Transcript Recurrent Head and Neck Cancer: Bevacizumab/Erlotinib

ASCO 2006 Update
Novel Therapeutics in Prevention and Treatment
for Breast Cancer
Hope S. Rugo, MD
Clinical Professor of Medicine
Director, Breast Oncology Clinical Trials Program
UCSF Comprehensive Cancer Center
Discussion Outline
•
Endocrine Therapy

Prevention
•

•
•
Updates from IES, ARNO95, GROCTA4/ITA, MA17
•
Bone health substudy from ATAC
Metronomic chemotherapy (SWOG 0012)
Adjuvant trastuzumab

•
Adjuvant therapy
Neoadjuvant

•
5: STAR NSABP P-2
Update on the HERA trial
New treatments for HER2+ disease – Lapatanib

Phase III trial with capecitabine

502: Inflammatory breast cancer

503: Treatment of CNS disease

583: Risk of cardiac toxicity
The Study of Tamoxifen and Raloxifene (STAR):
Initial Findings from the NSABP P-2 Breast
Cancer Prevention Study
TAMOXIFEN 20 mg/day
Eligibility:
X 5 years
• Postmenopausal
women at moderate
to high risk
• 5-year breast
cancer risk by
modified Gail score
= 1.66%
•
•
•
RALOXIFENE 60 mg/day
X 5 years
Accrual (July 1999-Nov 2004) – 19,747 women randomized
Interim results at 327 invasive breast cancer cases
Average follow-up 47.3 months
Wickerham, ASCO 2006, LBA#5
NSABP P-2: Results
• Patient Population
 Age: <49: 9%; 50-59: 50%; 60-69: 32%; 70+: 9%
 Prior hysterectomy: 51.5%
 Prior LCIS: 9.2%
 Prior Atypical Hyperplasia: 22.7%
Tamoxifen
Raloxifene
Relative
Risk
P Value
Invasive
Breast
Cancer*
163
168
0.83
-
Noninvasive
Breast Cancer
57
81
1.40
.052
* Gail Model Projected Incidence: 312
Wickerham, ASCO 2006, LBA#5
SAFETY
Tamoxifen
Raloxifene
Relative
Risk
Uterine Cancer
36
23
0.62
Endometrial Hyperplasia
84
14
-
Hysterectomy (noncancer)
244
111
-
Thromboembolic Events
141
100
0.70*
Strokes
53
51
-
Myocardial Infarction
48
37
0.77
Severe Angina
51
63
1.23
Acute Ischemic
Syndrome
15
26
1.72
Osteoporotic Fractures
106
98
0.92
Cataracts
394
313
0.79
*P=.01
Wickerham, ASCO 2006, LBA#5
STAR Trial: Summary
• Raloxifene compared to tamoxifen for breast cancer prevention in
postmenopausal women was
 As effective in preventing invasive disease
 Not as effective in preventing in situ disease
• And resulted in:
 Fewer thromboembolic events
 Fewer cataracts
 Fewer endometrial cancers
• Patient reported outcomes
 More musculoskeletal symptoms, weight gain, dyspareunia
with raloxifene
 More vasomotor symptoms, bladder problems, leg cramps,
gynecologic symptoms with tamoxifen
• The future of prevention trials?
 Comparison of aromatase inhibitors to placebo
• Map 3 – exemestane vs placebo (4560 pts)
• IBIS-2 – anastrozole vs placebo (6000 pts)
IES Trial Design
Tamoxifen
R
Exemestane
A
N
5162*
D
O 4724
M
Tamoxifen
I
5294*
Z
E
* Total women years
10335*
2-3 years study
treatment
2-3 years
Diagnosis
Post
Treatment
Follow-up
Start of
study
Total 5 years
endocrine therapy
Coombes, # LBA527
First Mature Survival Analysis of the IES Trial:
Switching to Exemestane after 2-3 Years of
Adjuvant Tamoxifen
Coombes, # LBA527
Hazard Ratio*
P Value
Intent to Treat
0.76
.0001
ER+/Unknown
0.75
.0001
Intent to Treat
0.85
.08
ER+/Unknown
0.83
Adjusted .88
.05
Adjusted .04
DFS
Overall Survival
122 pts found to be ER- on central review, 2.4 vs 2.8%
Median Follow-up: 55.7 months, 4.6 yrs
Cumulative Hazard Rate - OS
ER+/Unknown
0.14
0.12
0.12
0.08
0.06
0.04
0.10
0.08
0.06
0.04
0.02
0.02
0.00
0.00
0
1
2
3
4
5
End of
treatment
0.10
Cumulative Rate
0.14
End of
treatment
Cumulative Rate
ITT
0
1
Time since randomization (years)
2
3
4
Time since randomization (years)
Exemestane
Tamoxifen
Annual Hazard Rate, % (95% CI)
ITT
1
2
3
4
5
Exemestane
0.8 (0.5, 1.2)
1.8 (1.3, 2.5)
2.2 (1.6, 2.9)
3.6 (2.8, 4.5)
2.3 (1.6, 3.4)
Tamoxifen
1.0 (0.7, 1.5)
2.4 (1.8, 3.1)
2.5 (2.0, 3.3)
3.2 (2.5, 4.1)
2.9 (2.1, 4.1)
5
IES: Cardiovascular Safety
Exe
Tam
P-Value
Ischemic Cardiac Events
9.9%
8.6%
.12
Myocardial Infarction
1.3%
0.8%
.08
Angina
7.1%
6.5%
.44
Other cardiac events
11.3%
11.2%
.96
CVA
2.5%
2.4%
.89
Thromboembolic events
1.9%
3.1%
.01
Coombes, # LBA527
IES: Safety
Exe
Tam
P-Value
Fracture
7.0%
4.9%
.003
Osteoporosis
9.2%
7.2%
.01
Arthritis
17.5%
14.6%
.008
Musculoskeletal pain
25.7%
20.3%
<.001
Arthralgia
20.8%
15.1%
<.001
Cramp
2.5%
4.4%
<.001
Gastric Ulcer
1.2%
0.3%
.001
Serious gyn events
6.4%
9.8%
<.001
Vaginal Bleeding
4.8%
7.1%
.001
Endometrial hyperplasia
0.2%
1.0%
<.001
Uterine fibroids/polyps
1.4%
4.0%
<.001
Uterine D&C
0.7%
1.5%
.006
Endometrial Cancer
0.4%
0.7%
.17
ARNO 95:
Survival Benefit of Switching to Anastrozole after
2 yrs Tamoxifen vs Continued Tamoxifen
Kaufmann, # 547
• Small trial, small number of events
 N = 979
 No adjuvant chemotherapy given, 74% node negative
 Median follow-up 30 months
• Results
 Switching to anastrozole reduced risk of recurrence (HR 0.66;
P=.049)
• 3-year DFS
• Absolute difference of 4.2% (93.5% vs 89.3%)
 Switching to anastrozole improved OS (HR 0.53; P=.045)
 Serious adverse events were reported less frequently with
anastrozole (22.7% vs 30.8%; P=.0065)
• Vascular events 9.2% A vs 8.8% T
• Musculoskeletal events 16.8% A vs 8.0% T
• Endometrial events 4.5% A vs. 15.9% T
Pooled Analysis of Grocta 4 and ITA Trials:
Mortality Benefit of Switching to an AI
Boccardo, # 548
• Two consecutive small phase III trials
 Tamoxifen for 2-3 yrs followed by either aminoglutethimide
or anastrozole for a total of 5 yrs
• N=813 (pooled)
• 415 tamoxifen for 5 years
• 413 tam followed by either A
• Results
 All-cause mortality
 HR 0.61 favoring switch, P = .007
 Breast cancer mortality
 HR 0.61 favoring switch, P =0.25
 Breast cancer unrelated deaths HR = 0.62; P=.10
 Small studies, hard to evaluate P values in pooled analyses,
encouraging results!
Updated analysis of NCIC CTG MA.17 (letrozole vs.
placebo to letrozole vs placebo) post unblinding
Robert, # 550
Tamoxifen
N = 5187
5 years
Letrozole n= 2593
Letrozole
n = 2457
R
Placebo (PLAC)
Placebo
n = 613
n= 2594
Letrozole (PLAC-LET) n = 1655
0-3 mo
Median F/U (mo)
30
Unblinding
54
• Purpose: compare PLAC-LET vs PLAC to determine benefits/safety of
starting letrozole after prolonged periods (1-5 y) off tamoxifen
• Patients: those who switched (PLAC-LET) were younger, had more
advanced disease, and were more likely to have had adjuvant
chemotherapy than PLAC patients
Updated analysis of NCIC CTG MA.17 (letrozole vs.
placebo to letrozole vs placebo) post unblinding
0.6
PLAC-LET to PLAC
Hazard Ratio
0.53
0.5
P=0.05
0.4
0.31
0.3
P<0.0001
0.28
0.23
P=0.002
0.2
P=0.012
0.1
0
• Safety
DFS
Distant DFS
OS
CBC
 PLAC-LET vs PLAC: no significant increase in fractures (P=0.60); more new
osteoporosis (P=0.007); no difference in cardiovascular disease (P=0.84)
OS = overall survival; CBC = contralateral breast cancer.
Robert, ASCO 2006 # 550
NCIC CTG MA.17: Intent to treat analysis
(ITT) of randomized patients after a median
follow-up of 54 months
Ingle, # 549
Univariate
Multivariate
4 yr %
HR
P Value
HR
P Value
DFS
L 94.3%
P 91.4%
0.64
.00002
.64
.00003
DDFS
L 96.2%
P 94.9%
.76
.041
.76
.045
OS
L 95.0%
P 95.1%
1.00
.99
1.00
0.97
-
.061
.037
-
-
CL BC
•Advantage of letrozole for DFS, DDFS and contralateral breast
cancer reduction maintained despite 73% of patients on placebo
opting to receive letrozole after study unblinding
Effect of Anastrozole on Bone Mineral
Density: 5-year Results from the ATAC Trial
SubStudy
Coleman, # 511
• Bone subprotocol: Anastrozole N=81, Tamoxifen N=86
• More bone loss reported with anastrozole in lumbar
spine (P<.0001) and hip (P<.0001)
• No patients with normal bone at baseline became
osteoporotic while on treatment
 17% on anastrozole became osteopenic versus 3% on tamoxifen
• Of patients osteopenic at baseline
 5% became osteoporotic on anastrozole versus 1% on
tamoxifen
• On the ATAC trial, a total of 11% of patients on
anastrozole experienced bone fracture, versus 7.7% on
tamoxifen (HR 1.49; P<.0001)
SWOG 0012
Standard AC vs Weekly A and Daily C, followed by
Weekly T, a Randomized Phase III Comparison as
Neoadjuvant Therapy of Inflammatory and Locally
Advanced Breast Cancer
Ellis, # LBA537
Inflammatory or
Locally
Advanced BC
N=265
(IBC 31%)
R
A
N
D
O
M
I
Z
E
A (60 mg/m2) with
C(600 mg/m2) q 3 wks x 5
→ Paclitaxel 80 mg/m2 wkly x 12
A (24/m2/wk) with
C (60/m2/day) + G-CSF wkly x 15
→ Paclitaxel 80 mg/m2 wkly x 12
Primary endpoint: Pathologic CR
S
U
R
G
E
R
Y
SWOG 0012
Results
Standard AC
Continuous AC + G
P
pCR (% at breast)
19%
31%
.03
pCR and node-negative
15%
26%
-
Grade 3/4 AE
Standard AC
Continuous AC + G
Hand-foot syndrome 0
13%
Neutropenia
47%
16%
Febrile Neutropenia
1.8%
0.6%
Stomatitis
2%
11%
Nausea/Vomiting
11%
5%
Ellis, ASCO 2006 # LBA537
S0221 (Intergroup Trial)
Node (+)
and High
Risk Node
(-)
R
a
n
d
o
m
i
z
e
AC + pegfilgrastim q2 wk x 6
A = 60 mg/m2, C = 600 mg/m2
P + pegfilgrastim q2 wk x 6
P = 175 mg/m2
AC + filgrastim wkly x 15
A = 24 mg/m2, C = 60 mg qd
P + pegfilgrastim q2 wk x 6
P = 175 mg/m2
AC + pegfilgrastim q2 wk x 6
A = 60 mg/m2, C = 600 mg/m2
P wkly x 12
P = 80 mg/m2
AC + filgrastim wkly x 15
A = 24 mg/m2, C = 60 mg qd
P wkly x 12
P = 80 mg/m2
Cumulative Doses:
A = 360 mg/m2
C = 3,600 mg/m2(q2) vs. 900 mg(wkly)
P = 1,050 mg/m2(q2) vs. 960 mg/m2(wkly)
Conclusions
• We need to carefully select patients for adjuvant
clinical trials testing different chemotherapy regimens
 Differences in regimens will be magnified in specific
patient groups
• Topoisomerase II gene amplifications and
deletions associated with response to
anthracyclines
• Genes associated with cellular proliferation
correlate with response to chemotherapy
• Aromatase inhibitors should be part of adjuvant
hormonal therapy for postmenopausal women and are
beneficial even late after diagnosis
 Careful attention should be paid not only to side
effects, but risk factors that predispose women to
adverse events
HERA Trial: Median F/U 2 yrs
Women with locally determined HER2positive invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+ or FISH+
and LVEF ≥ 55%
Randomization
Observation
After ASCO 2005,
option of switch
to trastuzumab
1 year trastuzumab
8 mg/kg  6 mg/kg
3 weekly schedule
X
2 years trastuzumab
8 mg/kg  6 mg/kg
3 weekly schedule
861 observation patients
are known to have
switched to trastuzumab
Smith et al, ASCO 2005
Patient Characteristics
% patients
Observation
(n=1698)
Prior (neo)adjuvant CT
No anthracyclines
Anthracyclines, no taxanes
Anthracyclines + taxanes
Hormone receptor status
Negative
Positive
Nodal status
Neoadjuvant CT
Negative
1-3
>4
1 year trastuzumab
(n=1703)
5.9
68.1
26.0
5.9
67.8
26.3
50.4
49.6
50.5
49.5
10.5
32.7
28.9
27.9
11.4
31.9
28.5
28.1
539 events observed in the 2 arms (347 at ASCO 2005)
Disease-free survival (ITT)
Median FU 2 yrs
Patients
(%)
100
1 year trastuzumab
80
Observation
6.3%
60
3-year
Events DFS
40
218
321
20
80.6
74.3
HR
95% CI
p value
0.64 0.54, 0.76 <0.0001
0
No.
at risk
0
6
1703
1698
1591
1535
12
18
24
30
Months from randomisation
1434
1330
1127
984
742
639
383
334
36
140
127
Overall survival (ITT)
Median FU 2 yrs
Patients
(%)
1 year trastuzumab
100
2.7%
Observation
80
60
3-year
OS
Events
40
92.4
89.7
59
90
20
HR
0.66
95% CI
p value
0.47, 0.91 0.0115
0
No.
at risk
0
6
1703
1698
1627
1608
12
18
24
30
Months from randomisation
1498
1453
1190
1097
794
711
407
366
36
146
139
Secondary efficacy end points
(ITT analysis)
Observation
TTR
HR
1 year trastuzumab
TTDR
OS
1.0
0.62
305
198
255
160
0
95% CI
p value (log rank)
3-year percent, %
0.52, 0.74
<0.0001
75.4 vs 82.1
0.66
0.60
0.49, 0.73
<0.0001
79.4 vs 85.7
90
59
0.47, 0.91
0.0115
89.7 vs 92.4
TTR, time to recurrence; TTDR, time to distant recurrence; OS, overall survival
No.
events
Annualized DFS hazards - ITT
observation and 1 year trastuzumab
groups
Hazard Rates
0.2
0.15
0.1
0.05
0
1 to 6
7 to 12
13 to 18 19 to 24 25 to 30 31 to 36
Months since
randomisation
Months
Observation
1 Year Trastuzumab
ADJUVANT TRASTUZUMAB TRIALS
HERA
6000
4000
Total randomized : 13,365
Total analyzed : 10,192
T=trastuzumab
D=Docetaxel
P=paclitaxel
V=Vinorelbine
AC=adriamycin+
cyclophosphamide
N=5102
Analyzed=3387
Chemo
 T 2 year
Chemo
 T 1 year
2000
BCRIG006
N=3222
Analyzed=3222
C +D x 6
+ T 1y
AC x 4
D x 4 + T 1y
Chemo
 Nil
AC x 4
Dx4
0
N9831
N=2766
Analyzed=1736
ACx4P
wk x 12
+ T 1y
ACx4
Pwk x 12
+ T 1y
ACx4P
wk x 12
NSABP-B31
N=2046
Analyzed=1615
FINHER
N=232
Analyzed=232
ACx4Px4
+ T 1y
ACx4 
Px4
D or V+T 9wksFECx3
D or VFEC
F-up (months) 12 m
24 m
24 m
24 m
Control arms w/o trastuzumab (T)
Trastuzumab single agent following anthracycline  taxane
Trastuzumab with taxane following anthracycline regimen
Trastuzumab with chemo, avoiding or preceding anthracycline regimen
39 m
Lapatanib Mechanism of Action
• Binds to intracellular ATP binding site of
EGFR (ErbB-1) and HER2 (ErbB-2)
preventing phosphorylation and activation
Lapatinib
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
Phase I Trial of Lapatanib and Capecitabine vs
Cabecitabine in Advanced or Metastatic Breast
Cancer
• 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
Geyer et al, ASCO 2006
Protocol Specified Interim
Analysis Plan
Per Protocol
Number of
Investigator
Defined TTP
Events Required
for IA:
133 + 10% = 144
321 Patients
Accrued by Time
of Data Lock
IRC
IRC TTP Events
N=321
Imaging &
photograph
assessments
sent to IRC
Number of Events: 114
103 Progressive BC
11 BC Related Deaths
•
IDMC Recommendations
th, 2006
March
20
Agreed with superiority and futility boundaries
• Unanimous recommendation for termination of study
enrollment based on :
“clinically meaningful, statistically significant
advantage in primary endpoint (TTP) in the
capecitabine + lapatinib arm vs capecitabine
alone arm”
• No safety or tolerability concerns
• Accrual as of 3/20/06: 392 of 528
Disease Characteristics and Prior
Treatment
• Patients must have relapsed w/in 6 mo of adjuvant therapy or have
progression of metastatic disease
• Tumor
 35-38% hormone receptor positive
 96% stage IV disease, 50% > 3 metastatic sites
• Prior treatment
 98% prior anthracylines, 98% prior taxanes
 97% prior trastuzumab
• 91-93% metastatic
• 4-6% adjuvant
• 97-99% progressed on prior trastuzumab
• Median duration of prior trastuzumab 43 wks
• No difference in interval from last dose of T to randomization
(66-70% > 4 weeks)
Time to Progession – ITT Population
% of patients free from progression*
Lapatinib +
Capecitabine
100
No. of pts
Progressed or died*
Median TTP, wk
Hazard ratio (95% CI)
90
80
70
Capecitabine
160
45 (28%)
161
69 (43%)
19.7
36.9
0.51 (0.35, 0.74)
P-value (log-rank, 1-sided)
0.00016
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
Cumulative Progression-Free Survival, %
Progression-Free Survival - ITT Population
Lapatinib +
capecitabine
100
No. of pts
Progressed or died
Median PFS, wk
90
80
160
45 (28%)
36.9
Hazard ratio (95% CI)
P-value (log-rank, 1-sided)
70
60
Capecitabine
161
73 (45%)
17.9
0.48 (0.33, 0.70)
0.000045
50
40
30
20
10
0
0
10
20
30
40
Time (weeks)
50
60
70
Response Rate - ITT Population
Lapatinib + Capecitabine
(n=160)
Capecitabine
(n=161)
Complete response
1 (< 1%)
0 (0%)
Partial response
35 (22%)
23 (14%)
Overall response rate*
(95% CI)
22.5%
(16.3 - 29.8)
*P-value (Fisher’s exact, 2-sided) = 0.113
14.3%
(9.3 - 20.7)
Brain Metastases as Site of
Progression
Lapatinib +
Capecitabine
(n=160)
Capecitabine
(n=161)
2
2
4
11
3
10
Patients with CNS
metastases at baseline
Patients with CNS
relapse*
Patients with CNS as
only site of relapse
*P-value (Fisher’s exact, 2-sided) = 0.110
Investigator Assessed Endpoints
ITT Population
No. of pts progressed or died
Median TTP, wk
Hazard ratio for TTP
(95% CI)
P-value (log-rank, 2-sided)
Overall response rate*
(95% CI)
P-value (Fisher’s exact, 2-sided)
Lapatinib +
Capecitabine
(n=160)
Capecitabine
60 (38%)
78 (48%)
25.3
18.9
(n=161)
0.63
(0.44 – 0.89)
0.007
28.8%
(21.9 – 36.4)
16.1%
(10.8 – 22.8)
0.017
Most 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
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
• The planned interim analysis crossed pre-specified reporting
boundary and demonstrated a clinically meaningful and
statistically significant improvement in median TTP
 Lapatinib + capecitabine 8.5 mo vs capecitabine 4.5 mo
• Lapatinib + capecitabine well tolerated; declines in LVEF were
infrequent, asymptomatic, reversible
• Fewer patients developed brain metastases as first site of
progression in the group receiving lapatinib
• Trials evaluating lapatinib in earlier stages of HER2+ breast
cancer are warranted
Phase II Trial of Lapatanib in Patients with
Relapse/Refractory Inflammatory Breast Cancer
Cohort A
ErbB2+
Cohort B
ErbB1+/ErbB2-
Two Stage Green-Dahlberg Design
Pre-treatment tumor biopsy
Administer lapatinib (1500 mg/d)
Clinical Evaluation: according to RECIST criteria and *chest wall/skin
response documented by Canfield digital photography
*(CR: complete resolution of disease; PR >50% reduction; SD 20-49% reduction
Spector et al. ASCO 2006;Abstract 502
Baseline Characteristics/
Demographics
Median age, years (range)
53 (32-79)
Stage of disease
79% Stage IV
21% Stage IIIB
Median prior chemotherapy regimens (range)
4.5 (0-21)
–Prior anthracycline
98% (48/49)
–Prior anthracycline/taxane
78% (38/49)
–Prior anthracycline + taxane/navelbine
86% (42/49)
–Patients in Cohort A treated with trastuzumab
(in countries where trastuzumab is available)
75% (15/20)
Evidence of dermal lymphatic invasion
75%
HER2+
Cohort A
19% HER2 2+
81% HER2 3+
Sites of enrollment
71% N.America/EU/Israel
29% Tunisia
Spector et al. ASCO 2006;Abstract 502
Preliminary Results:
Treatment Response
100%
100% of responders
are ErbB2 (IHC
3+/FISH+)p-ErbB2
positive
17%
PD
PTEN
17%
pending
deficient
21%
SD
58%
PD
50%
62%
62%
100%
PR
69%
0%
clinical
responders
17%
SD
8.3%
Cohort A
ErbB2+
Cohort B
ErbB1+/ErbB2-
24 patients
12 patients
5 enrolled patients were not evaluable (did not express target or died prior to Day 28)
Spector et al. ASCO 2006;Abstract 502
Responses (RECIST and Skin)
Site
Skin
RECIST
US
PR
PR
PR
NA
NA
SD
PR
PR
SD
NA
Canada
PR
PR
PR
SD
PR
PR
Israel
SD
CR
PR
CR
CR
PR
PR
PR
PR
PR
PR
SD
PR
PR
UK
Tunisia
Spector et al. ASCO 2006;Abstract 502
Summary
Summary
Lapatinib monotherapy is clinically active
in heavily pre-treated IBC patients
• 62% response rate in ErbB2 overexpressors
Lapatinib is well tolerated
• Generally grade 1/2 GI and skin toxicity
Preliminary biomarker analysis suggests
• Correlation of ErbB2 (IHC3+ or FISH+) with response
• Responders are more likely to be p-ErbB2 positive
(which appears to correlate with FISH +)
• Co-expression of IGF-IR does not appear to preclude response
• PTEN deficiency does not appear to preclude response
Spector et al. ASCO 2006;Abstract 502
Phase 2 Trial of Lapatanib for Brain
Metastases in Patients with HER2+
Breast Cancer
 Lapatinib given in four week cycles
– 750 mg PO BID
– response assessed every 2 cycles
 Dose modifications
– grade 3 or 4  hold until grade 0 or 1 and
reduce one level
– grade 3 or 4 LVEF dysfunction or interstitial
pneumonitis off study
Lin et al, ASCO 2006, #503
Patients and Toxicity
 39 patients enrolled, all off study by 5/06
 Prior CNS radiation in 95% (37)
– 51% WBRT, 15% SRS, 28% both
 Toxicity
– No grade 4
– 21% grade 3 diarrhea, 22% grade 2
– Other common toxicities
 Fatigue
 Headache
 Mild rash
Best CNS Response (RECIST)
(N=39)
Complete Response (CR)
Partial Response (PR)
0
2 (5.1%)
[95% CI 1% to 17%]
*Both received prior WBRT and SRS
TTP 49 and 23 weeks
16 measurable disease, 4PR
Lin et al. ASCO 2006;Abstract 503
Best CNS Response (RECIST)
(N=39)
Complete Response (CR)
Partial Response (PR)
Baseline
0
2 (5.1%)
Week 8
Lin et al. ASCO 2006;Abstract 503
Conclusions
• Volumetric and PET changes also evaluated
 Significance still unclear but both volume and PET
changes noted
 Volumetric declines greater than 30% in 4 pts, 6 pts 1030%
• Quality of life generally stable at 8 weeks
• Some evidence of clinical activity
 2PR by RECIST
 8 progression free in CNS at 16 weeks
• What do we know about Lapatanib?
 Crosses the blood brain barrier
 Has activity against HER2+ brain metastases
 Is generally well tolerated
 May have activity in prevention of brain metastases?
Cardiac Function in 3127 Patients
Treated with Lapatanib
• Pooled analysis of 10 monotherapy trials and 8
trials of lapatanib in combination with chemotherapy
or anti-hormonal agents
• All studies required EF within institutional range of
normal
 Monitoring at baseline, q8 weeks on treatment
• Length of exposure (3535 including placebo)
 > 6 months in 1090
Perez E., ASCO 2006, #583
Results and Conclusion
•
•
•
•
•
•
Symptomatic LVEF decrease
 Breast cancer: 2 (0.1%)
 Non breast cancer: 2 (0.1%)
Asymptomatic LVEF decrease
 37 (1.2%)
Average duration of LVEF decrease was 40 days
 41% (9/22) with breast cancer recovered while continuing to
receive lapatanib
Avereage decrease relative to baseline was 29%
Potential risk factors
 Mediastinal/left sided radiation
 LVEF on trastuzumab (only 2 pts)
 Prior anthracyclines
 Past significant cardiac history
Overall risk appears to be very low
 1.3% across breast and other malignancies
 Further followup is ongoing
Sponsored and Cooperative Group Trials
with Lapatanib
•
First line metastatic



•
Trastuzumb resistant


•
Lapatanib alone vs lapatanib combined with trastuzumab
Lapatanib with bevacizumab (MSKCC and UCSF collaboration)
Brain metastases

•
Paclitaxel with trastuzumab with or without lapatanib
Aromatase inhibitors with lapatanib
Other chemotherapy combinations
Progression after radiation with lapatanib alone
Cooperative group (pending, will open in 2008)

Neoadjuvant chemotherapy with trastuzumab vs lapatanib vs the
combination (3 arm study)
 Adjuvant trial (Perez et al)
• Chemotherapy with:
• Lapatanib
• Trastuzumab
• The combination
•
Other interesting research directions for HER2+ disease



17AAG (HSP inhibitor)
IGFR inhibitors
MTOR inhibitors (inhibition of the downstream pathway)
Trial Assigning IndividuaLized Options
for Treatment (Rx): TAILORx Trial
Node Neg, ER (+), Breast Cancer
Register
Specimen
banking
RS < 10
Hormone
Therapy
Registry
Target Accrual: >10,000
Oncotype DX Assay
RS 11 – 25
Randomize
Hormone Rx
vs.
Chemotherapy
+ Hormone Rx
Primary study group
RS > 25
Chemotherapy
+
Hormone Rx
The Changing Paradigm of Clinical
Trials in Breast Cancer
Non Selected
Adjuvant Trials in
Breast Cancer