Lapatinib

Report
19th Annual NOCR Meeting
Session I: Breast Cancer
HER-2+ Disease
Christy A Russell, MD
Keck School of Medicine
University of Southern California
HER-2+ Breast Cancer
• Adjuvant and Neoadjuvant Therapy
• Combining Trastuzumab with other HER2directed agents
• Second generation choices
• Novel agents and conjugates
Signal Transduction by the HER Family and
Potential Mechanisms of Action of Trastuzumab
Hudis C. N Engl J Med. 2007;357:39-51.
Metastatic Breast Cancer
Front-line Options
Trastuzumab Combinations as First-line
Therapy for MBC: Pivotal Phase III Trial
Paclitaxel
Patients with
HER2+ (IHC 2+/3+)
MBC, no previous
chemotherapy,
measurable
disease, KPS ≥ 60%
(N = 469)
Previous
adjuvant
AC
(n = 96)
Trastuzumab
+ Paclitaxel
(n = 92)
AC
No previous
adjuvant
AC
(n = 138)
Trastuzumab
+ AC
(n = 143)
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
Trastuzumab in MBC: The Pivotal Trial
Treatment
Objective
Response Rate, %
Median TTP, Mos
Median OS, Mos
Chemo
32
4.6
20.3
Chemo +
Trastuzumab
50
7.4
25.1
P < .001 for all comparisons.
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
Trastuzumab in Recommended First-line
Combinations for HER2+ MBC
• HER2+ disease without previous trastuzumab: trastuzumab
plus
– Paclitaxel ± carboplatin
– Docetaxel
– Vinorelbine
– Capecitabine
NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.
Trastuzumab in Triple-Combination
Regimens: Response Rates
Yardley et al, 2004 (N = 24)
H+V+T
Untch et al, 2004 (N = 25)
H + E90 + C
Untch et al, 2004 (N = 26)
H + E60 + C
Dirix et al, 2006 (N = 34)
H + Carbo + T
Chan et al, 2007 (N = 34)
H+V+X
Fountzilas et al, 2004 (N = 40)
H+G+P
Yardley et al, 2006 (N = 41)
H + G + Carbo
Miller et al, 2002 (N = 45)
H+G+P
Venturini et al, 2006 (N = 45)
H+E+T
Perez et al, 2005 (N = 43)
H + Carbo + P every 3 wks
Perez et al, 2005 (N = 48)
H + Carbo + P every wk
Cortes et al, 2004 (N = 54)
H + TLC D-99 + P
Yardley et al, 2002 (N = 61)
H + Carbo + T
Pegram et al, 2004 (N = 59)
H + Carbo + T
Pegram et al, 2004 (N = 62)
H + Cisplatin + T
Robert et al, 2006 (N = 92)
H + Carbo + P
Wardley et al, 2006 (N = 111)
H+X+T
Forbes et al, 2006 (N = 130)
H + Carbo + T
0
10
20
30
40
50
ORR (%)
60
70
80
90
100
Hormonal Therapy in HER2+ MBC
Regimen
ORR, %
PFS, Mos
Trastuzumab (N = 79)[1]
26
3.5-3.8
Anastrozole + trastuzumab (N = 103)[2]
20
4.8
Anastrozole (N = 104)[2]
7
2.4
Lapatinib + letrozole (N = 642)[3]
28
8.2
Letrozole (N = 644)[3]
15
3.0
Lapatinib (N = 138)[4]
24
NA
1. Vogel C, et al. J Clin Oncol. 2002;20:719-726.
2. Mackey JR, et al. SABCS 2006. Abstract 3.
3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.
4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
Mechanism of Action of Lapatinib
Compared to Trastuzumab
Trastuzumab
T
1
1
2
2
1
2
L
L
L
L
L
L
Erb
receptors
Downstream signaling pathways
Cell proliferation Cell survival
Lapatinib
Lapatinib as First-line Treatment for HER2Amplified LABC or MBC
 Patients (N = 138) randomized to 2 schedules of lapatinib
monotherapy
Endpoint
Lapatinib
1500 mg/day
(n = 69)
Lapatinib
500 mg BID
(n = 69)
All Patients
(N = 138)
Response rate, n (%)
15 (22)
18 (26)
33 (24)
Clinical benefit rate, n (%)
20 (29)
23 (33)
43 (31)
41
45
43
6-mo PFS, %
 Median time to response (all patients): 7.9 wks; median duration
of response (all patients): 28.4 wks
 Safety: only grade 1/2 asymptomatic cardiac adverse events
(4 patients)
Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
Trastuzumab vs Lapatinib
First-Line Therapy for MBC
MA.31/EGF108919: Design
Randomize
Experimental Arm
24 Wks:
Lapatinib
+
taxane
Standard Arm
Until PD:
Lapatinib
24 Wks:
Trastuzumab
+
taxane
Until PD:
Trastuzumab
Primary Outcome: PFS
Sample size: ~ 600 (536 patients centrally confirmed with HER2+)
ClinicalTrials.gov. NCT00667251.
Gelmon, ASCO 2012
[TITLE]
NCCN: Treatment of HER2+ MBC Beyond First
Line With Previous Trastuzumab Exposure
• Continued HER2 blockade
– Chemotherapy + trastuzumab
– Trastuzumab + lapatinib
– Capecitabine + lapatinib
NCCN. Clinical practice guidelines in oncology: breast cancer. v.3.2012.
EGF100151 Phase III Study: Lapatinib +
Capecitabine in Advanced Breast Cancer
Patients with HER2+
progressive MBC or
stage IIIB/IIIC LABC with
T4 lesion and unlimited
previous therapies*
Lapatinib
1250 mg/day PO +
Capecitabine
2000 mg/m2/day on
Days 1-14 every 21 days
Capecitabine
2500 mg/m2/day on
Days 1-14 every 21 days
 Primary endpoint: TTP
 Secondary endpoints: OS, PFS, ORR
*No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or
adjuvant).
Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
100
TTP With 1 Previous Trastuzumab Regimen
80
Capecitabine
Lapatinib + capecitabine
60
40
20
0
0
20
40
Wks
60
80
Cumulative Progression Free (%)
Cumulative Progression Free (%)
Lapatinib + Capecitabine in HER2+ MBC:
TTP
TTP With > 1 Previous Trastuzumab
Regimen
100
80
Capecitabine
Lapatinib + capecitabine
60
40
20
0
0
20
40
Wks
60
Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced
breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed
through Copyright Clearance Center, Inc.
Cameron D, et al. Oncologist. 2010;15:924-934.
80
Lapatinib + Capecitabine in HER2+ MBC:
Efficacy
Result
Capecitabine
(n = 201)
Capecitabine +
Lapatinib
(n = 207†)
HR
P Value
Median TTP, wks[1]
18.6
31.3
0.50
< .001
OS, wks[1]
56.6
71.4
0.79
.077
ORR, %[2]
13.9
23.7
--
.017
13 (6)
4 (2)
--
.045
Brain mets as site of first
progression,* n (%)[2]
† n=198
in 2008 study.
*Exploratory analysis.
1. Cameron D, et al. Oncologist. 2010;15:924-934
2. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.
Tumor Volume (mm3)
Combining Lapatinib and Trastuzumab
Increases Antitumor Activity
1600
1400

1200
1000
800
Control
Trastuzumab
Lapatinib
Trastuzumab + lapatinib
*
*
†‡
600
400
200
†
†
§
0

13
16
19
21
23
Days After Injection
*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab;
§P < .01 vs both lapatinib and trastuzumab.
– Effect was durable: no tumor relapse
observed at 8 mos after treatment
Lapatinib induced accumulation of
inactive HER2 at plasma membrane
– Trastuzumab-mediated cytotoxicity
was higher with the addition of
lapatinib in MCF7/HER2 cells

Reprinted by permission from Macmillan Publishers Ltd:
Oncogene; Scaltriti, et al. 28:803-814, copyright 2009.
Treatment with lapatinib plus
trastuzumab resulted in complete
tumor remission in mouse model
In vivo activity was consistent with in
vitro data demonstrating the
combination as synergistic
Scaltriti M, et al. Oncogene. 2009;28:803-814.
Konecny GE, et al. Cancer Res. 2006;66:16301639. Xia W, et al. Oncogene. 2004;23:646-653.
Pivotal Trial EGF104900
Lapatinib 1500 mg/day PO
Patient Population
 HER2+ MBC
 Multiple lines of
trastuzumab
 Progression on
trastuzumab at
study entry
R
Crossover at the time of
progressive disease
Lapatinib 1000 mg/day PO +
trastuzumab 4 mg/kg then
2 mg/kg IV q wk
Primary endpoint: PFS
Secondary endpoints: OS, ORR, CBR
Blackwell KL, et al. J Clin Oncol. 2012;30:2585-2592.
Lapatinib ± Trastuzumab in MBC: PFS
Outcome
Lapatinib
(n = 145)
Lapatinib/
Trastuzumab
(n = 146)
HR
(95% CI)
P Value
6-mos PFS, %
13
28
0.73
(0.57-0.93)
.008
Progressed or died, n
128
127
--
--
Median PFS, wks
8.1
12.0
--
--
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
EGF104900: Overall Survival
L+T
(n = 148)
L
(n = 148)
n
146
145
Median OS, mos
14.0
9.5
100
80%
Survival(%)
80
HR (95% CI)
70%
60
56%
6-mo OS
40
0.74 (0.57-0.97)
Stratified log-rank P value
.026
52% of patients in the L arm crossed over to L + T
41%
12-mo OS
20
0
0
Pts at risk, n
Lap 1000/Tras 146
Lap 1500 145
5
120
100
10
25
15
20
Mos From Randomization
30
87
64
1
Blackwell KL, et al. J Clin Oncol. 2012;30:2585-2592.
63
46
42
28
25
13
35
Trastuzumab Beyond Progression in HER2+
MBC: BIG 03-05 Phase III Trial
Patients with progressive MBC or
LABC, HER2 overexpression, previous
trastuzumab within 6 wks,
and LVEF ≥ 50
(N = 156*)
 Primary endpoint: TTP
Trastuzumab
6 mg/kg every 3 wks +
Capecitabine
2500 mg/m2/day on
Days 1-14 every 21 days
(n = 78)
Capecitabine
2500 mg/m2/day on
Days 1-14 every 21 days
(n = 78)
 Secondary endpoints: OS, ORR, safety
*Study closed at 156 patients due to slow accrual following FDA approval of lapatinib for this indication.
von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.
BIG 03-05: Trastuzumab Beyond
Progression in HER2+ MBC
PFS
X
XH
Censored
Log-rank P = .0338
Probability of PFS
0.8
OS
1.0
0.6
0.4
0.2
X
XH
Censored
Log-rank P = .2570
0.8
Probability of OS
1.0
0.6
0.4
0.2
0
0
0
10
20
Mos
30
40
0
10
Pts at Risk, n
Pts at Risk, n
X 74
40
15
8
5
3
2
1
1
X 74
66
50
33
XH 77
55
29
12
4
3
1
1
1
XH 77
68
59
47
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.
20
Mos
21
27
30
10
15
3
6
40
3
1
2
1
New Option in the Front-Line:
Pertuzumab
Pertuzumab and Trastuzumab:
Mechanisms of Action
Pertuzumab
HER2
Trastuzumab
HER1/3/4
Dimerization
domain
Subdomain IV
Trastuzumab:
 Inhibits ligand-independent HER2 signaling
 Activates ADCC
 Prevents HER2 ECD shedding
Pertuzumab:
 Inhibits ligand-dependent HER2
dimerization and signaling
 Activates ADCC
Ferguson KM, et al. Mol Cell. 2003;11:507-517. Olayioye MA, et al. EMBO J. 2000;19:3159-3167.
Hynes NE, et al. Nat Rev Cancer. 2005;5:341-354. Rowinsky EK. Annu Rev Med. 2004;55:433-457.
Phase II Trial of Pertuzumab + Trastuzumab
in HER2+ MBC: Efficacy
60
SD
PR
CR
Patients (%)
50
40
Responses were durable:
 Median duration of response:
5.8 mos
 Median PFS (all patients):
5.5 mos
30
20
10
0
All Patients (N = 66)
Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.
CLEOPATRA Study Design
Docetaxel (≥ 6 cycles recommended)
Centrally confirmed HER2positive locally recurrent,
unresectable or MBC
N = 406
Trastuzumab
≤ 1 hormonal regimen for MBC
Prior (neo)adjuvant
systemic Rx, including
trastuzumab and/or taxane
allowed if followed by DFS
≥ 12 mos
R
Baseline LVEF ≥ 50%; no CHF
or LVEF < 50% during
or after previous trastuzumab
Placebo
1:1
Docetaxel (≥ 6 cycles recommended)
Trastuzumab
N = 402
Pertuzumab
Primary endpoint: Independently
assessed PFS
Baselga J, et al. N Engl J Med. 2012;366:109-119.
CLEOPATRA: Progression-Free Survival
Independently
Assessed
Median PFS
Pertuzumab,
Mos
(n = 402)
Placebo,
Mos
(n = 406)
HR
P Value
18.5
12.4
0.62
< .001
Baselga J, et al. N Engl J Med. 2012;366:109-119.
CLEOPATRA: Overall Survival (Confirmatory
Analysis)
Pertuzumab, % Placebo, %
(n = 402)
(n = 406)
Median
OS, mos
NR
Swain SM, et al. SABCS 2012. Abstract P5-18-26.
37.6
HR
P Value
0.66
.0008
CLEOPATRA: Safety Results
Select Adverse Events (Grade ≥ 3), % Pertuzumab Placebo
(n = 407)
(n = 397)
Neutropenia
48.9
45.8
Febrile neutropenia
13.8
7.6
Leukopenia
12.3
14.6
Diarrhea
7.9
5.0
Peripheral neuropathy
2.7
1.8
Left ventricular systolic dysfunction
1.2
2.8
Baselga J, et al. N Engl J Med. 2012;366:109-119.
NCCN: First-line Treatment of HER2+ MBC
With No Previous Trastuzumab Exposure
 Preferred regimens
– Docetaxel + trastuzumab + pertuzumab (category
1)
– Paclitaxel + trastuzumab + pertuzumab
 Other regimens
– Chemotherapy + trastuzumab
NCCN. Clinical practice guidelines in oncology: breast cancer. V.1.2013.
Second-line and Further Therapy
TDM-1
Trastuzumab/Emtansine: Novel Antibody–
Drug Conjugate
Target expression: HER2
Monoclonal antibody: trastuzumab
Trastuzumab
Cytotoxic agent: emtansine (DM1)
Highly potent cytotoxic agent
DM1
MCC
Linker: SMCC
T-DM1
Systemically stable
Average drug:antibody
ratio ≅ 3.5:1
EMILIA Phase III Study: T-DM1 vs
Lapatinib/Capecitabine in HER2+ MBC
Stratified by world region, number of previous
chemotherapy regimens for MBC or unresectable
locally advanced breast cancer, presence of
visceral disease
Patients with
HER2-positive
locally advanced
or MBC*
(N = 980)
*All pts received previous
taxane and trastuzumab
T-DM1 3.6 mg/kg by IV every 3 wks
(n = 495)
PD
Capecitabine 1000 mg/m2 orally twice daily
on Days 1-14, every 3 wks +
Lapatinib 1250 mg/day orally continuously
(n = 496)
 Primary endpoint: PFS by IRF, OS, safety
 Secondary endpoints: QoL (FACT B), DOR, PFS by investigator assessment
Verma S, et al. NEJM 2012;367:1783-91.
T-DM1 vs Lapatinib/Capecitabine in HER2+
MBC (EMILIA): PFS
Median, Mos
Proportion Progression Free
1.0
Capecitabine/lapatinib
T-DM1
0.8
6.4
9.6
Events, n
304
265
Stratified HR: 0.650 (95% CI: 0.55-0.77;
P < .0001)
0.6
0.4
T-DM1
Capecitabine/
lapatinib
0.2
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30
Mos
Verma S, et al. NEJM 2012;367:1783-91.
Overall Survival – Second Interim Analysis
Verma S, et al. NEJM 2012;367:1783-91.
T-DM1 vs Lapatinib/Capecitabine in HER2+
MBC (EMILIA): Adverse Events
T-DM1
(n = 490)
Adverse Event, %
Capecitabine + Lapatinib
(n = 488)
All Grades
Grades ≥ 3
All Grades
Grades ≥ 3
 Diarrhea
23.3
1.6
79.7
20.7
 Hand-foot syndrome
1.2
0
58.0
16.4
 Vomiting
19.0
0.8
29.3
4.5
 Hypokalemia
8.6
2.2
8.6
4.1
 Fatigue
35.1
2.4
27.9
3.5
 Nausea
39.2
0.8
44.7
2.5
 Mucosal inflammation
6.7
0.2
19.1
2.3
 Increased AST
22.4
4.3
9.4
0.8
 Increased ALT
16.9
2.9
8.8
1.4
5.9
2.0
8.6
4.3
0
0
1.0
1.0
 Anemia
10.4
2.7
8.0
1.6
 Thrombocytopenia
28.0
12.8
2.5
0.2
Nonhematologic
Hematologic
 Neutropenia
 Febrile neutropenia
Verma S, et al. NEJM 2012;367:1783-91.
T-DM1 vs Lapatinib/Capecitabine in HER2+
MBC (EMILIA): Expert Perspectives
• T-DM1 showed improved efficacy vs
capecitabine plus lapatinib
– Significant PFS improvement (HR: 0.650; P <
.0001)
– OS benefit (HR: 0.68; P =<0.001)
• Favorable safety profile
• T-DM1 is an important new therapeutic option
for patients with HER2+ MBC that has been
previously treated with trastuzumab.
Verma S, et al. NEJM 2012;367:1783-91.
Ongoing Clinical Trials
for Metastatic Breast Cancer
Phase III MARIANNE Study: T-DM1 ±
Pertuzumab in HER2+ MBC
PD
Trastuzumab + Taxane
(n = 364)
Patients with HER2+, previously
untreated MBC
T-DM1 + Pertuzumab
(n = 364)
(N = 1092)
T-DM1 + Placebo
(n = 364)
• Primary endpoints: PFS as assessed by IRF, AEs
– Superiority design with a noninferiority analyses
– Interim futility analysis: option to drop experimental arm
• Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR
ClinicalTrials.gov. NCT01120184.
mTOR Inhibition May Overcome
Trastuzumab Resistance
IGF-1R
Nutrients
Increased signaling through IGF-1R
EGFR/HER2
Truncated HER2
PI3K
PTEN
Constitutive PI3K/AKT activation
LKB1
AKT
Absent or low PTEN
AMPK
TSC1 TSC2
Elevated AKT or pAKT
RHEB
Growth &
proliferation
Angiogenesis
mTOR mTOR inhibitor
Cell
metabolism
Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.
Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.
 Downstream inhibition with mTOR inhibitor
counters these resistance mechanisms
 Synergy of mTOR inhibition and
trastuzumab in vitro and in vivo
BOLERO-1 Phase III Study: Paclitaxel +
Trastuzumab  Everolimus in HER2+ MBC
Stratification by previous adjuvant or
neoadjuvant trastuzumab
and presence of visceral metastases
Patients with HER2overexpressing, unresectable
locally advanced or metastatic
breast cancer, no previous
trastuzumab or chemotherapy
within 12 mos for
advanced disease
28-day cycle
2:1
(N = 717)
Everolimus 10 mg/day PO +
Paclitaxel 80 mg/m2 on Days 1, 8, 15 +
Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22
Paclitaxel 80 mg/m2 on Days 1, 8, 15 +
Trastuzumab 4 mg → 2 mg/kg on Days 1, 8, 15, 22
+ Placebo PO daily
 Primary endpoint: PFS
 Secondary endpoints: OS, ORR, CBR, safety, PK, biomarkers
ClinicalTrials.gov. NCT00876395.
Conclusions
• Multiple effective and available options in
HER2+ MBC
– Trastuzumab
– Pertuzumab
– Lapatinib
• Preferred first-line regimens include dual
HER2 inhibition with pertuzumab and
trastuzumab
• Other HER2 inhibition agents continue to
have a role outside the first-line setting
including the new availability of TDM-1.
Early Stage HER-2+ Breast Cancer
Neo-Adjuvant Therapy
GeparQuinto: HER2-Positive
Doc
Trastuzumab (T)
R
EC
T for 6 mos
Doc*
Lapatinib (L)
E:
C:
Doc:
Surgery
Core biopsy
EC
(d21-d35 after last infusion)
(n=615)
Epirubicin 90 mg/m²
Cyclophosphamide 600 mg/m²
Docetaxel 100mg/m² *+ G-CSF
T for 12 mos
T:
Trastuzumab 6 (8) mg/kg
L:
1000-1250 mg/d p.o.
(all 3 week cycles)
This presentation is the intellectual property of the author/presenter.
Contact them for permission to reprint and/or distribute.
Untch M, et al. Cancer Res. 2010;70(Nr. 24 Suppl):81s. Abstract # S3-1.
pCR Rates According to
Other Definitions
No invasive residual
in breast & nodes
No invasive residual
in breast
P<0.05
This presentation is the intellectual property of the author/presenter.
Contact them for permission to reprint and/or distribute.
Untch M, et al. Cancer Res. 2010;70(Nr. 24 Suppl):81s. Abstract # S3-1.
P<0.05
Neo-ALTTO Trial
José Baselga, Ian Bradbury, Holger Eidtmann, Serena DiCosimo, Claudia
Aura, Evandro de Azambuja, Henry Gomez, Phuong Dinh, Karine Fauria,
Veerle Van Dooren, Paolo Paoletti, Aron Goldhirsch, Tsai-Wang Chang,
Istvan Lang, Michael Untch, Richard D. Gelber and Martine Piccart-Gebhert
on behalf of the Neo-ALTTO Study Team
December 10, 2010
*FDA approved in combination with capecitabine, for the treatment of patients with advanced or
metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy
including an anthracycline, a taxane, and trastuzumab.
Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
Study Design
Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
Efficacy – pCR and to tpCR
Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
pCR by Hormone Receptor Status
Baselga J, et al. Cancer Res. 2010;70 (24 Suppl): Abstract S3-3.
*Pertuzumab is not approved by the FDA for treatment of breast cancer.
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
NeoSphere Study Design and Objectives
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
NeoSphere pCR Rates:
ITT Population Summary
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
NeoSphere: pCR and Hormone Receptors
Status
Gianni L, et al. Cancer Res. 2010;70 (24 Suppl): Abstract [S3-2].
NSABP B-41: Lapatinib in Neoadjuvant
Treatment of HER2+ Breast Cancer
Tissue biopsy for
biomarker analysis
Patients with
HER2+,
operable
breast
cancer
(N = 529)
Doxorubicin/Cyclophosphamide 60/600 mg/m2
q21d x 4 cycles →
Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles +
Trastuzumab weekly until 1 wk before surgery
(n = 178)
Doxorubicin/Cyclophosphamide 60/600 mg/m2
q21d x 4 cycles →
Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles +
Lapatinib 1250 mg/day until 1 day before surgery
(n = 173)
Tissue biopsy for
biomarker analysis
Surgery
Trastuzumab
1 yr
Doxorubicin/Cyclophosphamide 60/600 mg/m2
q21d x 4 cycles →
Weekly Paclitaxel 80 mg/m2 q28d x 4 cycles +
Trastuzumab weekly until 1 wk before surgery +
Lapatinib 750 mg/day until 1 day before surgery
(n = 173)
•
Primary endpoint: pCR
Robidoux A, et al. ASCO 2012. Abstract LBA506.
•
Secondary endpoints: pCR in N0, toxicity, cCR, RFS, OS
Lapatinib in Neoadjuvant Treatment of
HER2+ Breast Cancer (NSABP B-41): pCR
Regimen
P Value†
n
pCR*, %
AC → WP + T
176
49.4
AC → WP + L
171
47.4
.78
AC → WP + T + L
171
60.2
.056
*Absence of invasive tumor in resected breast specimen and histologically negative
axillary nodes.
†Relative to AC → WP + T regimen.
Robidoux A, et al. ASCO 2012. Abstract LBA506.
Adjuvant HER-2 Targeted Therapy
NCCTG N9831 Trial Incorporating Trastuzumab in
Adjuvant Therapy
Group A
HER2 positive
(FISH+ or
IHC 3+)
n=3,505
R
A
N
D
O
M
I
Z
E
AC
T
Group B
AC
T
H
Group C
AC
T
H
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)
CP1270832-60
NSABP B-31 Trial Incorporating Trastuzumab in
Adjuvant Therapy
Group 1
Node positive
HER2 positive
(FISH+ or
IHC 3+)
N=2,006
R
A
N
D
O
M
I
Z
E
AC
T
Group 2
AC
T
H
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)
CP1270832-61
Joint Analysis of HER2+ Adjuvant Trials
2 Arms of N9831 + B-31
Control Group (n=1,979): AC  T
N9831 Group A AC
B-31 Group 1 AC
T
T
Trastuzumab Group (n=1,989): AC  T+H
N9831 Group C AC
T
H
B-31 Group 2 AC
T
H
= AC
=T
=T
=H
CP1270832-62
(doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
(paclitaxel 80 mg/m2/wk × 12)
(paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2/wk × 12)
(trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51)
N9831 and NSABP B-31 Update
Kaplan-Meier estimates of (A) event-free survival and (B) overall survival.
P < .001
HR 0.52
P < .001
HR 0.61
©2011 by American Society of Clinical Oncology
Perez E A et al. JCO 2011;29:3366-3373
N9831 and NSABP B-31 Update
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
Events Per Year From Randomizaton
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
BCIRG 006 Update
Breast Cancer International Research Group
(BCIRG) 006 Trial: Treatment Schema
HER2-positive
tumor (FISH+);
node-positive
or high-risk
node-negative
disease
S
U
R
G
E
R
Y
R
A
N
D
O
M
I
Z
E
AC
T (n=1073)
AC
TH (n=1074)
52 weeks
TCH (n=1075)
52 weeks
Endpoints
1°: Disease-free survival (DFS)
2°: Overall survival, toxicity, pathologic and molecular
markers
= H = Trastuzumab 4 mg/kg loading dose
= AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w
= H = Trastuzumab 2 mg/kg qw
= T = docetaxel 100 mg/m2 q3w
= H = Trastuzumab 6 mg/kg q3w
= TC = docetaxel 75 mg/m2/carboplatin target AUC 6 mg/mL· min
Radiation therapy and/or hormonal therapy may be given after completion of chemotherapy if indicated
Slamon et al. 29th Annual San Antonio Breast Cancer Symposium, 2005; Herceptin ® (trastuzumab) PI.
March 2009.
68
Disease-Free Survival Among all Study Patients
DFS
AC-TH vs AC-T
HR .64 p<0.001
TCH vs AC-T
HR .75 p=0.04
OS
AC-TH vs AC-T
HR .63 p<0.001
TCH vs AC-T
HR .77 p=0.04
Overall
OverallSurvival
Survival
DFS by Nodal Status at Randomization
DFS by Nodal Status at Randomization
Role of Anthracyclines?
Controversies in Use of Anthracyclines
• Authors suggest TCH should not be a
preferred regimen for HER2+ early breast
cancer.
– BCIRG 006 not powered to show equivalence or
non-inferiority between the two H-based
regimens
– Numerically fewer recurrences and deaths in the
ACTH arm than TCH.
Controversies in Use of Anthracyclines
• Authors encourage use of anthracycline-based
adjuvant trastuzumab regimens as a mainstay
of therapy for women with higher-risk HER2+
tumors.
• TCH should only be considered for women
with lower-risk HER2+ tumors or in women
with clinical reasons to avoid anthracyclines.
Duration of Trastuzumab
Pending Clinical Trials
BETH Phase III Study: Chemotherapy +
Trastuzumab ± Bevacizumab
TCH
HER2+, N+ or
high-risk N-
6 x docetaxel and carboplatin
RT
(Group 1A)
1 yr of trastuzumab
Stratified by Ns
and HRS
6 x docetaxel and carboplatin
(N ~ 3500)
TCHB
RT
(Group 1B)
1 yr of trastuzumab

Primary endpoint: IDFS

Secondary endpoints: DFS, OS, RFI, DRFI, toxicity
ClinicalTrials.gov. NCT00625898.
1 yr of bevacizumab
ALTTO Trial Design
Women with
centrally
determined
HER2positive
invasive
breast cancer
(N = 8381
accrued)
Trastuzumab 8 mg/kg IV (loading dose)*  6 mg/kg
every 3 wks for 1 yr 
Paclitaxel 80 mg/m2 IV once wkly x 12
Surgery,
adjuvant
anthracyclinebased
therapy for
4 cycles;
LVEF ≥ 50
*For concomitant dosing with paclitaxel,
trastuzumab will be given on a weekly
schedule (4 mg/kg IV loading dose
followed by 2 mg/kg IV weekly).
Trastuzumab will revert to the 3-weekly
schedule (6 mg/kg without loading dose).
6-week wash-out
Trastuzumab 4 mg/kg IV
(loading dose)  2 mg/kg
once wkly x 11 
Paclitaxel 80 mg/m2 IV
once wkly x 12
Lapatinib
1500 mg orally
once daily x
34 wks
Lapatinib 1500 mg/kg orally once daily x 51 wks 
Paclitaxel 80 mg/m2 IV once wkly x 12
(This arm closed in 9/2011 due to inferiority)
Trastuzumab 8 mg/kg (loading dose)  6 mg/kg
every 3 wks for 1 yr
Lapatinib 1000 mg orally once daily x 51 wks 
Paclitaxel 80 mg/m2 IV once wkly x 12
APHINITY: Study Schema
N = 3806
S
U
R
G
E
R
Y
Central
confirmation
of HER2
status
Randomization
within 7 wks
of surgery
R
A
N
D
O
M
I
Z
A
T
I
O
N
Start
treatment
within
1 wk
ClinicalTrials.gov Identifier: NCT01358877
Chemotherapy + trastuzumab
and pertuzumab
Anthracycline or non-anthracycline–based
chemotherapy allowed
F
O
L
L
O
W
U
P
Chemotherapy + trastuzumab
and placebo
Anthracycline or non-anthracycline–based
chemotherapy allowed
Anti-HER2 therapy for a total of 1 yr (52 wks)
Radiotherapy and/or endocrine therapy may be started
at the end of adjuvant chemotherapy
10
Y
R
S
Conclusions
• Trastuzumab in addition to chemotherapy
remains the standard for all “high-risk” HER-2+
early breast cancer.
• Controversies exist regarding the following:
– Use of anthracyclines
– Definition of “high-risk”
– Role of additional biologic agents to trastuzumab
– Optimal duration of trastuzumab
Final Thoughts
• The addition of anti-HER2 therapy has changed
the natural history of HER2+ early and metastatic
breast cancer.
• Combining different anti-HER2 agents in these
settings also appears to have an improved
outcome.
• Pertuzumab and TDM-1 are newly approved for
women with HER2+ metastatic breast cancer.
• Their role in the adjuvant/neoadjuvant setting
depends upon the maturation of current clinical
trials.

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