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Title: PierFranco Conte


1
Highlights in the management of breast cancer
Lapatinib Rome,
november 17, 2006
PierFranco Conte
Dipartimento di Oncologia e Ematologia Università
di Modena e Reggio Emilia

2
HER2 beyond Herceptin
1985 human cDNA cloning 1987 disease
validation 1990 MAb 4D5 1998 Herceptin
approved by FDA for metastatic breast
cancer 2005 Herceptin becomes an essential
component of the adjuvant treatment of HER2
early breast cancer 2007 New HER2 targeted
agents are available
3
Non esiste vento favorevole per il marinaio che
non sa dove andare(there is no favourable wind
for a sailor who does not know where to go)
  • Seneca (5 aC-65 dC)

4
Why targeting HER2 beyond Trastuzumab in Breast
Cancer?
  • Efficacy
  • Primary resistance
  • Secondary resistance
  • Cardiac safety
  • HER2 molecular subtypes

5
FIRST-LINE SINGLE-AGENT TRIAL RESPONSE ACCORDING
TO HER2 STATUS
45
40
35
35
30
25
Patients ()
20
15
10
5
0
IHC 3
ICH lt 2
Adapted from Vogel C, et al. J Clin Oncol
20022071926
6
Efficacy data from Phase II and III trials of
trastuzumab combined with chemotherapy
P lt 0.05
7
Relationship of HER2 Status on Site of First
Relapse
Kallioniemi et al., Int J Cancer 1991
8
High incidence of CNS metastases among women
treated with trastuzumab
Study Incidence Bendell et al ASCO
2002 34 Weitzen et al ASCO 2002
29 Heinrich et al ASCO 2003 43 Clayton
et al Br J Cancer 2004 39 Altaha et
al ASCO 2004 33 Stemmler et al SABCS
2004 31
9
HER2 Advanced Breast Cancer
  • 60 70 of patients exhibit a primary
    resistance to Trastuzumab monotherapy
  • 30 50 of patients show a primary resistance
    to Trastuzumab plus chemotherapy
  • Eventually, all the patients become resistant to
    Trastuzumab within months or years
  • CNS MTS are frequent
  • Trastuzumab is ineffective for CNS MTS ( CSF
    levels 300-fold lower than in the serum)

10
Disease-free survival (censored)- Median FU 2 yrs
1 year trastuzumab
Patients()
100
19.4 Not effective
80
Observation
6.6 Necessary effective
74 Not necessary
60
3-yearDFS
40
Events
HR
95 CI
p value
218
0.63
0.53, 0.75
lt0.0001
80.6
20
316
74.0
0
0
Months from randomisation
1703
1591
1434
1127
No. at risk
742
383
140
1698
1533
1301
930
606
322
114
11
Higher Incidence of Isolated CNS Relapse As 1st
Event in Patients on Adjuvant Trials
H vs Ctr NSABP B-31 21 11 N9831
12 4 Total 33 15
Brain metastases as first or subsequent event
were diagnosed in 28 patients in the trastuzumab
group, compared to 35 patients in the control
group (HR 0.79, p0.35) The imbalance in brain
metastases as first events can be attributed to
earlier failures at other distant sites among
patients in the control group
Romond et al, NEJM 2005
12
HER2 Early Breast Cancer
  • gt 50 of patients do not need HER2 targeted
    therapy
  • gt 50 of patients show a primary resistance to
    Trastuzumab plus chemotherapy
  • CNS relapse as 1st event is more frequent in
    patients on adjuvant trastuzumab

13
Management of trastuzumab resistanceLesson 1
  • Check HER2 positivity on original tumor blocks
  • Whenever possible, test HER2 status on recurrent
    disease
  • Trastuzumab and chemotherapy can act synergically
    on apoptotic pathway
  • Other proteins in the EFGR-mediated signalling
    pathways are important
  • Other EGFRs (i.e.HER1) can be important

14
Trastuzumab resistance
  • Trastuzumab can induce apoptosis through
    inhibition of PI3K/Akt pathway
  • PTEN normally opposes PI3K/Akt signaling
  • trastuzumab stabilizes PTEN and downregulates Akt
    signaling
  • loss of PTEN can induce trastuzumab resistance

15
ErbB2/ErbB3 Expression and Estrogen Receptor
Status in Breast Carcinomas
(n 220)
Witton et al. J Pathol 2003 200290-7.
16
Survival Interrelationship Between ER/PR Status
and ErbB Expression
Reproduced with permission from Witton et al.
Expression of the HER14 family of receptor
tyrosine kinases in breast cancer. J Pathol 2003
200290-7.
17
Effect on survival of the expression of other
EGF-r family members
Robinson, ASCO 2005
18
Lapatinib Mechanism of Action
Lapatinib
11
22
12
  • Binds to intracellular ATP binding site of EGFR
    (ErbB-1) and HER2 (ErbB-2) preventing
    phosphorylation and activation
  • Blocks downstream signaling through homodimers
    and heterodimers of EGFR (ErbB-1) and HER2
    (ErbB-2)
  • Dual blockade of signaling may be more effective
    than the single-target inhibition provided by
    agents such as trastuzumab

Downstream signaling cascade
Rusnak et al. Mol Cancer Ther 2001185-94 Xia
et al. Oncogene 2002216255-6263 Konecny et al.
Cancer Res. 2006661630-1639
19
Dual kinase inhibitor lapatinib against HER-2
overexpressing and trastuzumab-treated breast
cancer cell lines
Konecny GE et al. Cancer Res, 2006
20
Combined effect of Trastuzumab and Lapatinib
21
Phase Ib Trial EGF10004Overview
  • Study objectives
  • Determine a dose or range of biologically active
    doses
  • Evaluate safety and tolerability
  • Examine dose pharmacokinetics and
    pharmacodynamics
  • Study design
  • Patients randomized to doses of 500, 650, 900,
    1200, or 1600 mg/day
  • Clinical response evaluated every 8 weeks
  • Biological effects examined by comparing
    biomarker results from biopsy samples obtained
    pretreatment and following 21 days of therapy

Burris et al. Breast Cancer Res Treat 2003
82(suppl 1)S18 (abstract 39).
22
EGF10004 Results Frequency of Achieving 75
Inhibition of p-EGFR, p-ErbB2, p-ERK1/2, or
p-AKT Expression in Tumors at Day 21
90
80
70
60
500 mg
650 mg
50
Frequency of Inhibition ()
900 mg
40
1200 mg
1600 mg
30
20
10
0
Dose (mg/day)
Burris et al. Breast Cancer Res Treat 2003
82(suppl 1)S18 (abstract 39).
23
EGF10004 Clinical Characteristics of
RespondersBreast Cancer Subset
  • Four of 59 evaluable patients achieved a PR with
    single-agent lapatinib
  • All had ErbB2 breast cancer
  • All were trastuzumab pretreated

Burris H et al. J Clin Oncol 2005 231-9.
24
EGF20009A Phase II, Randomized Trial Using the
Small Molecule Tyrosine Kinase Inhibitor
Lapatinib as a First-Line Treatment in Patients
with FISH Positive Advanced or Metastatic Breast
Cancer
  • H. L. Gomez, M. A. Chavez, D. C. Doval, L. W.
    Chow, B. Newstat, S. H. Stein, M. S. Berger, G.
    W. Sledge
  • ASCO 2005

25
EGF20009 Phase II Randomized Trial of Lapatinib
as First-line Treatment in FISH-Positive
Metastatic Breast Cancer
  • Eligibility criteria
  • Advanced or metastatic breast cancer
  • No prior therapy for advanced or metastatic
    disease
  • ERBB2 amplification by FISH

R A N D O M I Z E
Arm 1 Lapatinib 1500 mg/day p.o. 12 weeks
First efficacy assessment at 8 weeks Second
efficacy assessment at 12 weeks
Arm 2 Lapatinib 500 mg p.o. b.i.d. 12 weeks
  • Stratification
  • Visceral or nonvisceral disease
  • Hormone receptor status

(n 130)
Patients with clinical benefit may continue on
lapatinib
Primary endpoint Objective response
rate Secondary endpoints clinical benefit rate,
time to response, duration of response, TTF
26
Efficacy in All Patients
Two subjects considered to have a PR by
investigator had lt28 day confirmation scans.
One subject not evaluated due to death from
multiple injuries prior to tumor assessment. 1
subject by the investigator review and 4 subjects
by independent review had only one timepoint and
that timepoint did not meet the criteria for SD
per the protocol (8 weeks).
27
EGF20009 Lapatinib Monotherapy for First-line
FISH-Positive Metastatic Breast CancerSafety
Grade 1/2 Adverse Events
  • One grade 3 event (nausea)
  • One treatment-related serious adverse event,
    gastritis/esophagitis
  • No serious decrease in LVEF (gt 20 decrease from
    baseline
  • and below lower limit of normal)

Gomez et al. SABCS 2005 (abstract 1071).
28
Patient C Brain Lesion Baseline
29
Patient C Brain Lesion Week 12
30
Lapatinib Trastuzumab in Advanced Pretreated
Metastatic Breast Cancer Phase I Study EGF10023
  • Study objectives
  • Safety of lapatinib in combination with
    trastuzumab
  • Optimally tolerated regimen of combination
  • Pharmacokinetic parameters
  • Clinical activity
  • Eligibility criteria
  • Advanced ErbB2 MBC
  • Prior treatment with trastuzumab allowed but not
    required
  • Treatment consisted of escalating doses of
    lapatinib 750, 1000, 1250, or 1500 mg/day with
    trastuzumab (4-mg/kg loading dose 2 mg/kg/week)

Storniolo et al. ECCO 2005 (abstract 278) SABCS
2005 (abstract 1075).
31
Patient Characteristics of Responders
PK patient Prior lapatinib monotherapy
(EGF10004)
Lapatinib dose (mg/day)
32
Lapatinib Trastuzumab in Advanced Pretreated
Metastatic Breast Cancer Results
  • Optimally tolerated dose and dose-limiting
    toxicities
  • Lapatinib 1000 mg/day with standard trastuzumab
    was defined as optimally tolerated regimen (OTR).
  • The most frequent adverse at OTR were diarrhea,
    rash, fatigue, nausea, anorexia, and vomiting.
  • Pharmacokinetics
  • No effect on PK of lapatinib or trastuzumab was
    observed during coadministration.
  • Synergism of action of lapatinib and trastuzumab
    similar to preclinical studies reported.

Storniolo et al. ECCO 2005 (abstract 278) SABCS
2005 (abstract 1075).
33
Management of trastuzumab resistanceLesson 2
  • Combining two MoAbs binding at different epitopes
    of HER2 receptor can inhibit more efficiently
    HER2-driven signalling (trastuzumabPertuzumab)
  • Combining an anti-ErbB2 antibody with small
    molecule tyrosine kinase inhibitor, that act at
    different sites of the receptor with distinct
    mechanisms of action, might enhance the efficacy
    of both drugs (trastuzumab Lapatinib)
  • Inhibition of multiple EGFR-family receptors can
    be important (lapatinib)

34
A Phase III Randomized, Open-Label,
International Study Comparing Lapatinib
and Capecitabine vs. Capecitabine in Women with
Refractory Advanced or Metastatic Breast Cancer
(EGF100151)
  • C.E. Geyer, D. Cameron, D. Lindquist, S. Chan,
    T. Pienkowski, C.G. Romieu, A. Jagiello-Gruszfeld,
    J. Crown, B. Kaufman, A. Chan, J.K. Forster
  • Allegheny General Hospital, Pittsburgh, PA
    Western General Hospital, Edinburgh, UK US
    Oncolgy Research Network, Houston,TX Nottingham
    City Hospital, Nottingham, UK Cancer Center,
    Warsaw, Poland CRCC Val dAurelle Paul Lamarque,
    Montpellier, France ZOZ MSWiA, Olsztyn, Poland
    St. Vincents University Hospital, Dublin,
    Ireland Sheba Medical Center, Tel Hashomer,
    Israel Mount Medical Centre, Perth, Australia
    GlaxoSmithKline, Greenford, UK

35
Study Design
  • Progressive, HER2 MBC or LABC
  • Previously treated with anthracycline, taxane
    and trastuzumab
  • No prior capecitabine

R A N D O M I Z E
Lapatinib 1250 mg po qd continuously
Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk
Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk
  • Stratification
  • Disease sites
  • Stage of disease

Patients on treatment until progression or
unacceptable toxicity, then followed for survival
N528
Trastuzumab must have been administered for
metastatic disease
36
EGF 100151 - Study Objectives
  • Primary
  • TTP
  • Secondary
  • Overall survival
  • Progression free survival
  • 6-month progression free survival
  • Overall tumor response rate
  • Clinical benefit (complete, partial response or
    stable disease for at least 6 months)
  • Time to response
  • Duration of response

37
Prior Therapy
38
Prior Trastuzumab for Metastatic Disease
Lapatinib Capecitabine (n149)
Capecitabine (n146)
Progressed on trastuzumab
Yes
142 (97)
Median duration of trastuzumab (range)
44.1 wk (5-329)
42.3 wk (3-296)
Interval from last dose prior to randomization
lt 4 wks
42 (29)
51 (34)
48 (33)
4 - 8 wks
42 (28)
54 (37) 2 ( 1)
gt 8 wks Unknown
56 (38)
Based on those who received treatment for MBC
only.
39
  • Issued Monday 3 April 2006, London, UK
    Philadelphia, US -
  • LSE Announcement
  • GlaxoSmithKline Receives Positive Data and Halts
    Enrolment in Phase III Trial of Tykerb
    (Lapatinib) in Advanced Breast Cancer
  • First Regulatory Filings now Planned for 2nd Half
    of 2006
  • Based on the unanimous recommendation of an
    Independent Data Monitoring Committee (IDMC),
    GlaxoSmithKline (GSK) announced today that it has
    halted enrolment in its Phase III clinical trial
    evaluating the combination of Tykerb (lapatinib
    ditosylate) and capecitabine (Xeloda) versus
    capecitabine alone. The trial evaluated women
    with refractory advanced or metastatic breast
    cancer who have documented ErbB2 (HER2)
    overexpression and whose disease progressed
    following treatment with trastuzumab (Herceptin?)
    as well as other cancer therapies. A pre-planned
    interim analysis of 321 patients in the study
    yielded statistically significant results,
    exceeding the primary endpoint.

40
EGF100151 Phase III Trial of Capecitabine
Lapatinib in Advanced or Metastatic Breast Cancer
Efficacy
Geyer ASCO 2006 Special Session
41
Time to Progession ITT Population
of patients free from progression
100
70
Censors 4 patients who died due to causes other
than breast cancer
42
EGF100151 Phase III Trial of Capecitabine
Lapatinib in Advanced or Metastatic Breast
CancerBrain Metastases as Site of Progression
P .110
Geyer ASCO 2006 Special Session
43
EGF 100151-Most Frequent Adverse Events All
Grades
100
Severity
90
Gr 4
of Patients
80
Gr 3
70
Gr 2
LC
60
1
Gr 1
12
50
LC
C
6
LC
C
40
19
C
11
2.5
5
30
7
13
28
15
20
20
11
26
19
10
13
12
9
9
0
Diarrhea
Rash and/or Skin Reaction
PPE
L lapatinib C capecitabine.
44
EGF 100151-Mean LVEF at Scheduled Assessments
80
Lapatinib Capecitabine
Capecitabine
75
70
65
Mean LVEF ()
60
55
n160 n160
n108 n92
n84 n67
n63 n37
n37 n26
n15 n9
n7 n1
50
Week 24
Week 12
Week 18
Week 36
Week 48
Week 6
Screening
Assessment
45
Conclusions
  • Lapatinib with capecitabine is an effective new
    regimen for advanced HER2 breast cancer and
    should be considered a new standard of care for
    women meeting eligibility criteria of this trial

46
Summary Cardiac Effects Associated with
Lapatinib Therapy (n 3558)
  • 1097 pts with gt 6 mo exposure to lapatinib
  • In 598 patients pre-treated with A but no H
  • 1.2 LVEF decrease 0.3 symptomatic
  • In 759 patients pre-treated with H and
    chemotherapy
  • 1.7 LVEF decrease 0.1 symptomatic
  • In 2201 A and H naïve patients
  • 1.7 LVEF decrease 0.2 symptomatic

Perez EA, ESMO 2006
47
Effect of tumor selection and treatment selection
on response
Early closure of the Study due to the strong
advantage for H combination, after first 42 pts
Buzdar, JCO 2005
48
EGF109085/CHERLOBSTUDY DESIGN
Tumor biopsy for histological diagnosis and IHC
evaluation of tissue biomarkers
Stage II-IIIA, HER2
Random
A CT Trastuzumab
B CT LAPATINIB
C CT LAPATINIB Trastuzumab
Surgery within 5 weeks from the last
administration of CT and after at least 1 week
from the last administration of lapatinib and/or
trastuzumab
49
DOSES AND TREATMENT REGIMENS
  • Arm A Paclitaxel 80 mg/m2 weekly for 12 weeks ?
    FE75C q 21 X 4 courses plus trastuzumab 4 mg/kg
    loading dose followed by 2mg/kg weekly
  • Arm B Paclitaxel 80 mg/m2 weekly for 12 weeks ?
    FE75C q 21 X 4 courses plus Lapatinib 1500 mg po
    daily
  • Arm C Paclitaxel 80 mg/m2 weekly for 12 weeks ?
    FE75C q 21 X 4 courses plus trastuzumab 4 mg/kg
    loading dose followed by 2mg/kg weekly plus
    Lapatinib 1000 mg po daily
  • Lapatinib and trastuzumab administration will
    start on the same day of the 1st infusion of CT,
    will continue throughout all the duration of the
    treatment and will be discontinued 1 week before
    surgery

5FU 600 mg/m2, Epirubicin 75 mg/m2,
Cyclophosphamide 600 mg/m2
50
EGF109077/LET-LOBSTUDY DESIGN
Tumor biopsy for histological diagnosis and IHC
evaluation of tissue biomarkers
Stage II-IIIA, HR , HER2 -
Random
A LETROZOLE PLACEBO x 6 mos
B LETROZOLE LAPATINIB1500mg/die x 6 mos
Surgery within 2 weeks after the last
administration of study drug
51
BIOMARKER EVALUATION
  • The following biomarkers will be evaluated, to
    define the inhibition of the down-stream pathways
    of EGFR-family
  • - EGFR, HER2
  • - pTEN, pAKT, pMAPK
  • - Apoptosis with TUNEL Test
  • - Ki 67
  • These parameters will be evaluated by IHC, on
    paraffin-embedded specimens obtained from
    diagnostic core biopsy of the primary lesion and
    from surgical specimens.
  • Fresh tumor tissue from core-biopsy must be snap
    frozen, to perform a microarray analysis of the
    gene expression profile before treatment and to
    evaluate its correlation with response.

52
LOB TRIALS (EGF109085-EGF109077) Participating
Centers
53
Molecular subtypes of breast cancer and clinical
management
  • Her2 represents a distinct molecular subtype
  • Her2 tumors have a unique clinical behaviour
    (shorter DFI, more visceral and CNS metastases)
  • Her2 tumors exhibit a peculiar pattern of
    sensitivity to chemo and hormonal therapy
  • Her2 targeting agents have dramatically changed
    the course of this disease and represent now the
    foundation of treatment in early and advanced
    disease
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