herceptin ® : leading the way in metastatic breast cancer care steffen kahlert

Herceptin®:

leading the way in metastatic breast cancer care

Steffen Kahlert

runcie_k

Dr Kahlert, please could you supply institution details. Thank you.

Herceptin® in metastatic breast cancer HER2-positive breast cancer is an aggressive cancer

and is associated with a poor prognosis

Herceptin® is currently licensed for the treatment of HER2-positive metastatic breast cancer (MBC)– first-line in combination with docetaxel in patients

with no prior chemotherapy for MBC– first-line in combination with paclitaxel in patients

who have received prior anthracyclines or for whom an anthracyline is not suitable

– as monotherapy in patients who have received prior treatment for MBC

Herceptin® plus docetaxel (M77001)

Herceptin® plus docetaxel (M77001): trial design

HER2-positive MBC (IHC 3+ and/or FISH+) n=188

Docetaxel*100mg/m2 q3w x 6

Docetaxel100mg/m2 q3w x 6

Herceptin®

4mg/kg loading, 2mg/kg weekly

until PD

+*Patients progressing on docetaxel alone could crossover to receive Herceptin®

Two patients did notreceive study medication

n=92n=94

Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin® plus docetaxel (M77001): inclusion criteria

MBC– measurable disease

HER2-positive – IHC 3+ and/or FISH+– IHC 2+ initially allowed (July 1999–August 2000)

ECOG 2 Life expectancy 12 weeks LVEF >50% Adequate bone marrow, hepatic and renal function Prior chemotherapy

– none for MBC

– no prior taxanes or anti-HER therapy


Herceptin® plus docetaxel (M77001): patient demographics

Herceptin® + docetaxel

(n=92)

Docetaxel alone (n=94)

Age median (range)

53 (32–80)

55 (24–79)

HER2 status (%)

IHC 3+ and/or FISH+ 97 94

Other* 3 6 ER+ and/or PgR+ (%) 41 56

ECOG median (range)

0 (0–4)

0 (0–2)

*Eight patients IHC 2+/FISH–; one patient IHC 0/1+/FISH unknown (docetaxel alone)


Herceptin® plus docetaxel (M77001): patient demographics

Herceptin® + docetaxel (n=92)


Metastases median (range) No. lesions/patient No. sites/patient

4 (1–12) 2 (1–5)

4 (1–12) 2 (1–5)

Site (%) Lung Liver Bone Soft tissue Other

40 49 34 48 60

43 54 38 50 59

Previous therapy (%) Chemotherapy Anthracyclines Hormonal therapy Radiotherapy

71 64 44 64

68 55 47 66


Herceptin® plus docetaxel (M77001): OS at 24 months

Intent-to-treat population, 24-month cut-offDocumented crossover = 57%

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed p

rob

abil

ity

0 5 10 15 20 25 30 35 40 45 50

Months

8.5 months

Herceptin® + docetaxelDocetaxel alone

22.7 31.2


Herceptin® plus docetaxel (M77001): OS at 24 months

Intent-to-treat population, 24-month cut-off

Est

imat

ed p

rob

abil

ity

Months

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Herceptin® + docetaxel (n=92)Docetaxel alone/crossover (n=45)Docetaxel alone (n=49)

16.6 31.230.3


Herceptin® plus docetaxel (M77001): efficacy 24 month follow up

Outcome


(n=92)


p-value

ORR (%) 61.0 34.0 0.0002

DR (median, months) 11.7 5.7 0.009

TTP (median, months) 11.7 6.1 0.0001

OS (median, months) 31.2 22.7 0.0325


Herceptin® plus docetaxel (M77001): non-haematological toxicity (grade 3/4)

Adverse event (%)


(n=92)


Alopecia 10 6

Asthenia 10 6

Diarrhoea 5 2

Headache 5 1

CHF 1 0

Adverse events occurring in ≥5% and congestive heart failure (CHF)


Herceptin® plus docetaxel (M77001): haematological toxicity (grade 3/4)

Adverse event (%)


(n=92)


Anaemia 1 1

Thrombocytopenia 0 0

Leucopenia 21 17

Neutropenia 32 22

Febrile neutropenia/ neutropenic sepsis

23

17


Herceptin® plus docetaxel (M77001): conclusions

Adding Herceptin® to docetaxel improves all clinical outcomes parameters

– ORR (from 34 to 61%)

– TTP (from 6.1 to 11.7 months)

– OS (from 22.7 to 31.2 months)

Herceptin® adds little to the toxicity profile of docetaxel

Herceptin® plus docetaxel should be used upfront for greatest clinical benefit in patients with HER2-positive MBC

These 24-month data provide evidence of a long-term survival benefit following the addition of Herceptin® to docetaxel

Herceptin® plus paclitaxel (H0648g)

Herceptin® plus paclitaxel (H0648g):design and enrolment

No prior anthracyclines Prior anthracyclines

Paclitaxel(n=96)

Herceptin® + paclitaxel(n=92)

AC(n=138)

Herceptin® + AC(n=143)

MBC HER2 IHC 2+/3+ (CTA) No prior CT for MBC Measurable disease KPS 60%

Patients (n=469)

Slamon DJ, et al. N Engl J Med 2001;334:783–92

Herceptin® plus paclitaxel (H0648g): treatment plan

Chemotherapy q3w x 6

– AC = doxorubicin (60mg/m2) or epirubicin (75mg/m2) + cyclophosphamide (600mg/m2)

– Paclitaxel (175mg/m2)

Herceptin®

– 4mg/kg loading, 2mg/kg qw until PD


Herceptin® + AC

(n=143)

AC

(n=138)

Herceptin® + paclitaxel

(n=92)

Paclitaxel

(n=96)

Mean age / range (years) 54 (27–76) 54 (25–75) 51 (25–77) 51 (26–73)

KPS 80 (%) 34 34 24 35

Metastatic sites 3 (%) 40 29 31 35

liver or lung (%) 76 71 65 71

HER2 3+ (%) 76 70 74 80

ER negative (%) 46 49 55 63

>4+ nodes (%) 30 27 59 64

Median DFI (months) 25 23 22 19

Herceptin® plus paclitaxel (H0648g): demographics


Herceptin® + AC

(n=143)

AC

(n=138)

Herceptin® + paclitaxel

(n=92)

Paclitaxel

(n=96)

Prior anthracyclines (%) 1 1 91 97

Prior adjuvant CT (%) 57 37 97 100

Prior transplant (%) 0 0 13 22

Prior hormonal (%) 62 57 55 56

Prior radiotherapy (%) 48 56 67 76

Herceptin® plus paclitaxel (H0648g): prior therapy


H + AC (n=143)

AC (n=138)

H + P (n=92)

P (n=96)

H + CT (n=235)

CT (n=234)

ORR (%)

56

42

41*

17

50*

32

Median TTP (months) 7.8*

6.1

6.9*

2.7

7.4*

4.6

Median DR (months) 9.1*

6.7

10.5*

4.5

9.1*

6.1

Survival (months) 26.8 21.4 22.1 18.4 25.1* 20.3

*p<0.05

Herceptin® plus paclitaxel (H0648g): efficacy (all patients)


0 2 4 6 8 10 12 14 16 18 20 22 24

Herceptin® + chemotherapyChemotherapy

Time (months)

Pro

bab

ilit

y

p=0.0001

1.0

0.8

0.6

0.4

0.2

0

Herceptin® plus paclitaxel (H0648g): TTP


Herceptin® plus paclitaxel (H0648g): OS (all patients)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 5 10 15 20 25 30 35 40 45 50

Pro

bab

ilit

y

20.3 25.1

Herceptin® + CT

CT alone

p<0.05

Time (months)

Slamon DJ, et al. N Engl J Med 2001;334:783–92Crossover 72%

Herceptin® plus paclitaxel (H0648g): summary of SAEs


SAE (%)

H + AC (n=143)

AC

(n=138)

H +

paclitaxel (n=92)

Paclitaxel

(n=96) Alopecia 25 42 26 26 Anaemia 3 2 1 1 Asthenia 7 7 8 8 Diarrhoea 1 3 1 3 Headache 3 5 7 2 Leucopenia 15 11 6 5 Nausea 6 10 3 3

Herceptin® plus paclitaxel (H0648g): summary of cardiac safety

H+AC (n=143)

AC (n=135)

H+P (n=91)

P (n=95)

NYHA III-IV (%)

28.0

9.6

8.8

4.2

Symptomatic cardiac event (%)

19.0

3.0

4.0

1.0

Suter T, et al. Breast 2004;13:173–83

H + AC AC H + P P H + CT CT

ORR (%)

3+ All

60 56*

42 42

49 41*

17 17

56* 50

31 32

Median TTP (months)

8.1* 7.8*

6.0 6.1

7.1* 6.9*

3.0 3.0

7.8* 7.4*

4.6 4.6

Median DR (months) 9.3 9.1*

5.9 6.7

10.9 10.5*

4.6 4.5

10.0 9.1*

5.6 6.1

Survival (months)

31* 26.8

21 21.4

25 22.1

18 18.4

29* 25.1*

20 20.3

*p<0.053+: n=349 All: n=469

Slamon DJ, et al. N Engl J Med 2001;344:783–92Baselga J. Oncology 2001;61 (Suppl 2):15–21

Herceptin® plus paclitaxel (H0648g): efficacy (IHC 3+ versus all)

Herceptin® plus paclitaxel (H0648g): conclusions

Adding Herceptin® to paclitaxel improves all clinical outcome parameters – ORR (from 17 to 49%*)– TTP (from 3 to 7 months*)– OS (from 18 to 25 months*)

Herceptin® adds little to the toxicity profile of paclitaxel

Herceptin plus paclitaxel should be considered as first-line therapy in HER2-positive MBC

*IHC 3+ patients

Other Herceptin® trials in MBC

Phase II Herceptin® plus vinorelbine:efficacy

Vinorelbine (n=33)

Vinorelbine + Herceptin (n=35)

Overall response (%) 27.3

(95% CI 12.1, 42.5)

51.4

(95% CI 32.9, 68)

Complete response (%) 3.0 2.9

Partial response (%) 24.2 48.5

Stable disease (%) 36.4 28.6

Progressive disease 36.4 20.0

Median TTP (months) 6.0 (95% CI: 4, 8) 9.0 (95% CI: 7, 11)

Median OS (months) 22 (95% CI: 12, 32) 27 (95% CI: 19, 35)

Papaldo P, et al. Ann Oncol 2006

Phase II Herceptin® plus vinorelbine:safety

Toxicity (Grade 3/4) (%) Vinorelbine (n=33) Vinorelbine + Herceptin (n=35)

Leucopenia 3 -

Neutropenia 51 49

Febrile neutropenia 6 -

Anaemia 6 3

Thrombocytopenia 3 -

Nausea/vomiting - -

Mucositis 3 -

Peripheral neuropathy - -

Liver - -

Diarrhoea 3 -

Stipsis - -

Cardiac toxicity - 3

Papaldo P, et al. Ann Oncol 2006

Herceptin® q3w: rationale

Ghahramani P, et al. The Breast 2003;12(Suppl. 1):S40 (Abstract P89)

1,000

100

10

1Ser

um

co

nce

ntr

atio

n (

µg

/mL

)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Time (weeks)

3-weekly regimen

Weekly regimen

Herceptin q3w plus paclitaxel(BO15935)

Outcome n=32

ORR (%) 59

CR (%) 13

PR (%) 47

SD (%) 22

Median TTP (months) 12.2

Median DR (months) 10.5

Leyland-Jones B, et al. J Clin Oncol 2003;21:3965–71

Herceptin® monotherapy trials in MBCH0650g WO16229 H0649g

Line of therapy First First Second/third

Regimen 4mg/kg LD, 2mg/kg qw or 8mg/kg LD,

4mg/kg qw8mg/kg LD, 6mg/kg

q3w4mg/kg LD, 2mg/kg

qw

No of patients 114 83* 222

ORR (%)

Overall 26 23 15

IHC 3+ 35 NR 18

IHC 2+ 0 NA 6

FISH positive 34 NR 19

FISH negative 7 NR 0

TTP (months) 3.5, 3.8† 3.4 3.1

DR (months) NR 10.0 9.1

OS (months 24.4 NR 13LD=loading dose; NR=not recorded; NA=not applicable; qw=weekly; q3w= every 3 weeks*Results from per protocol subset†TTP given for standard and higher Herceptin® dose regimens, respectively

Summary:Herceptin® combinations in MBC

1Slamon DJ, et al. N Engl J Med 2001;344:783–92 2Leyland-Jones B, et al. J Clin Oncol 2003;21:3965–71

3Marty M, et al. J Clin Oncol 2005;23:4265-744Papaldo P, et al. Ann Oncol 2006

H0648g1 BO159352 M770013

H + PP

alone H + P H + DD

alone H + V4

V alone4

ORR (%) 41 17 59 61 34 51.4 27.3

TTP (months)

6.9 2.7 12.2 11.7 6.1 9.0 6.0

OS (months)

22.1 18 NR 31.2 22.7 27 22

NR=not recordedH=Herceptin®; P=paclitaxel; D=docetaxel; V=vinorelbine

Herceptin® in MBC: conclusions

In metastatic breast cancer patients– Herceptin® in combination with chemotherapy leads

to an improvement in survival compared to chemotherapy alone• adverse events associated with chemotherapy

are not exacerbated by addition of Herceptin®

– Herceptin® monotherapy has also been shown to be effective

Cardiac events are reversible and manageable– the rate of asymptomatic cardiac events in clinical

trials has fallen to 2% based on selection criteria and cardiac monitoring

herceptin ® : leading the way in metastatic breast cancer care steffen kahlert

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