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

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

• Marco Venturini
• Roma, Febbraio 2005

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Tailored Treatment of HER2 MBC
Hormonal therapy /- Trastuzumab
ER, Low Risk
HER2 MBC
ER-,ER, High Risk
Prior taxanes
No prior taxanes
Trastuzumab other CT
Trastuzumab Taxanes
Trastuzumab monotherapy
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Trastuzumab Taxanes Consistent Benefit
1 Slamon et al. N Engl J Med. 2001344783792. 2
Baselga J. Oncology. 200161(Suppl. 2)1421.3
Extra et al. Eur J Cancer. 20042125. Abstract
239.
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CALGB 9840Schema
N735
N580 First-Second Line MBC (no taxane for MBC or
LABC gt 12 mo since adjuvant taxane)
Pos Trastuzumab
Paclitaxel 175 mg/m2 q 3 wk Paclitaxel 80-100
mg/m2 q wk
Stratify by Her-2
Paclitaxel 175 mg/m2 q 3 wk Paclitaxel 80-100
mg/m2 q wk
Neg
Trastuzumab
R
borrow 158 pts
Paclitaxel 175 mg/m2 q 3 wk Paclitaxel 80-100
mg/m2 q wk
CALGB 9342
Paclitaxel 175 mg/m2 q 3 wk Paclitaxel 210 mg/m2
q 3 wk Paclitaxel 250 mg/m2 q 3 wk
32 randomization q wk to q 3 wk
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CALGB 9840Efficacy Outcomes (all patients)
Multivariate p-value
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
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Weekly Paclitaxel ? TrastuzumabDisegno dello
studio
Ca mammario avanzato HER2-positivo (IHC 2/3 )
non pretrattato (n160)
Paclitaxel80 mg/m2 weekly fino a PRO
Paclitaxel80 mg/m2 weekly fino a
PRO

Trastuzumab 4 mg/kg?2 mg/kg weekly fino a PRO
Papaldo P. Roma ottobre 2004
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Results
T alone TTrastuzum.
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
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Weekly or 3-weekly Docetaxel
RANDO MIZATION
Docetaxel 40 mg/m2 6 weeks on and 2 weeks off
N83 1st 2nd line CT Measurable disease
Docetaxel 100 mg/m2 every 3 weeks
Tabernero J et al. Ann Oncol 2004
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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
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Trastuzumab Docetaxel Weekly Multicenter Phase
II Trial
TREATMENT
N 26 HER2-positive MBC (IHC 2-3 and/or
FISH)
Docetaxel 35 mg/m2 qw x 6 2 wk
rest Trastuzumab 4 mg/kg ? 2 mg/kg qw ? PD
Results
ORR 50 Median TTP 12.4 moIHC 3
only 63 Median OS 22.1 moFISH 65IHC 2
FISH (-) 0
Tedesco et al. J Clin Oncol. 2004221071-1077.
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Standard vs. Investigational AgentsCross-over
effect
Regimen Regimen Crossover Crossover survival benefit
Std Invest Agent n survival benefit
Sledge 03 A or T AT T or A 57 NO
Paridaens 00 A T T 47 NO
Nabholtz 99 MV D D 24 YES
OShaughnessy 02 D XD X 17 YES
Albain 04 T GT G 14 YES
Bishop 99 CMFP T T 6 YES
Breast Cancer II ASCO2004 Discussant Antonio C. Wolff, MD
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Standard vs. Investigational AgentsCross-over
effect
Regimen Regimen Crossover Crossover survival benefit
Std Invest Agent n survival benefit
Slamon 01 CT HCT H 65 YES
Marty 03 D HD H 44 YES
Sledge 03 A or T AT T or A 57 NO
Paridaens 00 A T T 47 NO
Nabholtz 99 MV D D 24 YES
OShaughnessy 02 D XD X 17 YES
Albain 04 T GT G 14 YES
Bishop 99 CMFP T T 6 YES
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Trastuzumab Triple Combinations

• Combining gt 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)

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TCH in HER2 MBC Results of Phase II Pilot
Studies
UCLA
BCIRG 101
Parameter
59
62
No. eval. pts
Regimen
D 75 mg/m2 q3w x 6 Cb AUC6 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
586341
797784
ORR All FISH FISH-
12.7 mo15.6 mo 7.4 mo
9.9 mo12.7 mo 7.9 mo
TTP Median FISH FISH-
Following 4 mg/kg loading dose H
Trastuzumab D docetaxel Cb carboplatin
Cis cisplatin.
Pegram et al. J Natl Cancer Inst. 200496759-769.
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Phase III Trial of 1st Line Trastuzumab
Paclitaxel Carboplatin
Primary end point ORR Secondary end points DOR,
TTP, OS
3-week cycle 1 2 3
4 5 6
RANDOMIZATION
196 patients HER2 ABC (IHC 3 and/ or FISH)
Trastuzumab 4 mg/kg day 1, 2 mg/kg qw until PD
Paclitaxel 175 mg/m2 q3w 6 cycles or more
Paclitaxel 175 mg/m2 carboplatin AUC 6, q3w 6
cycles or more
Robert et al. Breast Cancer Res Treat.
200276S37. Abstract 35.
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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
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Trastuzumab other CT
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Cardiotossicità. Trastuzumab da solo o in
associazione
Percentuale
AC
Altre CT
Paclitaxel
Trastuzumab
Cisplatino
Modified from Seidman A et al J Clin Oncol
20(5)1215-1221, 2001
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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

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Normal cardiac biopsy following co-administration
of doxorubicin, cyclophosphamide and trastuzumab
to women with HER2 positive metastatic breast
cancer
Valero V. et al. Proc ASCO. Vol 22, No 14S,
2004572

• 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 gt 20
• Cardiac function normalized in all patients
• Ten cardiac biopses, at 240 mg/m2. No cardiac
  abnormalities

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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 ATT, and 33 in
  AT?T. No CHF
• LVEF recovered to normal levels with continued
  trastuzumab, and cardiac function normalized in
  all patients.

Bianchi G. et al. Clin Cancer Res 95944, 2003
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Study Design

Epirubicin 75 mg/m2 q 21 days x 8
cycles Docetaxel 75 mg/ m2 q 21 days x 8 cycles
Herceptin 2 mg/kg weekly
LVEF
LVEF
LVEF
LVEF
LVEF
Inclusion criteria metastatic breast cancer
pts 2/3 by IHC-
Dako Herceptest no
prior CT for MBC
epirubicin permitted (lt360 mg/m2)
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HET (Roche M77022 Study)Cardiac events

• First 29 pts
• ? 2 asymptomatic decline of LVEF
• ? 1 CHF
• Recruitment continued
• During follow-up
• ? 4 asymptomatic decline of LVEF
• ? 3 CHF
• Stop recruitment at 45th patient
• Total of 10 cardiac events (22)

Venturini M. et al. ASCO 2003
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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

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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

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Rational combination of trastuzumab with
chemotherapeutics drugs used in the treatment of
breast cancer
Pegram MD. et al. J Natl Cancer Inst Vol 96 739,
2004

• 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

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Trastuzumab Vinorelbine Clinical Trials
All patients treated first line. Trastuzumab
administered at standard dose of 4mg/kg loading
followed by 2mg/kg weekly.
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GEMZAR Trastuzumab
Reference Regimen mg/m2 N eval ORR (CR) TTPD (mos) MS (mos)
OShaughnessy 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
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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 gt50 ng/mL (vn lt 15) indicated HER2
  metastatic spread)

Meng S. et al. Proc Natl Acad Sci 1019393, 2004
Lueftner DI. et al. Abstract 49 ESMO 2004
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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
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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
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Preoperative therapy with epidoxorubicin and
docetaxel plus trastuzumab in patients with
primary breast cancer a pilot study
Wenzel C. et al. J Cancer Res Clin Oncol Vol
130 400, 2004

• 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

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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 gt10
• pCR 26 vs 65

Wenzel C. J Cancer Res Clin Oncol Vol 130 400,
2004
Buzdar AU et al. Proc ASCO 2004
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Adjuvant Trials
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Early Breast CancerTrastuzumab 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

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National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-31
AC q3w x 4
P q3w x 4 orP qw x 12
RANDOMIZATION
Target N 2,700 Total accrual as of Mar 04
1,673

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

AC q3w x 4
P q3w x 4 orP qw x 12
Trastuzumab qw x 52
Revised study design. Choice of paclitaxel
schedule and hormonaltherapy at discretion of
investigator stratification factors.
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B-31 Design Assumptions

• 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

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B-31 Cardiac Safety Study
Primary Endpoint Analysis
Defined as definite/probable cardiac death OR
dyspnea at rest or with normal activity and
decline of LVEF to below gt 5 below lower limit
of normal
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N9831 Intergroup Trial (NCCTG)
AC q3w x 4
Paclitaxel qw x 12
RANDOMIZATION
Target N 3,300 Total accrual as of Mar 04
2,342
AC q3w x 4
Paclitaxel qw x 12

• Patient Population
• N or high-risk N- breast cancer
• HER2 (IHC 3 or FISH)

Trastuzumab qw x 52
AC q3w x 4
Paclitaxel qw x 12
Trastuzumab qw x 52
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HERceptin Adjuvant (HERA) Trial
RANDOMIZATION
Target N 4,482
Trastuzumab q3w x 1 y
Stratification
Primary management (surgery, neoadjuvant
chemotherapy adjuvant RT)
Trastuzumab q3w x 2 y
Observation
Observation group to receive the same follow-up
as the Trastuzumab treatment groups
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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

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Breast Cancer International Research Group
(BCIRG) 006 Trial
4 x AC60/600 mg/m2
4 x Docetaxel 100 mg/m2
RANDOMIZATION
Target N 2,700 Accrual completed as of Mar 04

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

1-year Trastuzumab
6 x Docetaxel Carboplatin75 mg/m2
AUC 6
1-year Trastuzumab
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BCIRG 006 Interim Cardiac Analyses

• March 2003 First cardiac analysis 300 patients
  with 9 months follow-up
• Sept 2003 Second cardiac analysis 900 patients
  with 9 months follow-up
• IDMC did not express any concerns recommended
  the study to continue as planned
• April 2004 Third cardiac analysis 1,500
  patients with 9 months follow-up