Targeted therapy in EarlyBreast Cancer

Paul Ellis

Guy’s Hospital, London

Targeted therapy

Key principles for targeted therapeutics:– the target must be relevant to the disease– a clear scientific rationale must exist for the therapeutic– patients can be selected for on basis of tumour

expression of the target

• Questions for clinical trials of targeted therapeutics:– Are the most appropriate population of patients being

treated? – Has the trial been designed correctly, with most

appropriate biological / clinical endpoints?

Molecular targets:– Hormone Receptors

• ER, PgR• AR

– Cell Surface Receptors• HER family (EGFR, HER2)• IGFR-I

– Angiogenesis– PARP– Signal Transduction

• Src • MEK • PI3-Kinase / Akt • mTOR • HSP-90

Treatment choices based on molecular features:

• ER / PgR positive• HER2 positive

• Basal type (triple negative) ?• BRCA status ?

Targeted Therapy of Breast Cancer 2008

Background HER2 positive EBC

Global Adjuvant trial update

Current UK practice

Application of targeted therapies

Neoadjuvant therapy

Triple Negative EBC Summary

HER2+ EBC

Drugs to block HER Family Receptors

Tyrosine kinaseinhibitors

EGFR: gefitinib, erlotinibHER2: AEE-788, lapatinib

Pan-erb: CI-1033, HKI-569

Monoclonalantibodies

cetuximab, ABX-EGF, EMD72000, h-R3,

trastuzumab, pertuzumab

Signal Transduction

R R

Ligand

K K

Adjuvant trastuzumab trials:>13,000 patients

NCCTG N9831 (USA)

HERA (ex-USA) BCIRG 006 (global)

NSABP B-31 (USA)

Piccart-Gebhart et al 2005;Romond et al 2005;

Slamon et al 2006

IHC orFISH

(n=5090)2 years Herceptin

Observation

Standard chemotherapy

1 year Herceptin

IHC orFISH

(n=2030)

Herceptin 1 year

IHC orFISH

(n=3505)

Herceptin 1 year

FISH(n=3222)

Herceptin 1 year

IHC or FISH

(n=5090)

Docetaxel Docetaxel + carboplatin Doxorubicin + cyclophosphamide Paclitaxel

ASCO 2007: Updated N9831/B-31 Joint Analysis: DFS

168460 87531,2351,800Numberat risk

N=619 eventsHR*adj = 0.48 (95% CI: 0.41-0.57)*Nodes, receptor status, paclitaxel schedule, protocol

73.1%

86.4%

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Follow-up (yrs)

Aliv

e a

nd

dis

ea

se-f

ree

(%

) AC P (n=1,979; 397 events)

P < 0.0000177.6%

202522 48681,3471,854

85.9%

92.3% AC P+ H(n=1,989; 222 events)87.9

%

*Intent to treat events: recurrent disease, contralateral bc, 2nd primary, death

21% crossover

aBased on small subgroups of patients with HER2-positive breast cancer; brelapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil

DFS benefit across 5 out of 6 trials

4

2

3

4

Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007

Spielmann et al 2007

3

3

Median follow-up, years

0 1 2FavoursHerceptin

Favours noHerceptin

HR

DFS benefit

B-31 / N9831 ACPH

HERA CTxH 1 year

FinHera VH / DHCEFb

PACS-04a CTxH 1 year

BCIRG 006 ACDH

BCIRG 006 DCarboH

0 1 2Favours

HerceptinFavours noHerceptin

HR

Adjuvant trastuzumab trials:proven OS benefit

B-31 / N9831 ACPH

BCIRG 006 ACDH

HERA H 1 year

BCIRG 006 DCarboH

FinHer VH / DHa

4

3

2

Median follow-up,years

3

Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2006

3

Cumulative incidence of cardiac events: N9831/NSABP B31 updated analysis

Longer follow-up showed no additional concerns regarding the cardiac safety profile Cardiac events occurred early No evidence of increased toxicity or late toxicity

In NSABP B 31 the following factors were shown to be predictive for CHF: Age (p=0.03) Hypertensive medications (p=0.02) Baseline LVEF (p=0.0003)

The incidence of cardiac events reach a plateau at around 1 year Cardiac effects of trastuzumab were largely reversible

Perez et al Abs 512 ASCO 2007

Slamon et al 2006 Rastogi et al 2007

Suter et al 2007 Perez et al 2008

Incidence of trastuzumab-related cardiac events in EBC trials

3.0

NR

NR

18.0

8.6

Asymptomatic LVEF decline, %a

H 1 year

ACPH

ACPH

ACDH

DCarboH

Arm

HERA

NSABP B-31

NCCTG N9831

BCIRG 006

1,678

947

570

1,068

1,056

nSevere CHF, %

0.6

3.8cum (5 yr)

3.3cum (3 yr)

1.9

0.4

Cardiac death, n

0

0

0

0

0

Ongoing Trial Questions

Duration- Greater than 1 yr (HERA 1 v 2 yr awaited - ? SA 08 ) - Shorter – 6 v 12 months (Separate UK & French trials)

Concurrent or Sequential- N 9831 update - ? SA 09

Older / Lower risk patients- Herceptin needed in addition to AI?

Can we do without anthracyclines? Translational Biology

– How do we Identify subgroups that gain most benefit?

aBased on small subgroups of patients with HER2-positive breast cancer; brelapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil

Duration: Vast majority of evidence in trials of 12 months

4

2

3

4

Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007

Spielmann et al 2007

3

3

Median follow-up, years

0 1 2FavoursHerceptin

Favours noHerceptin

HR

DFS benefit

B-31 / N9831 ACPH

HERA CTxH 1 year

FinHera VH / DHCEFb

PACS-04a CTxH 1 year

BCIRG 006 ACDH

BCIRG 006 DCarboH

What is the optimum scheduling of Herceptin and chemotherapy?

HERA0.180.160.140.120.100.080.060.040.020.00

1-6 7-12 13-18 19-24 25-30 31-36

Months since randomisation

HRObservation1 year H

PACS-040.012

6

Months

HR

0 12 18 24 30 36 42 48

0.010

0.008

0.006

0.004

0.002 1 year HObservation

HR=0.5795% CI (0.30-1.09) HR=1.04

NSABP B-31 / NCCTG N9831120

0Years since randomisation

Rate per1,000 women/year

1 2 3 4

100

80

60

40

20

0

AC→TH

AC→T

Romond et al 2005Smith 2006

Spielmann et al 2007

Should we treat the “low risk” HER2+patient?

Poor 10-year Breast Cancer Specific Survival Poor 10-year Breast Cancer Specific Survival (BCSS) and RFS for HER2+ pT1N0 tumours(BCSS) and RFS for HER2+ pT1N0 tumours

3836 tissue microarray cohort of ebc diagnosed in British Columbia 1986-92, confirmed invasive with ER and HER2

1245 cases T1pN0 (952 of these no adjuvant therapy) HER2 +ve defined as IHC 3+ or FISH+ 13% of total were HER2 +ve 9.4% of TIpN0 were HER2 +ve

Norris et al. SABCS 2006. Poster 2031

10-year BCSS and RFS by HER2 and ER in the pT1N0 cohort

HER2- (All) HER2+ (All) HER2+ER+ HER2+ER-

All cases n = 3836

3336 (87%) 500 (13%) 204 (5.3%) 296 (7.7%)

10-year BCSS

76.5 58.1 62% 55.4%

10-year RFS 68.5 49.5 52.2% 47.6%

T1pN0 n = 1245

1128 (90.6%) 117 (9.4%) 40 (3.2%) 77 (6.2)

10-year BCSS

90.1 81.3 91.7 76.2

10-year RFS 78.7 71.6 77.5 68.3

Adapted from Norris et al. SABCS 2006. Poster 2031

BCSS, breast cancer-specific survival

RFS, relapse-free survival

Adjuvant Trastuzumab in ‘Low-Risk’ Patients:T1N0M0

T1 (≤ 1 cm ) N0 excluded from adjuvant trials

T1 (> 1 cm) were recruited into HERA, N9831, and BCIRG 006

- 32% (HERA)

- 29% (BCIRG006)

- 11% (N9831), patients had node-negative disease

In HERA 994 of 1099 N0 pts had tumours >1cm

Smith IE et al. Lancet 2007; 369: 29–36Perez EA et al. ASCO 2007. Abstract #512Slamon D. SABCS 2006

DFS benefit across different tumour sizes

Slamon et al 2006 Perez et al 2007; Smith et al 2007

>2-5 cm

BCIRG 006

>2-5 cm

>5 cm

0.0 0.5 2.51.0 1.5 2.0

0-2 cm

N9831 / B-31 0-2 cm

>5 cm

ACDH <2 cm

DCarboH <2 cm≥2 cm

≥2 cm

Favours Herceptin Favours no HerceptinHR

HERA

DFS, disease-free survival

Trastuzumab for Low Risk Breast CancerThe Contradiction

St Gallen and NCCN guidelines

Adjuvant CT plus trastuzumab is indicated for patients with N0 tumours if ≥ 2 cm.

HERA Conclusions

‘We were unable to identify a subgroup for which the potential absolute benefit of trastuzumab was small enough to indicate that treatment might not be clinically beneficial’

(Based on 510 pts randomised with T1(1.1-2cm)N0 tumours)

HER2+ve ‘Low Risk’ Breast CancerKey Issues

Should women with HER2+ve low risk breast cancer be given CT and trastuzumab?

Would women with HER2+ve low risk breast cancer benefit from trastuzumab alone (or with endocrine therapy if ER+ve?)

If so would the gain from additional chemotherapy be clinically worthwhile?

Anthracyclines – Do we need them in HER2+ pts?

Anthracyclines – Do we need them?

Increasing concern re potential long term morbidity – cardiac tox/leukeamia risk

Adjuvant anthracyclines are effective in patients whose tumors have topo II alpha amplification (7% of total)

However, almost all of those tumors have simultaneous amplification of Her2

We now have very effective targeted therapies for these tumors (trastuzumab) (BCIRG 006 - TCH)

26

BCIRG006: DFS and OS

Disease Free Survival - 2nd Interim AnalysisAbsolute DFS benefits

(from years 2 to 4):AC TH vs AC T: 6%

TCH vs AC T: 5%

% D

ise

ase

Fre

e

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Patients Events

1073 192 AC->T1074 128 AC->TH1075 142 TCH

81%

87%

86%

77%

83%

82%87%

93%

92%

HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003

Year from randomization

Overall Survival – 2nd Interim Analysis

HR (AC->TH vs AC->T) = 0.60 [0.42;0.85] P=0.004

HR (TCH vs AC->T) = 0.66 [0.47;0.93] P=0.017

% S

urvi

val

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Patients Events1073 80 AC->T1074 49 AC->TH

1075 56 TCH

97%

99%98%

93%

97%

95% 92%

91%

86%

Year from randomization

27Smith I et al. Lancet 2007;369:29–36; 2. Rastogi et al. ASCO 2007. Abstract LBA513; 2. Perez et al. ASCO 2007. Abstract 512; 3.

Slamon D et al. SABCS 2006;Abstract 52

Cardiotoxicity and trastuzumab: pivotal adjuvant trastuzumab trials

CHF, congestive heart failure; LLN, lower limit of normal

HERA1

NSABP B-312

NCCTG N98312

BCIRG 0063

Trial

ChemoChemo H

ACPACPH

ACPACPHACPH

ACDACDHDCarboH

Arm

>55

LLN (typically >50)

LLN (typically >50)

LLN (typically >50)

BaselineLVEF, %

0.6

3.8

2.53.5

1.90.4

Severe CHF, %

3

15.9

1417

18.18.6

Contractile dysfunction, %

28

Patients should receive Trastuzumab upfront

In the joined analysis 5-7% of patients receiving AC have cardiac dysfunction that they never receive Trastuzumab – 15% receive less than 1 year of Herceptin

In the BCIRG006, 23 pts in the ACTH arm never got Herceptin due to unacceptable declines in LVEF following AC

Combined Targeted agents in EBC

6 wk breakLapatinib x

7.5 mo

Trastuzumabfor 1 yr

Lapatinibfor 1 yr

Trastuzumabfor 3 mo

Trastuzumab3-weekly +lapatinibfor 1 yr

1:1 RANDOMIZATION (N=8000)1:1 RANDOMIZATION (N=8000)

ALTTO Study Design

HER2+ invasive breast cancerHER2+ invasive breast cancer

Centrally-determined HER2+Centrally-determined HER2+

Surgery, complete (neo)adjuvant anthracycline-basedchemotherapy (approved list)

Surgery, complete (neo)adjuvant anthracycline-basedchemotherapy (approved list)

LVEF 50LVEF 50

*

* = weekly paclitaxel x 12w; as per investigator’s discretion. PIs. M Piccart, EA PerezPIs. M Piccart, EA Perez

Early breast cancer, HER2 +ve(n=3600)

Early breast cancer, HER2 +ve(n=3600)

BETH: Study design

Primary Endpoint: Invasive Disease-Free Survival Randomized, open label trial TCH: docetaxel + carboplatin (q3w x 6

cycles) + Herceptin® (q3w x 1 year)

THFECH: docetaxel + Herceptin® (q3w x 3 cycles) 5-FU, epirubicin, and cyclophosphamide (q3w x 3 cycles) Herceptin® (q3w x 43 weeks)

TH FEC or TCH

+ Avastin®

TH FEC or TCH

+ Avastin®

TH FEC or TCH

TH FEC or TCH

H + Avastin® 15 mg/kg/q3wk

to complete 1 year

H + Avastin® 15 mg/kg/q3wk

to complete 1 year

H to complete 1 year

H to complete 1 year

BEATRICE: BEvacizumab as adjuvant treatment of triple negative breast cancer

DFS

Triple negative

EBCa

(n=2530)

aHER2− & ER/PgR status confirmed centrally before randomisation; DFS, disease-free survival

BEATRICE includes patients with early triple negative breast cancer (basal phenotype) End points

– primary end point: disease-free survival

– secondary end points: overall survival, recurrence-free survival, distant disease-free survival, time to recurrence, and time to distant recurrence

Efficacy and

safety follow-up

Chemo

Chemo + bev (1 year)

Are taxane chemotherapy regimens better or worse for “basal-like” cancers?

4162 women(3610 TMA)

800 predicted ER/PR/HER2 -ve

Effect of being “Basal-like”

“Basal-like”“Triple Negative

The RestThe Rest of ER-ve

Randomise

FEC x 8 or Epi/CMF

FEC x 4Docetaxel x 4

MetastasisFree

Survival

Formal test of interactionSub-group and treatment effect

Hypothesis taxane resistance7 IHC markers

Nielsen “basal-like” definition

Sufficient PowerFormal test of

interaction HRs

UK TACTAdjuvant study

P Ellis, P Barrett-Lee, J Bliss

S Johnston - Trans-TACT TRICC

ER-ve + EGFrAnd /orCK5/6

P-CadherinCK14 CK17

Neoadjuvant Trastuzumab

Neoadjuvant trial in HER2-positive operable BC: pathCR rates

0

10

20

30

40

50

60

70

80

90

DSMB reviewed data Final results

26.3%n=19

65.2%n=2325.0%

n=16

66.7%n=18

95% CI(41–87%)p=0.02

95% CI(43–84%)p=0.016

(n=34) (n=42)

pC

R (

%)

P + FEC alone

H + (P FEC)

Buzdar A, et al. Proc ASCO 2004;23:7

NOAH study: neoadjuvant Herceptin for LABC

aHormone receptor-positive patients receive adjuvant tamoxifen AP, doxorubicin 60 mg/m2, paclitaxel 150 mg/m2; H, Herceptin 8 mg/kg loading then 6 mg/kg P, paclitaxel 175 mg/m2; CMF, cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2 LABC, locally advanced breast cancer; q3w, every 3 weeks; q4w, every 4 weeks

HER2-positive LABC(IHC 3+ and/or FISH+)

n=113H + APq3w x 3

H + Pq3w x 4

H q3w x 4 + CMF q4w x 3

Surgery followed byradiotherapya

H continued q3wto Week 52

n=115

Pq3w x 4

CMFq4w x 3

Surgery followed byradiotherapya

APq3w x 3

APq3w x 3

Pq3w x 4

CMFq4w x 3

Surgery followed byradiotherapya

n=99

HER2-negative LABC(IHC 0/1+)

p=0.002

p=0.004

pCR (%)

Baselga et al 2007; Gianni et al 2007

HER2 positive (n=228)

HER2 positive(n=62)

Neoadjuvant Herceptin significantly improves pCR rates in the NOAH trial

Without Herceptin

With Herceptin

90

80

70

60

50

40

30

20

10

0HER2 negative

(n=99)HER2

negative(n=14)

23 43 17 19 55 29

Total population IBC population

pCR, pathological complete response in the breastIBC, inflammatory breast cancer

0 10 20 30 40 50 60 70 80 90 100

Baldini et al 2004, n=68

Veyret et al 2006, n=102

Gonzales-Angulo et al 2004, n=48

Ditsch et al 2006, n=51

Ditsch et al 2006, n=42

Vandebroek et al 2003, n=19

Franco et al 2002, n=10

Viens et al 1998, n=17

pCR rate in context: IBC irrespective of HER2 status

A, doxorubicin; C, cyclophosphamide; D, docetaxel; E, epirubicin; F, 5-fluorouracil; HD, high-dose 5-fluorouracil (750 mg/m2); SCT, stem cell transplantation

Baselga et al 2007, n=31 AT → T → CMF + H

FEC-HD

FAC or FAC + T

ET

E →T

ET

CAF or CEF

D + carboplatin (including non-IBC)

FAC → mitoxantrone + C + melphalan + SCT

Chemotherapy

NOAH (trastuzumab)

Study

pCR (%)

Baselga J et al ECCO 2007 Abs O#2030

NOAH: cardiac safety

LVEF worst value

no change

absolute decrease ≥10%

or <20%

absolute decrease ≥20%

CHF responsive to treatment

+ H(n=114)

75

21

2

2

- H(n=113)

84

15

1

0

87

12

1

0

HER2 positive HER2 negative(n=99)

LVEF worst value

LVEF, left ventricular ejection fraction

Two patients experienced LVEF declines to <45%: one patient during H who withdrew from study and one patient after completing H as per protocol Gianni et al ASCO Breast 2007, Abs 144

Patients %

Trastuzumab for EBC has changed approaches to treating breast cancer1

During the first 10 years, it is predicted that the use of trastuzumab will result in an annual decline in MBC patients of 2.5%1

Trastuzumab treatment of HER2+ EBC is expected to prevent almost 28,000 women from developing metastases over a 10-year period in five EU countries alone, including the UK, which may result in a similar number of breast cancer deaths being avoided1

“According to our model, [trastuzumab] will be one of the rare examples of current drugs actually changing the epidemiology of a disease” Weisgerber-Kriegl et al. 20081

Adapted from Reference 1

Weisgerber-Kriegl et al. ASCO 2008; Abs 6589

Summary

Trastuzumab remains the cornerstone of adjuvant systemic therapy

12 months remains current standard but duration question remains important eg HERA 1 v 2 yrs; shorter duration therapy 3-6months being tested

Real alternatives to anthracyclines now available –TCH Addition of novel therapeutics (e.g. Bevacizumab,

Lapatinib) may offer more patients the potential for cure Adjuvant trastuzumab is changing the natural history of

the disease Neoadjuvant trastuzumab promising – safe and effective