptin20 Pts.

RR = 60%

Jahanzeb - Asco 2001 - Abst 1986

TRastuzumab And VInorelbine Or Taxane(TRAVIOTA)

Eligibility:1st line chemoHER2+RECIST

Multicentern=250

Endpoints:RR, TTPX-over RR, TTP

HER2 + MBCFirst-line Chemo & Trastumuzab

Trastuzumab &Vinorelbine

Trastuzumab &Weekly Taxane

(paclitaxel or docetaxel)

Progressive Disease Progressive Disease

Xeloda® plus Herceptin®: activity against BT474 breast cancer xenografts

Ouchi KF et al. Cancer Chemother Pharmacol (in press)

1,000

800

600

400

200

10020 25 30 35 40 45 50 55

***Tu

mo

ur

volu

me

(mm

3 )

ControlXelodaHerceptinXeloda + Herceptin

Days after inoculation

*p<0.05

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/m2 twice daily, days 1–14

• 47% ORR in 13 patients

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

• Minimal side effectsBangemann N et al. Ann Oncol 2000; 11:143 (Abst 653P)

Gemzar + Herceptin3 + Overexpression

Population = HeavilyPretreated (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 signaltransduction 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

Platinum Salt

Every 3 weeks At least 6 cycles

Herceptin weekly until PD

Premedication•Standard Taxotere premed •Standard CDDP hydration

TCH - Response Rates First Line Patients

7/17 (41%) [19-67]

7/17 (41%) [19-67]

23/36 (64%)[46-79]

23/36 (64%)[46-79]

FISH negative**

FISH negative**

FISH positive**

FISH positive**OverallOverall

ORR95% CIORR95% CI

31/55 (56%) [40-69]

31/55 (56%) [40-69]

ORR95% CIORR95% CI

49/62 (79%)[66-88]

49/62 (79%)[66-88]

27/35 (77%)[59-90]

27/35 (77%)[59-90]

16/19 (84%)[60-96]

16/19 (84%)[60-96]

UCLAcarboUCLAcarbo

BCIRGcis

BCIRGcis

FISH Positive

FISH Negative

0 2 4 6 8 10 12 14 16 18 20Time to Disease Progression (months)

Number at Risk38 37 32 26 19 15 12 10 8 4 019 17 15 13 8 6 5 3 1 1 0

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rog

ress

ion

Fre

eTCarboH – 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]

Events 15 15

Censored •Still responding•Further Therapy•Lost to Follow-up

231580

4112

NE* = Not Estimable

* 3 patients were treated in second line, 2 patients did not have tumor samples available for FISH testing

Dana - FarberPreoperative Trastuzumab &

Paclitaxel: Tumor Response Rates

No. cPR cCR pCR

Total 4017

43%12

30%7

18%

3+ 3216

50%11

34%6

19%

2+ 81

13%1

13%1

13%

SchemaSchema

Reevaluate Reevaluate

(Week 17)(Week 17)

Reevaluate Reevaluate

(Week 17)(Week 17)

ProgressionProgressionProgressionProgression

StableStableStableStable

Stop Herceptin Stop Herceptin Begin Pac / CarboBegin Pac / CarboStop Herceptin Stop Herceptin Begin Pac / CarboBegin Pac / Carbo

Continue Continue 8-week8-weekcourses courses until PD until PD or 12 or 12 monthsmonths

Continue Continue 8-week8-weekcourses courses until PD until PD or 12 or 12 monthsmonths

CR, PR, MRCR, PR, MRCR, PR, MRCR, PR, MR

Continue Weekly Continue Weekly Herceptin for 8 Herceptin for 8 addt’l weeks addt’l weeks (weeks 9-16)(weeks 9-16)

Continue Weekly Continue Weekly Herceptin for 8 Herceptin for 8 addt’l weeks addt’l weeks (weeks 9-16)(weeks 9-16)

Begin weeklyBegin weeklyHerceptin / Herceptin / Pac / Carbo ---Pac / Carbo ---Continue 8-wk Continue 8-wk courses until courses until progression or progression or total 12 mos. total 12 mos. treatmenttreatment

Begin weeklyBegin weeklyHerceptin / Herceptin / Pac / Carbo ---Pac / Carbo ---Continue 8-wk Continue 8-wk courses until courses until progression or progression or total 12 mos. total 12 mos. treatmenttreatment

HerceptinHerceptinWeeklyWeeklyx 8x 8

HerceptinHerceptinWeeklyWeeklyx 8x 8

ReevaluateReevaluateReevaluateReevaluate

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%

NeoadjuvantCisplat + Taxotere + Herceptin

U of Miami (16 Pts.)

PREHerceptin Std. Dose

T/C 70 mg/m2 each q 21 d

POSTAC x 4

Asco 2001 - Abst. 1871

100% RR25 % pCR

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

0

20

40

60

80

100

120

140

1 4 7 10 13 16 19 22 25 28 31 34

Week Number

Her

cep

tin

(u

g/m

L)

0

20

40

60

80

100

120

140

1 4 7 10 13 16 19 22 25 28 31 34

Week Number

Her

cep

tin

(u

g/m

L)

Weekly Administration Q-3 Weekly Administration

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 HerceptinQ3 Wk 2001

HeraIntergroupBCIRG - 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 + VinorelbineStudy Design (MDACC)

Progressive disease after Herceptin + Taxane-based Therapy

(HER2 +)

Vinorelbine(Single Agent)

Vinorelbine +

Herceptin

(q3w x 4) (q3w x 4)

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)

(qw x 10)

LVEF testing

Taxol 175 mg/m2 q3w

Herceptin 4 mg/kg first wk, then 2 mg/kg qw

Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w

(3-wkbreak)

(qw x 52)

6 mo1 y

(qw x 10)

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+†)

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

(q3w x 4)

Taxol® 175 mg/m2 q3wHerceptin 4 mg/kg first wk, then 2 mg/kg qw

Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w

Adjuvant tamoxifen for ER+ or PR+ patients.

Romond. Protocol NSABP-B-31.

Activation: March 2000

(n = 2700)

(q3w x 4)

(qw x 52)

(n = 3000)

(qw x 52)

Adjuvant Therapy With Herceptin® in the Intergroup Trial (N9831):

Schema• Patient characteristics: node+, HER2 IHC 3+ or FISH+ (> 5 copies/cell)

(q3w x 4)

(qw x 12)

(qw x 52)

Taxol® 80 mg/m2 qwHerceptin 4 mg/kg first wk, then 2 mg/kg qw

Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w

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.

(n = 3150)

Node+/High Risk

Node–/FISH+

Adjuvant Therapy With Herceptin®: Breast Cancer International Research

Group Trial (BCIRG 006)

(q3w x 4) (q3w x 4)

(qw x 12) (q3w x 14)(q3w x 6)

(q3w x 12)(qw x 18)

Herceptin 4 mg/kg first wk, then 2 mg/kg qw Herceptin 6 mg/kg q3w

Taxotere® 100 mg/m2 q3w

A 60 mg/m2 + C 600 mg/m2 q3w

Carboplatin AUC 6 + Taxotere 75 mg/m2 q3w

Randomize

Primary Management (chemotherapy, local or locoregional radiation)

Stratify

Surgery

Herceptin® q3w x 12 mo

N=1100

Herceptin q3w x 24 mo

N=1100

ObservationN=1100

HER2 Adjuvant (HERA) Trial: Schema

Patients HER2 IHC 3+/FISH+

Courtesy of Clifford Hudis.

Number of Patients in Adjuvant Herceptin Trials

Accrual(~June ’02)

Target

NSABP 720 (27%) 2700

Intergroup 781 (26%) 3000

BCIRG 006 679 (22%) 3150

HERA 50 (2%) 3300

Total 2230 (18%) 12150