Title: PierFranco Conte
1Highlights in the management of breast cancer
Lapatinib Rome,
november 17, 2006
PierFranco Conte
Dipartimento di Oncologia e Ematologia Università
di Modena e Reggio Emilia
2HER2 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
3Non 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)
4Why targeting HER2 beyond Trastuzumab in Breast
Cancer?
- Efficacy
- Primary resistance
- Secondary resistance
- Cardiac safety
- HER2 molecular subtypes
5FIRST-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
6Efficacy data from Phase II and III trials of
trastuzumab combined with chemotherapy
P lt 0.05
7Relationship of HER2 Status on Site of First
Relapse
Kallioniemi et al., Int J Cancer 1991
8High 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
9HER2 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)
10Disease-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
11Higher 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
12HER2 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 -
13Management 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
14Trastuzumab 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
15ErbB2/ErbB3 Expression and Estrogen Receptor
Status in Breast Carcinomas
(n 220)
Witton et al. J Pathol 2003 200290-7.
16Survival 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.
17Effect on survival of the expression of other
EGF-r family members
Robinson, ASCO 2005
18Lapatinib 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
19Dual kinase inhibitor lapatinib against HER-2
overexpressing and trastuzumab-treated breast
cancer cell lines
Konecny GE et al. Cancer Res, 2006
20Combined effect of Trastuzumab and Lapatinib
21Phase 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).
22EGF10004 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).
23EGF10004 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.
24EGF20009A 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
25EGF20009 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
26Efficacy 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).
27EGF20009 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).
28Patient C Brain Lesion Baseline
29Patient C Brain Lesion Week 12
30Lapatinib 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).
31Patient Characteristics of Responders
PK patient Prior lapatinib monotherapy
(EGF10004)
Lapatinib dose (mg/day)
32Lapatinib 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).
33Management 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)
34A 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
35Study 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
36EGF 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
37Prior Therapy
38Prior 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.
40EGF100151 Phase III Trial of Capecitabine
Lapatinib in Advanced or Metastatic Breast Cancer
Efficacy
Geyer ASCO 2006 Special Session
41Time to Progession ITT Population
of patients free from progression
100
70
Censors 4 patients who died due to causes other
than breast cancer
42EGF100151 Phase III Trial of Capecitabine
Lapatinib in Advanced or Metastatic Breast
CancerBrain Metastases as Site of Progression
P .110
Geyer ASCO 2006 Special Session
43EGF 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.
44EGF 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
45Conclusions
- 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
46Summary 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
47Effect 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
48EGF109085/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
49DOSES 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
50EGF109077/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
51BIOMARKER 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.
52LOB TRIALS (EGF109085-EGF109077) Participating
Centers
53Molecular 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