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New Directions in the Treatment
of Patients With HER2-Positive
Breast Cancer
This program is supported by an educational grant from
Image: Dr. Torsten Wittmann/Copyright©2010 Photo Researchers, Inc. All Rights Reserved
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New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Faculty
Dennis J. Slamon, MD, PhD
Professor and Chief
Division of Hematology/Oncology
Department of Internal Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
Sara Hurvitz, MD
Assistant Professor of Medicine
Director, Breast Oncology Program
Division of Hematology-Oncology
Department of Internal Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
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Disclosure of Conflicts of Interest
 Postgraduate Institute for Medicine (PIM) assesses conflict
of interest with its instructors, planners, managers, and other
individuals who are in a position to control the content of
CME activities. All relevant conflicts of interest that are identified
are thoroughly vetted by PIM for fair balance, scientific
objectivity of studies utilized in this activity, and patient care
recommendations. PIM is committed to providing its learners
with high-quality CME activities and related materials that
promote improvements or quality in healthcare and not
a specific proprietary business interest of a commercial interest.
 The faculty and CCO staff reported the following financial
relationships or relationships to products or devices they or their
spouse/life partner have with commercial interests related to the
content of this CME activity.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Disclosures
Dennis J. Slamon, MD, PhD, has disclosed that he has
served on advisory boards for GlaxoSmithKline and
Roche/Genentech.
Sara Hurvitz, MD, has disclosed that she has received
consulting fees from Abraxis, fees for non-CME services
from Abraxis and Bristol-Myers Squibb, and contracted
research from Roche/Genentech.
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Disclosures
Jennifer Swanson; Edward King, MA; Andrew D.
Bowser; Gordon Kelley; Jennifer M. Blanchette, PhD;
and Jim Mortimer have no significant financial relationships
to disclose.
The following planners and managers, Jan Hixon, RN, BSN,
MA; Trace Hutchison, PharmD; Julia Kimball, RN, BSN;
Samantha Mattiucci, PharmD; Jan Schultz, RN, MSN,
CCMEP; and Patricia Staples, MSN, NP-C, CCRN, hereby
state that they or their spouse/life partner do not have any
financial relationships or relationships to products or devices
with any commercial interest related to the content of this
activity of any amount during the past 12 months.
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Disclosure of Unlabeled Use
 This educational activity may contain discussion of
published and/or investigational uses of agents that are
not indicated by the FDA. Postgraduate Institute for
Medicine (PIM) and Clinical Care Options, LLC do not
recommend the use of any agent outside of the labeled
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 The opinions expressed in the educational activity are
those of the faculty and do not necessarily represent the
views of PIM and Clinical Care Options, LLC. Please refer
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New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Goal
The goal of this activity is to provide participants with practical approaches on
managing patients with HER2-positive metastatic breast cancer.
Target Audience
This program is intended for physicians and other healthcare providers
who care for patients with breast cancer.
Learning Objectives
At the conclusion of this activity, participants should be able to:

Distinguish between the mechanisms of action and rationale for HER2-targeting
approaches that have demonstrated efficacy in patients with HER2-positive breast
cancer

Select treatment plans for patients with HER2-positive metastatic breast cancer based
on available data on best management approaches

Formulate treatment approaches for women with breast cancer that progresses after
treatment with HER2-targeted therapy

Discuss with patients agents in development for the treatment of HER2-positive
metastatic breast cancer for which clinical trials may be available
Case 1
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Case 1: Woman With MBC and No
Previous Trastuzumab
 Presentation: 58-yr-old woman was found to have
architectural distortion in the right breast, upper outer
quadrant, on routine screening mammography
– Core needle biopsy confirmed invasive ductal carcinoma,
estimated by imaging to be a T1 lesion
 Treatment: She underwent lumpectomy/SLNB that
revealed a 0.9-cm intermediate-grade invasive ductal
carcinoma that was ER+/PgR+/HER2+ by FISH, with a
Ki-67 value of 30%
– 2 sentinel nodes were removed and found to be uninvolved
by cancer
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 1: Woman With MBC and No
Previous Trastuzumab
 Follow-up: She received adjuvant radiation therapy followed by
letrozole for 1 yr, at which time she was seen by her oncologist for
new cough and mild shortness of breath
– CT scan of the chest revealed a mild right pleural effusion and several
nodules up to 1 cm in size in the right, middle, and lower lobes
– Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC,
consistent with breast primary
– No other metastases were detected by CT or bone scan
 There are no clinical trials available at your center for which she is
eligible. You review multiple treatment options with her and she tells
you she would like to take the treatment that has the highest chance of
leading to a response and to a prolonged survival, as she recently
found out her daughter is pregnant with her first grandchild
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 1: Woman With MBC and No
Previous Trastuzumab
What treatment option would you recommend at this time?
A. Trastuzumab plus chemotherapy
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 1: Woman With MBC and No
Previous Trastuzumab
What treatment option would you recommend at this time?
A. Trastuzumab plus chemotherapy (preferred choice)
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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HER2 Overexpression in Breast Cancer
HER2 is overexpressed in
~ 25% of breast cancers
Normal (1x)
~ 25,000-50,000 HER2
receptors
Overexpressed
HER2 (10-100x)
up to ~ 2,000,000
HER2 receptors
Pegram MD, et al. Cancer Treat Res. 2000;103:57-75.
Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71.
Slamon DJ, et al. Science. 1987;235:177-182.
Excessive cellular division
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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HER2 Overexpression Shortens Survival
HER2 oncogene
amplification
HER2 oncoprotein
overexpression
Shortened survival
Slamon DJ, et al. Science. 1987;235:177-182.
Slamon DJ, et al. Science. 1989;244:707-712.
Median Survival From First Diagnosis
HER2 overexpressing
3 yrs
HER2 normal
6-7 yrs
HER2-Targeted Agents
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Trastuzumab: Mechanism of Action
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Single-Agent Trastuzumab in First-line
Treatment of HER2+ MBC
Patients
Response Rate, %
Median Time to
Progression, Mos
HER2+ by IHC
(N = 111)
26
3.5
HER2+ by FISH
(n = 79)
34
4.9
Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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 3 comparisons.
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
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Trastuzumab in Recommended First-line
Combinations for HER2+ MBC
 HER2+ disease without previous trastuzumab: trastuzumab
plus
– Paclitaxel ± carboplatin
– Docetaxel
– Vinorelbine
– Capecitabine
 HER2+ disease with previous trastuzumab: trastuzumab plus
– Other first-line agents
– Capecitabine
– Lapatinib (without cytotoxic therapy)
NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Addition of Carboplatin to Docetaxel/
Trastuzumab Does Not Improve Efficacy
 BCIRG 007 phase III study (N = 263 patients with HER2-amplified
MBC)
 No significant differences seen in responses, survival, or TTP
– Differences in docetaxel dose between 2 groups
Outcome
Docetaxel/Carboplatin/
Trastuzumab (n = 132)
Docetaxel/Trastuzumab
(n = 131)
ORR, %
72
72
 PR
55
54
 CR
17
18
Median TTP, mos
10.35
11.07
Median OS, mos
37.4
37.1
Valero V, et al. J Clin Oncol. 2011;29:149-156.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Lapatinib Blocks Signaling Through
Multiple Receptor Combinations
 Blocks signaling through
ErbB1 and ErbB2 homodimers
and heterodimers
1+1
2+2
1+2
 Might also prevent signaling
through heterodimers between
these receptors and other ErbB
family members
 Potentially blocks multiple ErbB
signaling pathways
Downstream signaling
cascade
Lapatinib is indicated in MBC only for patients with progression
after trastuzumab, anthracycline, and taxane treatment
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Recap Case 1: Woman With MBC and No
Previous Trastuzumab
What treatment option would you recommend as first-line
therapy for the 58-year-old woman with MBC?
A. Trastuzumab plus chemotherapy (preferred choice)
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent
Case 2
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 2: Woman With HER2+ MBC and
Progression Following Trastuzumab
 Background: 39-yr-old woman diagnosed with stage IIA, breast cancer
in 2004
– 2.6-cm tumor
– ER+/PgR-/HER2+
 Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen
 Follow-up: 1 yr after end of chemotherapy, she is found to have bone
and lymph node metastases
– Lymph node biopsy reveals the tumor is negative for hormone receptors
(ER/PgR) and continues to overexpress HER2
 Treatment: she receives 6 cycles of TCH and achieves CR
– She continues on maintenance single-agent trastuzumab without
progression for almost 2 yrs
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 2: Woman With HER2+ MBC and
Progression Following Trastuzumab
Scans reveal new liver metastases, and vinorelbine is added
to trastuzumab. She has another CR that lasts 9 mos, at
which time scans reveal progressive disease in the liver and
bones.
What treatment option would you recommend at this time?
A. Switch to lapatinib/capecitabine
B. Switch to lapatinib/trastuzumab
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 2: Woman With HER2+ MBC and
Progression Following Trastuzumab
Scans reveal new liver metastases, and vinorelbine is added
to trastuzumab. She has another CR that lasts 9 mos, at
which time scans reveal progressive disease in the liver and
bones.
What treatment option would you recommend at this time?
A. Switch to lapatinib/capecitabine (preferred choice)
B. Switch to lapatinib/trastuzumab (reasonable)
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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
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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.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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
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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.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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.
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EGF104900 Phase III Study: Dual HER2
Blockade in MBC
Patients with HER2+
(FISH/IHC3+) MBC and
progression on
anthracycline, taxane, and
trastuzumab
Lapatinib 1500 mg/day PO
(n = 148)
Crossover allowed to lapatinib +
trastuzumab if progression after at
least 4 weeks on therapy
Lapatinib 1000 mg/day PO +
Trastuzumab 4 mg/kg → 2 mg/kg IV weekly
(n = 148)

Primary endpoint: PFS

Secondary endpoints: OS, ORR, clinical benefit
•  Staging
occurred
at 4, 8, 12, 16
weeks,
and of
then
every 8monotherapy
weeks
Patients
with progression
after
≥ 4 wks
lapatinib
allowed to
•
crossstate
over of
to single-agent
receive trastuzumab
Steady
lapatinib occurs at approximately 7 days
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
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Lapatinib ± Trastuzumab in MBC: Efficacy
Outcome
Lapatinib, %
(95% CI)
(n = 145)
Lapatinib/
Trastuzumab, %
(95% CI)
(n = 146)
OR
(95% CI)
P Value
ORR*
6.9
(3.4-12.3)
10.3
(5.9-16.4)
1.5
(0.6-3.9)
.46
Clinical benefit rate†
12.4
(7.5-18.9)
24.7
(17.9-32.5)
2.2
(1.2-4.5)
.01
*Confirmed CR + PR.
†Confirmed CR + PR + stable disease ≥ 6 mos.
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
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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.
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Alive without Progression (Cumulative %)
EGF104900: OS With Lapatinib ±
Trastuzumab in MBC (ITT Population)
100
80%
80
OS Outcome
L
L+T
(n = 145) (n = 146)
Died, n (%)
113 (78)
105 (72)
9.5
14
Median, mos
60
HR (95% CI)
56%
70%
0.74 (0.57-0.97)
Log-rank P value
.026
6 Month OS
40
41%
L
L+T
20
12 Month OS
0
0
5
10
15
20
Mos From Randomization
Patients at Risk, n
L
148
121
88
L + T 148
102
65
Blackwell KL, et al. SABCS 2009. Abstract 61.
64
47
43
28
25
30
25
13
1
35
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Lapatinib ± Trastuzumab in Heavily
Pretreated MBC: Selected Adverse Events
Adverse Event (All Grades), %
Lapatinib + Trastuzumab
(n = 149)
Lapatinib
(n = 146)
P Value
Nausea
28
28
NS
Fatigue
21
19
NS
Diarrhea*
60
48
.03
Rash
22
29
NS
*7% grade 3/4 events on each treatment arm.
Cardiac Events†
Lapatinib + Trastuzumab
(n = 149)
Lapatinib
(n = 146)
Total no. patients with events‡
Symptomatic
8
3
3
2
Therapy related
8
3
Deaths
1§
0
†Defined
by ≥ 20% LVEF drop relative to baseline and below institution’s lower limits of normal.
patients had > 1 occurrence.
§Cause of death: pulmonary thromboembolism.
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
‡2
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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.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncology
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 Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Trastuzumab Beyond Progression in
HER2+ MBC: Effect of Previous Treatment
Previous treatments (N = 156)

First-line taxane + trastuzumab (n = 111)

Trastuzumab alone or with other first-line chemotherapy (n = 42)

Taxane + trastuzumab as adjuvant therapy (n = 3)
Outcome
Capecitabine
Capecitabine +
Trastuzumab
HR
P Value
Median TTP, mos
5.6
8.2
0.69
.034
Median OS, mos
20.4
25.5
0.76
.26
ORR, %
27.0
48.1
--
.012
CBR,* %
54.1
75.3
--
.0068
*CBR: CR + PR + SD > 24 wks.
von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncology
Recap Case 2: Woman With HER2+ MBC
and Progression Following Trastuzumab
What treatment option would you recommend for the 39year-old woman who has progressed following trastuzumab?
A. Switch to lapatinib/capecitabine (preferred choice)
B. Switch to lapatinib/trastuzumab (reasonable)
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone
Case 3
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 3: Woman With HER2+ MBC and
Relapse Following Trastuzumab/Lapatinib
 Presentation: 56-yr-old woman was diagnosed with stage III ER+/
PgR-/HER2+ breast cancer
– Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab
 Follow-up: 3 yrs after completing maintenance trastuzumab, she was
diagnosed with bone and lung metastases
– Treatment: docetaxel/trastuzumab
 Follow-up: after achieving PR that lasted for 9 mos, she developed
liver metastases
– Treatment: lapatinib/capecitabine
 Follow-up: she achieved SD for 6 mos, after which she developed
lung and lymph node metastases
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 3: Woman With HER2+ MBC and
Relapse Following Trastuzumab/Lapatinib
What treatment options do you feel are appropriate to
consider for this patient at this time?
A. Lapatinib/trastuzumab
B. Enrollment in a trial evaluating a new agent for HER2+ breast
cancer
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Case 3: Woman With HER2+ MBC and
Relapse Following Trastuzumab/Lapatinib
What treatment options do you feel are appropriate to
consider for this patient at this time?
A. Lapatinib/trastuzumab (reasonable)
B. Enrollment in a trial evaluating a new agent for HER2+ breast
cancer (preferred choice)
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy (reasonable)
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Trastuzumab-DM1: Novel Antibody-Drug
Conjugate
Target expression: HER2
Monoclonal antibody: Trastuzumab
Trastuzumab
Cytotoxic agent: DM1
Highly potent cytotoxic agent
Linker: SMCC
Systemically stable
DM1
MCC
T-DM1
Average drug:antibody
ratio ≅ 3.5:1
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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T-DM1 Safety in MBC: Every-3-Wk and
Weekly Schedules (Phase I Studies)
 Safety profile was similar between every-3-wk and weekly schedules
 MTD: determined for each schedule tested
– Every-3-wk schedule: 3.6 mg/kg
– Weekly schedule: 2.4 mg/kg
 Efficacy: similar between every-3-wk and weekly schedules
– 15 patients treated at every-3-wk MTD (3.6 mg/kg)
– Median PFS: 10.4 mos
– Clinical benefit rate with every-3-wk schedule: (ORR + SD at 6 mos): 73%
– Measurable disease: 9 patients; confirmed response rate in these patients
was 44%
Krop IE, et al. J Clin Oncol. 2010;28:2698-2704. Holden SN, et al. ASCO 2008. Abstract 1029.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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T-DM1: Phase II Results in Previously
Treated HER2+ MBC
 Treatment: single-agent T-DM1 3.6 mg/kg every 3 wks
TDM4258[1]
(N = 112)
TDM4374[2]
(N = 110)
ORR, %
25.9
32.7
CBR, %
34.8
44.5
Median PFS, mos
5.3
7.3
 Confirmed HER2+
8.2
--
 Thrombocytopenia
8.0
5.4
 Fatigue
4.5
2.7
 Hypokalemia
8.9
--
Outcome
Grade 3/4 AEs, %
1. Burris HA, et al. J Clin Oncol. 2011;29:398-405. 2. Krop I, et al. SABCS 2009. Abstract 5090.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Phase II Study of First-line T-DM1 vs
Trastuzumab/Docetaxel in HER2+ MBC
Stratified by region (US vs ROW), previous adjuvant trastuzumab,
disease-free interval (≤ 24 mos vs > 24 mos)
Patients with
HER2+ MBC
or recurrent
LABC and no
previous chemo for
metastatic disease
(N = 137)
PD
T-DM1 3.6 mg/kg q3w
(n = 67)
Trastuzumab
8 mg/kg dose → 6 mg/kg q3w
followed by Docetaxel
75 or 100 mg/m2
(n = 70)

No statistically significant differences between study groups

Primary endpoint: PFS

Secondary endpoints: ORR, CBR, OS, QoL, symptom control

Patients in trastuzumab/docetaxel arm allowed to cross over to T-DM1 on progression
Perez EA, et al. ESMO 2010. Abstract LBA3.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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First-line T-DM1 vs Trastuzumab/
Docetaxel in HER2+ MBC: Prior Treatment
Trastuzumab +
Docetaxel
(n = 70)
T-DM1
(n = 67)
Trastuzumab
 Yes
 No
18 (25.7)
52 (74.3)
13 (19.4)
54 (80.6)
Taxane
 Yes
 No
28 (40.0)
42 (60.0)
22 (32.8)
45 (67.2)
Trastuzumab and/or taxane
 Yes
 No
31 (44.3)
39 (55.7)
24 (35.8)
43 (64.2)
Previous Treatment, n (%)
Perez EA, et al. ESMO 2010. Abstract LBA3.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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First-line T-DM1 vs Trastuzumab/
Docetaxel in HER2+ MBC: Adverse Events
Trastuzumab +
Docetaxel
(n = 68)
T-DM1
(n = 67)
Any AE
68 (100)
63 (94.0)
Grade ≥ 3 AE
51 (75.0)
25 (37.3)
Serious AE*
15 (22.1)
13 (19.4)
Most common AEs (any grade) on trastuzumab + docetaxel arm
 Alopecia
 Neutropenia
 Diarrhea
45 (66.2)
39 (57.4)
31 (45.6)
1 (1.5)
5 (7.5)
7 (10.4)
Most common AEs (any grade) on T-DM1 arm
 Nausea
 Fatigue
 Pyrexia
27 (39.7)
29 (46.2)
14 (20.6)
32 (47.8)
31 (46.3)
24 (35.8)
Adverse Event, n (%)
*Resulting in death, life threatening situation, in-patient hospitalization, prolongation of existing
hospitalization, persistent or significant disability/incapacity, or birth defects.
Perez EA, et al. ESMO 2010. Abstract LBA3.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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First-line T-DM1 vs Trastuzumab/
Docetaxel in HER2+ MBC: Grade ≥ 3 AEs
Grade ≥ 3 AEs, n (%)
NCI CTCAE
Grade
Trastuzumab + Docetaxel
(n = 68)
T-DM1
(n = 67)
Neutropenia
3
4
6 (8.8)
30 (44.1)
(0)
(0)
Leukopenia
3
4
12 (17.6)
5 (7.4)
(0)
(0)
Febrile neutropenia
3
4
6 (8.8)
1 (1.5)
(0)
(0)
Pneumonia
3
4
1 (1.5)
0 (0)
3 (4.5)
0 (0)
Hypercalcemia
3
4
(0)
(0)
1 (1.5)
1 (1.5)
Thrombocytopenia
3
1 (1.5)
5 (7.5)
Perez EA, et al. ESMO 2010. Abstract LBA3.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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First-line T-DM1 vs Trastuzumab/Docetaxel
in HER2+ MBC: Efficacy Summary
Objective Response Rate,
n/N (%; range)
Trastuzumab +
Docetaxel
T-DM1
Overall population
29/70 (41.4; 30.2-53.8)
32/67 (47.8; 35.4- 60.3)
Previous trastuzumab
and/or taxane therapy
11/31 (35.5; 20.0-53.4)
13/24 (54.2; 33.9-74.5)
No previous trastuzumab
and/or taxane therapy
18/39 (46.2; 30.1-61.7)
19/43 (44.2; 29.5-60.1)
Perez EA, et al. ESMO 2010. Abstract LBA3.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Phase III MARIANNE Study: T-DM1 ±
Pertuzumab in HER2+ MBC
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.
PD
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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EMILIA (TDM4370g) Phase III Study: T-DM1
vs Lapatinib/Capecitabine in HER2+ MBC
PD or unacceptable toxicity
Patients with HER2+ locally
advanced or metastatic
breast cancer following
treatment with a taxane
and trastuzumab
(N = 980)
T-DM1 q3w
(n = 490)
Lapatinib + Capecitabine q3w
(n = 490)
 Primary endpoint: PFS by IRF, OS, safety
 Secondary endpoints: QoL (FACT B), DOR, PFS by investigator
assessment
ClinicalTrials.gov. NCT00829166.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Pertuzumab and Trastuzumab Bind to
Distinct Extracellular HER2 Epitopes
Pertuzumab-HER2 Complex
Trastuzumab-HER2 Complex
Pertuzumab
I
Dimerization domain
I
II
II
III
III
IV



Inhibits HER2 dimerization with other HER
family receptors (particularly HER3)
Trastuzumab
IV

Activates ADCC

Inhibits HER-mediated signaling pathways

Prevents HER2 domain cleavage
Activates ADCC
Inhibits multiple HER-mediated signaling
pathways
Hubbard SR. Cancer Cell. 2005;7:287-288.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Phase II Trial of Pertuzumab +
Trastuzumab in HER2+ MBC: Efficacy
60
SD
PR
CR
Patients (%)
50
Responses were durable:
 Median duration of response:
5.8 mos
 Median PFS (all patients):
5.5 mos
40
30
20
10
0
All Patients (N = 66)
Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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CLEOPATRA Phase III Trial: Trastuzumab
+ Docetaxel ± Pertuzumab in HER2+ MBC
Patients with HER2+ MBC
and no previous treatment
for metastatic disease
(N = 808)
Docetaxel 75 mg/m2 +
Trastuzumab 8 mg/kg → 6 mg/kg
+ Placebo q3w
Docetaxel 75 mg/m2 +
Trastuzumab 8 mg/kg → 6 mg/kg
+ Pertuzumab 840 mg → 420 mg
q3w
 Primary endpoint: PFS (IRF evaluation)
 Secondary endpoints: OS, incidence of CHF and LVEF
events, safety
ClinicalTrials.gov. NCT00567190.
mTOR Inhibitors
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Everolimus, Trastuzumab, and Paclitaxel
in HER2+ MBC (J2101 Phase I Study)
 Women with HER2overexpressing MBC and
progression after
trastuzumab, WHO PS 0-1
– Previous exposure to
lapatinib allowed
– Unrestricted number of
previous antineoplastic
therapy lines
Everolimus: 5 mg → 2.5 or
10 mg/day, or 30 mg → 20, 50, or
70 mg/wk
Trastuzumab: 4 mg/kg →
2 mg/kg/wk
Paclitaxel: 80 mg/m2
on Days 1, 8, 15, every 4 wks
(N = 33)
Andre F, et al. J Clin Oncol. 2010;28:5110-5115.
Endpoints:
safety, tumor
response,
cardiac toxicity
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Everolimus, Trastuzumab, and Paclitaxel
in HER2+ MBC: Baseline Characteristics
Characteristic, %
Patients
(N = 33)
Visceral disease
73
Trastuzumab resistant
97
Taxane pretreated
 Taxane resistant
94
39
Resistant to lapatinib
48
Pretreated with anthracyclines
73
Prior endocrine treatment
70
Andre F, et al. J Clin Oncol. 2010;28:5110-5115.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Everolimus, Trastuzumab, and Paclitaxel
in HER2+ MBC (J2101): Antitumor Activity
Response/Outcome, n (%)
Everolimus Dose
5 mg/day
(n = 5)
10 mg/day
(n = 13)
30 mg/wk
(n = 9)
All
(N = 27)
Objective response
5 (100)
4 (31)
3 (33)
12 (44)
CR
1 (20)
1 (8)
0 (0)
2 (7)
PR
4 (80)
3 (23)
3 (33)
10 (37)
Clinical benefit rate
(CR + PR + SD ≥ 24 wks)
5 (100)
8 (61)
7 (78)
20 (74)
Worse patient characteristics in 10-mg arm vs 5-mg arm

More visceral disease (82% vs 50%)

Median number of previous treatments (3 vs 2 [range: 1-6 vs 0-4])

More patients ongoing (7 vs 1)
Andre F, et al. J Clin Oncol. 2010;28:5110-5115.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Everolimus, Trastuzumab, and Paclitaxel
in HER2+ MBC (J2101): PFS
Regimen
Median PFS, Wks
95% CI
Daily
33.0
23.7-NA
Weekly
40.7
30.0-NA
Overall
34.0
29.1-40.7
Andre F, et al. J Clin Oncol. 2010;28:5110-5115.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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.
Targeting Angiogenesis
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Angiogenesis in MCF-7 Spheroids: Day 14
MCF-7 Neo:
3.5 x mag.
 Mature vasculature
 No vessel buds
 Development stopped
MCF-7 HER-2/neu:
10 x mag.
 High number mature vessels
 Vessel buds in center of tumor
 Vasculature still growing
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Phase I/II Trial of Trastuzumab +
Bevacizumab in Relapsed/MBC
Phase I
Cohort 1 (n = 3)
Trastuzumab qw +
Bevacizumab 3 mg/kg on Day 7, then q2w
HER2+
(FISH+)
Cohort 2 (n = 3)
Trastuzumab qw +
Bevacizumab 5 mg/kg on Day 7, then q2w
(N = 9)
Cohort 3 (n = 3)
Trastuzumab qw +
Bevacizumab 10 mg/kg on Day 7, then q2w*

Investigator-initiated, investigator held IND

First report of 2 humanized MAbs in human subjects

Primary endpoints: PK and safety
Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124.
*RP2D
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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PK/Toxicity/Efficacy Data in 9 Patients
 No change in PK of either antibody when used as combination
 No untoward toxicity induced by combination
– 1 patient with mild increased blood pressure
– 1 patient with decreased LVEF
 Response
– 1 CR
– 4 PRs
– 2 SDs > 11 mos
– 2 PDs
Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Phase I/II Trial of Trastuzumab and
Bevacizumab in Relapsed/MBC (TORI B03)
Hypothesis: Upregulation of VEGF in HER2+ MBC contributes to the aggressive phenotype
of HER2+ MBC. The “angiogenic switch” modulated by trastuzumab can be exploited in the
clinic by combined blockade of these 2 “linked” pathways
Inclusion Criteria:
 LABC or MBC
 HER2+ by FISH
 ECOG 0-1
 > 18 yrs of age
 LVEF WNL
Trastuzumab 4 mg/kg  2 mg/kg qw
+
Bevacizumab dose escalation (n = 24)
3 mg/kg  5 mg/kg 10 mg/kg IV on Day 7,
then q14d
Trastuzumab 4 mg/kg  2 mg/kg qw
+
Bevacizumab q14d
Pegram MD, et al. SABCS 2006. Abstract 301.
Study endpoints
1. Clinical safety
2. Pharmacokinetics
3. Efficacy
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Phase II Trial of Trastuzumab and
Bevacizumab in Relapsed/MBC (TORI B03)

No change in PK of either antibody when used as combination in phase I;
currently being tested in phase II

Toxicity
– 1 patient with grade IV decreased LVEF and CHF
– 1 patient with gastric perforation

Response: ORR 48%
– 2 CR
– 22 PRs (many with continued response → ? CR)
– 15 SDs (out to minimum of 24 wks)
– 5 PDs

Median TTP: 7.1 mos (95% CI: 5.5-12.9)

Median OS: 43.8 mos (95% CI: 40.6-not reached)

Clinical benefit: 86%
Hurvitz, S, et al. SABS 2009. Poster 6094.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncology
AVEREL Phase III Study: Trastuzumab ±
Bevacizumab in 1st-line HER2+ MBC
 Locally recurrent or MBC,
HER2+
Trastuzumab 8 mg/kg IV loading dose,
6 mg/kg IV q3w +
Docetaxel 100 mg/m2 IV q3w
 No previous chemotherapy for
MBC
 RT for metastatic bone pain
relief only
(N = 407)
Trastuzumab 8 mg/kg IV loading dose,
6 mg/kg IV q3w +
Bevacizumab 15 mg/kg IV q3w +
Docetaxel 100 mg/m2 IV q3w

Primary endpoint: PFS

Secondary outcomes: OS, OR, DR, TTF, QoL, safety/tolerability
ClinicalTrials.gov. NCT00391092.
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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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
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Targeted Agents for HER2+ Breast Cancer
Trastuzumab
Bevacizumab
phase III
T-DM1
phase III
VEGF
Sunitinib
phase II
EGFR
VEGFR
P
P
P
P
PI3-K
HER2
P
P
P
P
Pertuzumab
phase III
Akt/PKB
PTEN
Everolimus
phase III
mTOR
Lapatinib
phase III
Neratinib
phase III
4E-BP1
S6K1
elF-4E
Gefitinib
phase II
Protein synthesis
Cell growth, proliferation, survival, metastasis, angiogenesis
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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Recap Case 3: Woman With HER2+ MBC,
Relapse Following Trastuzumab/Lapatinib
What treatment options do you feel are appropriate to
consider for this 56-year-old woman who has relapsed?
A. Lapatinib/trastuzumab (reasonable)
B. Enrollment in a trial evaluating a new agent for HER2+ breast
cancer (preferred choice)
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy (reasonable)
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Interactive Virtual Presentations review and consider challenging
patient cases with guidance from expert faculty members
Interactive Case Challenges work through challenging
patient cases and review the implications
of treatment choices
Text-Based Modules plus
downloadable PowerPoint slides
clinicaloptions.com/oncology