HER-2 targeting: dalla malattia avanzata alla fase pre-operatoria

Marco VenturiniRoma, Febbraio 2005

Tailored Treatment of HER2+ MBC

Hormonal therapy +/- Trastuzumab

Trastuzumab + other CT

Trastuzumab +Taxanes

ER+, Low Risk

Trastuzumab monotherapy

Prior taxanesNo prior taxanes

HER2+ MBC ER-,

ER+, High Risk

Trastuzumab + Taxanes: Consistent Benefit

1 Slamon et al. N Engl J Med. 2001;344:783–792.2 Baselga J. Oncology. 2001;61(Suppl. 2):14–21.3 Extra et al. Eur J Cancer. 2004;2:125. Abstract 239.

H0648g1,2 M770013

OutcomeH + P(n=68)

P(n=77)

H + D(n=92)

D(n=94)

ORR (%) 49.0 17.0 61.0 34.0

TTP (months) 7.1 3.0 10.6 5.7

OS (months) 24.8 17.9 30.5 22.1

*3:2 randomization q wk to q 3 wk

N=580First-

Second Line MBC(no taxane

for MBC or LABC; > 12 mo

since adjuvant taxane)

Paclitaxel 175 mg/m2 q 3 wk

Paclitaxel 80-100 mg/m2 q wkStratify by

Her-2

R

Pos Trastuzumab +

Neg

R*

R*

R*

Trastuzumab +

Paclitaxel 175 mg/m2 q 3 wk

Paclitaxel 80-100 mg/m2 q wk

Paclitaxel 175 mg/m2 q 3 wk

Paclitaxel 80-100 mg/m2 q wkCALGB 9342

RPaclitaxel 175 mg/m2 q 3 wkPaclitaxel 210 mg/m2 q 3 wkPaclitaxel 250 mg/m2 q 3 wk

“borrow” 158 pts

N=735N=735

CALGB 9840Schema

CALGB 9840Efficacy Outcomes (all patients)**

q.wk q.3wk N = 344/350 N = 373/385

Response Rate (CR+PR)* 40% 28% 0.017

Time to Progression 9 mo 5 mo 0.0008

Overall Survival 24 mo 16 mo 0.17

* ITT Response rates are 39% (q.wk) and 27% (q.3wk) ** Includes 158 q.3wk patients “borrowed” from CALGB 9342

Seidman A et al. Proc ASCO 2004 Abs 512

Multivariate p-value

Ca mammario avanzato HER2-positivo (IHC 2+/3+ ) non pretrattato (n=160)

Paclitaxel80 mg/m2 weekly

fino a PRO

Paclitaxel80 mg/m2 weekly

fino a PRO

Trastuzumab4 mg/kg2 mg/kg weekly fino a PRO

+

Weekly Paclitaxel TrastuzumabDisegno dello studio

Papaldo P. Roma ottobre 2004

Results

T alone T+Trastuzum.

ORR 60% 78%

TTP (weeks) 28 52

1-yr PFS 21% 48%

Neutropenia 12% 13%

F. Neutropenia

2% -

Neuropathy 7% 4%

Asthenia 6% 7%Grade 3 & 4

Papaldo P. Roma ottobre 2004

Weekly or 3-weekly Docetaxel

N=83N=83

1st & 2nd 1st & 2nd line CTline CT

MeasurablMeasurable disease e disease

RANDO MIZATION

Docetaxel 40 mg/m2Docetaxel 40 mg/m26 weeks on and 2 weeks off 6 weeks on and 2 weeks off

Docetaxel 100 mg/m2Docetaxel 100 mg/m2every 3 weeksevery 3 weeks

Tabernero J et al. Ann Oncol 2004

Weekly or 3-weekly Docetaxel

weekly 3-weekly

ORR 34% 33%

TTP (months) 5.7 5.3

F. Neutropenia

4.9% 19.5%

Neuropathy 2.4% 17.1%

Stomatitis 7.3% 17.1%

Fluid Retention

2.4% 7.3%

Fatigue 14.6% 12.2%Grade 3 & 4

Tabernero J et al. Ann Oncol 2004

Trastuzumab + Docetaxel Weekly Multicenter Phase II Trial

TREATMENT

N = 26

HER2-positive MBC (IHC 2-3+ and/or FISH+)

Tedesco et al. J Clin Oncol. 2004;22:1071-1077.

ORR 50% Median TTP 12.4 moIHC 3+ only 63% Median OS 22.1 moFISH+ 65%IHC 2+ & FISH (-) 0%

Results

Docetaxel 35 mg/m2 qw x 6; 2 wk rest+

Trastuzumab 4 mg/kg 2 mg/kg qw PD

Standard vs. Investigational AgentsCross-over effect

Regimen Crossover survival benefit

Std Invest

Agent

Sledge 03 A or T AT T or A

57% NO

Paridaens 00

A T T 47% NO

Nabholtz 99 MV D D 24% YESO’Shaughnessy 02

D XD X 17% YES

Albain 04 T GT G 14% YESBishop 99 CMFP T T 6% YES

Breast Cancer II ASCO2004 Discussant: Antonio C. Wolff, MD

Standard vs. Investigational AgentsCross-over effect

Regimen Crossover survival benefitStd Invest Agent

Slamon 01 CT HCT H 65% YESMarty 03 D HD H 44% YESSledge 03 A or T AT T or A 57% NOParidaens 00 A T T 47% NONabholtz 99 MV D D 24% YESO’Shaughnessy 02 D XD X 17% YESAlbain 04 T GT G 14% YESBishop 99 CMFP T T 6% YES

Trastuzumab Triple Combinations

• Combining > 2 agents has the potential to further improve ORR and increase survival

• Several Trastuzumab triple combinations under investigation:

– Trastuzumab/paclitaxel/carboplatin

– Trastuzumab/docetaxel/epirubicin

– Trastuzumab/paclitaxel/gemcitabine

– Trastuzumab/docetaxel/capecitabine

(CHAT study)

TCH in HER2+ MBC: Results of Phase II Pilot Studies

5962No. eval. pts

12.7 mo

15.6 mo

7.4 mo

9.9 mo

12.7 mo

7.9 mo

TTP Median

FISH +

FISH-

58%

63%

41%

79%

77%

84%

ORR All

FISH+

FISH-

D 75 mg/m2 q3w x 6 Cb AUC=6 q3w x 6 H 2 mg/kg qw* x 52

D 75 mg/m2 q3w x 6Cis 75 mg/m2 q3w x 6

H 2 mg/kg qw* x 52

Regimen

UCLABCIRG 101Parameter

*Following 4 mg/kg loading dose; H = Trastuzumab; D = docetaxel; Cb = carboplatin; Cis= cisplatin.

Pegram et al. J Natl Cancer Inst. 2004;96:759-769.

Primary end point: ORRSecondary end points: DOR, TTP, OS

196 patients HER2+ ABC(IHC 3+ and/ or FISH+)

Phase III Trial of 1st Line Trastuzumab

+ Paclitaxel ± Carboplatin

Paclitaxel 175 mg/m2 q3w × 6 cycles or more

Paclitaxel 175 mg/m2 + carboplatin AUC 6, q3w × 6 cycles or more

Trastuzumab4 mg/kg day 1,2 mg/kg qw until PD

3-week cycle: 1 2 3 4 5 6

Robert et al. Breast Cancer Res Treat. 2002;76:S37. Abstract 35.

RANDOMIZATION

Rand. ph III trial of trastuzumab + paclitaxel carboplatin (196 pts)

TPC TP

OR 52% 36% p=.04

TTP 11.9 m 6.8 m p=.02

OS 42.1 m 33.3 m p= 0.2

Robert N et al. ASCO 2003

Trastuzumab + other CT

Cardiotossicità. Trastuzumab da solo o in associazione

0

5

10

15

20

25

30

Modified from Seidman A et al J Clin Oncol 20(5):1215-1221, 2001

Perc

en

tuale

Tras

tuzu

mab

+ C

ispl

atin

o

+ A

ltre

CT

+ A

C

+ P

aclit

axel

Anthracyclines, Trastuzumab and Cardiotoxicity

Within 1 year of therapy Reflects progressive

injury and loss of cardiac myocites

Life-Threatening, related to cumulative doses, rapid onset and progression, may be resistant to treatment

Treatment with anthracyclines should be stopped

During trastuzumab therapy

The pathophysiology of cardiac dysfunction is nor clear defined

No dose related It is almost always

responsive to medical management

Treatment with trastuzumab may be continued

Normal cardiac biopsy following co-administration of doxorubicin, cyclophosphamide and trastuzumab to women with HER2 positive metastatic breast cancer

Ten patients. First line CT. No prior RT or prior doxo

Median doxo dose 360 mg/m2 (240-360); median of 35 trastuzumab doses

Median LVEF 64% (baseline), 53% at week 22 Two patients had cardiac disfunction (NYHA

grade II, and grade IV), one LVEF decline > 20% Cardiac function normalized in all patients Ten cardiac biopses, at 240 mg/m2. No cardiac

abnormalities

Valero V. et al. Proc ASCO. Vol 22, No 14S, 2004:572

Trastuzumab starting with or after doxorubicin and paclitaxel

Two cohorts of 16 patients AT + Trastuzumab or AT Trastuzumab LVEF decrease in 75% of pts in AT+T, and 33%

in ATT. No CHF LVEF recovered to normal levels with

continued trastuzumab, and cardiac function normalized in all patients.

Bianchi G. et al. Clin Cancer Res 9:5944, 2003

Herceptin 2 mg/kg weekly

LVEF LVEF LVEF LVEF LVEF

Study Design

Epirubicin 75 mg/m2 q 21 days x 8 cyclesDocetaxel 75 mg/ m2 q 21 days x 8 cycles

Inclusion criteria: metastatic breast cancer pts 2+/3+ by IHC- Dako Herceptest® no prior CT for MBC epirubicin permitted (<360 mg/m2)

First 29 pts:● 2 asymptomatic decline of LVEF● 1 CHF

Recruitment continuedDuring follow-up● 4 asymptomatic decline of LVEF● 3 CHF

Stop recruitment at 45th patientTotal of 10 cardiac events (22%)

HET (Roche M77022 Study)Cardiac events

Venturini M. et al. ASCO 2003

Dosage and Administration

• Myocet 50 mg/m2 IV 1 hr infusion q 21d

• Docetaxel 75 mg/m2 IV 1 hr infusion q 21 d

• Trastuzumab 4 mg/Kg IV 90’ loading dose, 2 mg/Kg IV 30’ q 7 d

Trastuzumab and Anthracyclines

Metastatic Breast Cancer Increased ORR, TTP, OS Cardiac Toxicity in 25% of patients Cardiac Disfunction improved in most patients,

with standard medical treatment, and in some cases even when trastuzumab was continued

Acute reversible decline in LVEF do not necessarily portend a risk for chronic cardiac disfunction

Rational combination of trastuzumab with chemotherapeutics drugs used in the treatment

of breast cancer

Four HER2-overexpressing breast cancer cell lines Sinergistic interactions:

– Carboplatin

– 4-hydroxycyclophosphamide

– Docetaxel

– Vinorelbine Additive interactions:

– Doxorubicin

– Epirubicin

– Paclitaxel Gemcitabine (sinergistic at [low], antagonistic at [high]

Pegram MD. et al. J Natl Cancer Inst Vol 96: 739, 2004

*All patients treated first line.Trastuzumab administered at standard dose of 4mg/kg loading followed by 2mg/kg weekly.

Trastuzumab + Vinorelbine: Clinical Trials

Author

Jahanzeb et al. 2002*

Bernardo et al. 2002*

Burstein et al. 2003*

Burstein et al. 2001

Untch et al. 2004*

Bayo et al. 2004

Vinorelbinedose

30 mg/m2

25 mg/m2

25 mg/m2

25 mg/m2

30 mg/m2

25 mg/m2

285

N

40

35

55

40

69

46

ORR (%)

78

84

68

75

59

66

GEMZAR + TrastuzumabReference Regimen

mg/m2

N eval ORR %

(CR)

TTPD

(mos)MS (mos)

O’Shaughnessy

Semin Onc Apr 2003

G 1200 (1,8)

HER 4 mg/kg 2 mg/kg q21

38 32(0)

6.7 10.2

Christodoulou

ASCO 2003

G 1000 (1,8,15)

HER 4 mg/kg 2 mg/kg q28

28 36 (4)

7.8 18.7

Sledge

Oncology Dec 2003

G 1200 (1,8)

P 175 (1)

HER 4 mg/kg 2 mg/kg q21

42 67(10)

9 NR

Heinemann

ASCO 2002

G 750 (1,8)

CDDP 30 (1,8)

HER 4 mg/kg 2 mg/kg q21

26 42.3(7.7)

6.6 12.3

Breast cancers can acquire HER-2 gene amplification during tumor

progression• Evaluation of HER2 status of CTCs (CK+ CD45-) in

42 patients with at least 10 CTCs/10 mL• 97% (84%-100%) concordance, primary tumor and CTCs• At recurrence, 9/24 patients changed from HER2- to

HER2+

• 80 patients HER2+ with asynchronous distant metastases• 18% changed from HER2- to HER2+• 6% changed from HER2+ to HER2-• authors suggested to test ECD HER2 levels (ECD HER2

levels >50 ng/mL (vn < 15) indicated HER2+ metastatic spread)

Meng S. et al. Proc Natl Acad Sci 101:9393, 2004

Lueftner DI. et al. Abstract 49 ESMO 2004

ECD HER2 levels and response to therapy

• Pooled analysis on 375 patients enrolled in 4 phase II/III trials

• ECD levels at baseline were not predictive of ORR

• The magnitudine of ECD reduction was not predictive of a best outcome

• The magnitudine of ECD increase was not predictive of a progressive disease

Leyland-Jones B. et al. Abstract 51 ESMO 2004

Primary Chemotherapy

pCR

Mono CT1 4% - 8%

Poli CT1 4% - 31%

AC 10% - 14%

CAF 16% - 19%

FEC 4% - 23%

ECisF or MVAC 27%

Antracycline/Taxane-based 8% - 31%

Trastuzumab2 non-antracycline-based 19% - 35%

1Randomized trials 2Non-randomized trials

Preoperative therapy with epidoxorubicin and docetaxel plus trastuzumab in patients with primary

breast cancer: a pilot study

Weekly doses of Epirubicin (30 mg/m2) and Docetaxel (35 mg/m2) plus trastuzumab.

Fourteen patients. Median epirubicin dose 360; median of 12 weeks of treatment and trastuzumab doses

No cardiotoxicity pCR 7%

Wenzel C. et al. J Cancer Res Clin Oncol Vol 130: 400, 2004

Preoperative Epirubicin and Trastuzumab

• Epirubicin (30 mg/m2) Docetaxel (35 mg/m2) Trastuzumab, q. 7d

• 14 patients• Median of 12 weeks

of treatment• Median epirubicin

dose 360 mg/m2

• No cardiotoxicity• pCR 7%

• Paclitaxel225 24h x 4 F500 1-4E75C500 x 4 q 21d ±Trastuzumab q 7d

• 19 vs 25 patients• Median of 24 weeks of

treatment• Median epirubicin dose

300 mg/m2

• 5/15 vs 7/23 EF >10%• pCR 26% vs 65%

Wenzel C. J Cancer Res Clin Oncol Vol 130: 400, 2004 Buzdar AU et al. Proc ASCO 2004

Adjuvant Trials

Early Breast Cancer:Trastuzumab Adjuvant Trials

• Four large multicenter phase III trials; over 12,000 patients will be randomized

• Two strategies:Sequence approach

• NSABP B-31, North American Intergroup (N9831), HERA

Combination approach• BCIRG 006: based on preclinical data on

synergism between chemotherapy and Trastuzumab

Patient Population • Operable Breast Cancer• HER-2+• Path Positive Axillary Nodes

RANDOMIZATION

*Revised study design. Choice of paclitaxel schedule and hormonaltherapy at discretion of investigator – stratification factors.

National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31

AC q3w x 4

AC q3w x 4P q3w x 4 orP qw x 12*

Trastuzumab qw x 52

Target N = 2,700Total accrual as of Mar ’04 = 1,673

P q3w x 4 orP qw x 12*

• Potential increased incidence of 4% clinical CHF was anticipated with administration of Trastuzumab with paclitaxel following prior AC

• This incidence of CHF would be acceptable if a 25% or greater relative risk reduction for death were demonstrated, particularly if cardiac effects were largely reversible

B-31 Design Assumptions

B-31 Cardiac Safety Study Primary Endpoint Analysis

% Trastuzumab pts with Cardiac Event*4.28 % (23/538)

- % Control pts with Cardiac Event0.78 % (4/510)

D = 3.50% (CI 1.6% - 5.3%)

*Defined as definite/probable cardiac death OR dyspnea at rest or with normal activity and decline of LVEF to below > 5% below lower limit of normal

RANDOMIZATION

Patient Population• N+ or high-risk

N- breast cancer • HER2+ (IHC 3+ or

FISH)

Target N = 3,300Total accrual as of Mar ’04 = 2,342

N9831 Intergroup Trial (NCCTG)

AC q3w x 4 Paclitaxel qw x 12

Trastuzumab qw x 52

AC q3w x 4 Paclitaxel qw x 12

AC q3w x 4 Paclitaxel qw x 12

Trastuzumab qw x 52

Observation*

Stratification

Primary management (surgery, [neo]adjuvant chemotherapy ± adjuvant RT)

*Observation group to receive the same follow-up as the Trastuzumab treatment groups

RANDOMIZATION

Target N = 4,482

HERceptin Adjuvant (HERA) Trial

Trastuzumab q3w x 1 y

Trastuzumab q3w x 2 y

HERA Trial: Interim Cardiac Safety Analyses

• Three cardiac safety interim analyses have been completed

– June 2003 (1,360 patients)

– September 2003 (1,924 patients)

– November 2003 (2,265 patients)

No safety concerns identified

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel + Carboplatin75 mg/m2 AUC 6

1-year Trastuzumab

Patient Characteristics:• HER2+ (FISH)• Node +• High-risk N-

1-year Trastuzumab

RANDOMIZATION

Breast Cancer International Research Group (BCIRG) 006 Trial

Target N = 2,700Accrual completed as of Mar ’04

BCIRG 006: Interim Cardiac Analyses

March 2003: First cardiac analysis300 patients with 9 months follow-up

Sept 2003: Second cardiac analysis900 patients with 9 months follow-up

IDMC did not express any concerns; recommended the study to continue as planned

April 2004: Third cardiac analysis1,500 patients with 9 months follow-up