Transcript Lapatinib

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA
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
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
“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)
Why targeting HER2 beyond
Trastuzumab in Breast Cancer?
•
•
•
•
•
Efficacy
Primary resistance
Secondary resistance
Cardiac safety
HER2 + molecular subtypes
FIRST-LINE SINGLE-AGENT TRIAL RESPONSE
ACCORDING TO HER2 STATUS
45
40
35
Patients (%)
35
30
25
20
15
10
5
0
ICH < 2+
IHC 3+
Adapted from Vogel C, et al. J Clin Oncol 2002;20:719–26
Efficacy data from Phase II and III trials of
trastuzumab combined with chemotherapy
Author
Slamon
Regimen
#
Response
Median
patients
Rate %
TTP (mos)
Median
OS
(mos)
Chemo + H
Chemo
235
234
50*
32
7.4*
4.6
25.1*
20.3
Marty
Doc + H
Doc
92
94
61*
34
10.6*
5.7
30.5*
22.1
Seidman
Pw + H
88
61
7.0
NR
Burstein
VNB + H
54
70
5.6
NR
* P = < 0.05
Relationship of HER2 Status
on Site of First Relapse
HER-2/neu not
overexpressed
44.5%
HER-2/neu
overexpressed
31.9%
Locoregional
17.8%
18.8%
Bone
16.1%
5.8%
Lung
7.6%
21.7%
Liver
1.7%
5.8%
Brain
0.4%
4.3%
No relapse
Kallioniemi et al., Int J Cancer 1991
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%
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)
Disease-free survival (censored)- Median FU 2 yrs
1 year trastuzumab
Patients
(%)
100
19.4% Not effective
Observation
80
6.6% Necessary & effective
74% Not necessary
60
40
Events
3-year
DFS
218
316
80.6
74.0
20
HR
0.63
95% CI
p value
0.53, 0.75 <0.0001
0
No.
at risk
0
6
1703
1698
1591
1533
12
18
24
30
Months from randomisation
1434
1301
1127
930
742
606
383
322
36
140
114
Higher Incidence of Isolated CNS Relapse
As 1st Event in Patients on Adjuvant Trials
H
vs
Ctr
NSABP B-31
N9831
21
12
11
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, p=0.35) 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
HER2+ Early Breast Cancer
• > 50% of patients do not need HER2 targeted
therapy
• > 50% of patients show a primary resistance
to Trastuzumab plus chemotherapy
• CNS relapse as 1st event is more frequent in
patients on adjuvant trastuzumab
Management of trastuzumab resistance
Lesson # 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
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
ErbB2/ErbB3 Expression and Estrogen
Receptor Status in Breast Carcinomas
ER+
61%
ER–
39%
ErbB1+
3%
ErbB1+
38%
ErbB2+
11%
ErbB2+
41%
ErbB3+
11%
ErbB3+
27%
(n = 220)
Witton et al. J Pathol 2003; 200:290-7.
Survival Interrelationship Between
ER/PR Status and ErbB Expression
Reproduced with permission from Witton et al. Expression of the HER1–4 family of receptor tyrosine kinases in
breast cancer. J Pathol 2003; 200:290-7.
Effect on survival of the expression of other
EGF-r family members
Robinson, ASCO 2005
Lapatinib Mechanism of Action
Lapatinib
• Binds to intracellular ATP binding site of
EGFR (ErbB-1) and HER2 (ErbB-2)
preventing phosphorylation and activation
1+1
2+2
1+2
• 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 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;
Konecny et al. Cancer Res. 2006;66:1630-1639
Dual kinase inhibitor lapatinib against HER-2 overexpressing
and trastuzumab-treated breast cancer cell lines
Konecny GE et al.: Cancer Res, 2006
Combined effect of
Trastuzumab and Lapatinib
Phase Ib Trial: EGF10004
Overview
• 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).
Frequency of Inhibition (%)
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
500 mg
650 mg
900 mg
1200 mg
1600 mg
60
50
40
30
20
10
0
Dose (mg/day)
Burris et al. Breast Cancer Res Treat 2003; 82(suppl 1):S18 (abstract 39).
EGF10004: Clinical Characteristics of
Responders––
Breast Cancer Subset
Efficacy Data
Patient Characteristics
Number of
Patients
ErbB2+
4
ErbB1+
3
Prior Treatment
Trastuzumab
4
Taxane
3
Anthracycline
3
Number of
Patients
Partial Response
4
650 mg/day
1
900 mg/day
1
1200 mg/day
2
Response Duration
Median
5.5 months
Range
3-8 months
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; 23:1-9.
EGF20009:
A Phase II, Randomized Trial Using the Small
Molecule Tyrosine Kinase Inhibitor Lapatinib as a FirstLine 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
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
Stratification:
• Visceral or nonvisceral
disease
• Hormone receptor
status
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*
(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
Efficacy in All Patients
Response
Investigator Review
N=40
Independent Review
N=40
CR
0
0
PR
12 (30%)
14 (35%)
Unconfirmed PR*
3 (7.5%)
2 (5%)
SD
13 (32.5%)
14 (35%)
PD
10 (25%)
5 (12.5%)
Unknown
2 (5%)**, †
5 (12.5%) **, †
*Two subjects considered to have a PR by investigator had <28 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).
EGF20009: Lapatinib Monotherapy for First-line
FISH-Positive Metastatic Breast Cancer
Safety
Grade 1/2 Adverse Events
1500 mg q.d.
500 mg b.i.d.
40%
27%
23%
17%
23%
16%
3%
17%
Pruritis
Rash
Diarrhea
Dry Skin
• One grade 3 event (nausea)
• One treatment-related serious adverse event, gastritis/esophagitis
• No serious decrease in LVEF (> 20% decrease from baseline
and below lower limit of normal)
Gomez et al. SABCS 2005 (abstract 1071).
Patient C: Brain Lesion Baseline
Patient C: Brain Lesion Week 12
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).
Patient Characteristics of Responders
Prior MBC Treatment
Treatment
Duration
(Months)
Dose
(mg/day)†
ER/PR
Status
Chemo
Hormone
Trastuzumab ±
Chemo
CR
11+
1500, 1000
-
2
0
1
PR
10
1000
+
2
0
5
PR
6
1000
-
1
0
2
PR
5+
1250, 750
-
1
0
1
PR
4
1000, 750
+
4
2
4
PR
4
1000
-
1
1
6
PR*
4+
1000
-
3
0
3
PR*
2+
1000
-
0
0
4
SD
7
750
-
3
0
2
SD
6
1000
+
4
3
0
SD**
5
750
-
7
1
3
Response
†
Lapatinib dose (mg/day)
*PK patient
**Prior lapatinib monotherapy (EGF10004)
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).
Management of trastuzumab resistance
Lesson # 2
• Combining two MoAbs binding at different epitopes of
HER2 receptor can inhibit more efficiently HER2-driven
signalling (trastuzumab+Pertuzumab)
 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)
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
d’Aurelle Paul Lamarque, Montpellier, France; ZOZ MSWiA, Olsztyn,
Poland; St. Vincent’s University Hospital, Dublin, Ireland; Sheba Medical
Center, Tel Hashomer, Israel; Mount Medical Centre, Perth, Australia;
GlaxoSmithKline, Greenford, UK
Study Design
• Progressive, HER2+
MBC or LABC
• Previously treated
with anthracycline,
taxane and
trastuzumab*
• No prior
capecitabine
Stratification:
• Disease sites
• Stage of disease
R
A
N
D
O
M
I
Z
E
N=528
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
Patients on treatment until
progression or unacceptable
toxicity, then followed for survival
*Trastuzumab must have been administered for metastatic disease
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
Prior Therapy
Lapatinib +
Capecitabine
(n=160)
Capecitabine
(n=161)
Anthracyclines
156 (98%)
156 (97%)
Taxanes
157 (98%)
159 (99%)
Trastuzumab
Metastatic
156 (97%)
149 (93%)
156 (97%)
146 (91%)
Adjuvant
7 (4%)
10 (6%)
Prior Trastuzumab for Metastatic Disease
Lapatinib + Capecitabine Capecitabine
(n=149)
(n=146)
Progressed on
trastuzumab*
Yes
Median duration
of trastuzumab (range)
Interval from last
dose prior to
randomization*
< 4 wks
4 - 8 wks
> 8 wks
Unknown
147 (99%)
142 (97%)
42.3 wk (3-296)
44.1 wk (5-329)
51 (34%)
42 (28%)
56 (38%)
* Based on those who received treatment for MBC only.
42 (29%)
48 (33%)
54 (37%)
2 ( 1%)
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.
EGF100151: Phase III Trial of
Capecitabine ± Lapatinib in Advanced or
Metastatic Breast Cancer Efficacy
Median TTP
Capecitabin Capecitabine
e
Plus
Lapatinib
19.7 weeks
36.9 weeks
P Value
.00016
Median PFS
17.9 weeks
36.9 weeks
.000045
Median OS
Not reached
Not reached
.800
Overall RR
14.3%
22.5%
.113
CR
0 (0%)
1 (1<%)
–
PR
23 (14%)
35 (22%)
–
Geyer ASCO 2006 Special Session
% of patients free from progression*
Time to Progession – ITT Population
Lapatinib +
Capecitabine Capecitabine
No. of pts
160
161
Progressed or died* 45 (28%)
69 (43%)
Median TTP, wk
19.7
36.9
Hazard ratio (95% CI)
0.51 (0.35, 0.74)
P-value (log-rank, 1-sided)
0.00016
100
90
80
70
60
50
40
30
20
10
0
0
1
0
20
30
40
50
60
Time (weeks)
* Censors 4 patients who died due to causes other than breast cancer
70
EGF100151: Phase III Trial of Capecitabine ± Lapatinib
in Advanced or Metastatic Breast Cancer
Brain Metastases as Site of Progression
Patients With CNS
Metastases at
Baseline
Patients With CNS
Relapse*
Patients With CNS as
Only Site of Relapse
* P =.110
Geyer ASCO 2006 Special Session
Capecitabine
(n = 161)
Capecitabine
Plus
Lapatinib
(n = 160)
2
2
11
4
10
3
EGF 100151Most Frequent Adverse Events
All Grades
% of Patients
100
90
Severity
80
Gr 4
Gr 3
70
60
50
40
L+C
10
0
1
12
19
26
Gr 1
L+C
C
30
20
Gr 2
6
C
L+C
5
2.5
C
13
7
11
15
13
Diarrhea
L = lapatinib; C = capecitabine.
28
20
11
19
9
PPE
9
12
Rash and/or
Skin Reaction
EGF 100151-Mean LVEF at Scheduled
Assessments
80
Mean LVEF (%)
75
Lapatinib + Capecitabine
Capecitabine
70
65
60
55
n=160
n=160
n=108
n=92
n=84
n=67
n=63
n=37
Week 12
Week 18
50
Screening
Week 6
n=37
n=26
n=15
n=9
Week 24 Week 36
Assessment
n=7
n=1
Week 48
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
Summary: Cardiac Effects Associated
with Lapatinib Therapy (n = 3558)
• 1097 pts with > 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
Effect of tumor selection and
treatment selection on response
T-FEC
T-FEC + H
26.3 %
66.7 %
pCR ER pos
27 %
61 %
pCR ER neg
25 %
70 %
78.9 %
90.3 %
pCR
pN0
Early closure of the Study due to the strong
advantage for H combination, after first 42 pts
Buzdar, JCO 2005
EGF109085/CHERLOB
STUDY 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
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
EGF109077/LET-LOB
STUDY 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
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 paraffinembedded 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.
LOB TRIALS (EGF109085-EGF109077):
Participating Centers
PI
Center
PI
Center
Prof PF Conte
Modena
Dr G. Giardina
Varese
Dr L. Cavanna
Piacenza
Prof S. Iacobelli
Chieti
Dr. M.Danova
Pavia
Dr L. Crinò
Perugia
Prof D. Amadori
Forlì
Prof S. Cascinu
Ancona
Dr. M. Margelí
Badalona (Spain)
Dr A. Ardizzoni
Parma
Dr. A. Guerreo
Valencia (Spain)
Prof M. Aglietta
Candiolo
Prof J. Jassem
Gdansk (Poland)
Carpi
Prof M. Untch
Berlin (Germany)
Dr K. Cagossi
Dr C. Boni
Reggio Emilia
Dr A. Michelotti
Pisa
Dr S. Crispino
Prof A. Llombart
Prof H. Cortes-Funes
Lérida (Spain)
Madrid (Spain)
Prof M Verrill
Newcastle, ( UK )
Siena
Prof. C. Szczylik
Warsaw, (Poland)
Dr S. Barni
Treviglio
Prof. C. Jackisch
Offenbach, (Germany)
Dr A. Bottini
Cremona
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