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Transcript of New Directions in the Treatment of Patients With HER2-Positive Breast Cancer Jointly sponsored by...
New Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Image: Dr. Torsten Wittmann/Copyright©2010 Photo Researchers, Inc. All Rights Reserved
This program is supported by an educational grant from
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
About These Slides
Our thanks to the presenters who gave permission to include their original data
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These slides may not be published or posted online without permission from Clinical Care Options
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Faculty
Dennis J. Slamon, MD, PhDProfessor and Chief Division of Hematology/OncologyDepartment of Internal MedicineDavid Geffen School of Medicine at UCLALos Angeles, California
Sara Hurvitz, MDAssistant Professor of Medicine Director, Breast Oncology ProgramDivision of Hematology-Oncology Department of Internal Medicine David Geffen School of Medicine at UCLALos Angeles, California
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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 indications.
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 to the official prescribing information for each product for discussion of approved indication, contraindications, and warnings.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
GoalThe goal of this activity is to provide participants with practical approaches on managing patients with HER2-positive metastatic breast cancer.
Target AudienceThis program is intended for physicians and other healthcare providerswho care for patients with breast cancer.
Learning ObjectivesAt 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 1: Woman With MBC and No Previous TrastuzumabWhat 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 1: Woman With MBC and No Previous TrastuzumabWhat 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Normal (1x)~ 25,000-50,000 HER2
receptors
Overexpressed HER2 (10-100x)
up to ~ 2,000,000 HER2 receptors
Excessive cellular division
HER2 Overexpression in Breast Cancer
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.
HER2 is overexpressed in ~ 25% of breast cancers
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
HER2 Overexpression Shortens Survival
HER2 oncogeneamplification
HER2 oncoproteinoverexpression
Shortened survivalMedian Survival From First DiagnosisHER2 overexpressing
3 yrsHER2 normal
6-7 yrs
Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ, et al. Science. 1989;244:707-712.
HER2-Targeted Agents
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.
Trastuzumab: Mechanism of Action
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Single-Agent Trastuzumab in First-line Treatment of HER2+ MBCPatients 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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Trastuzumab Combinations as First-line Therapy for MBC: Pivotal Phase III Trial
Patients with HER2+ (IHC 2+/3+) MBC, no previous
chemotherapy, measurable
disease, KPS ≥ 60%
(N = 469)No previous
adjuvantAC
Paclitaxel(n = 96)
Trastuzumab+ Paclitaxel
(n = 92)
AC(n = 138)
Trastuzumab+ AC
(n = 143)
Previousadjuvant
AC
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Trastuzumab in MBC: The Pivotal Trial
Treatment ObjectiveResponse Rate, %
Median TTP, Mos Median OS, Mos
Chemo 32 4.6 20.3
Chemo +Trastuzumab
50 7.4 25.1
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
P < .001 for all 3 comparisons.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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
Valero V, et al. J Clin Oncol. 2011;29:149-156.
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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Trastuzumab in Triple-Combination Regimens: Response Rates
ORR (%)
H + Carbo + T
H + V + T
H + E90 + C
H + E60 + C
H + Carbo + T
H + V + X
H + G + P
H + G + Carbo
H + G + P
H + E + T
H + Carbo + P every 3 wks
H + Carbo + P every wk
H + TLC D-99 + P
H + Carbo + T
H + Carbo + T
H + Cisplatin + T
H + Carbo + P
H + X + T
Forbes et al, 2006 (N = 130)
Wardley et al, 2006 (N = 111)
Robert et al, 2006 (N = 92)
Pegram et al, 2004 (N = 62)
Pegram et al, 2004 (N = 59)
Yardley et al, 2002 (N = 61)
Cortes et al, 2004 (N = 54)
Perez et al, 2005 (N = 48)
Perez et al, 2005 (N = 43)
Venturini et al, 2006 (N = 45)
Miller et al, 2002 (N = 45)
Yardley et al, 2006 (N = 41)
Fountzilas et al, 2004 (N = 40)
Chan et al, 2007 (N = 34)
Dirix et al, 2006 (N = 34)
Untch et al, 2004 (N = 26)
Untch et al, 2004 (N = 25)
Yardley et al, 2004 (N = 24)
0 10 20 30 40 50 60 70 80 90 100
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Lapatinib Blocks Signaling Through Multiple Receptor Combinations
Downstream signaling cascade
Downstream signaling cascade
1 + 11 + 1 2 + 22 + 2 1 + 21 + 2 Blocks signaling throughErbB1 and ErbB2 homodimers and heterodimers
Might also prevent signaling through heterodimers between these receptors and other ErbB family members
Potentially blocks multiple ErbB signaling pathways
Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment
Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy
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)
Lapatinib as First-line Treatment for HER2-Amplified LABC or MBC
Endpoint Lapatinib1500 mg/day
(n = 69)
Lapatinib500 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)
6-mo PFS, % 41 45 43
Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Recap Case 1: Woman With MBC and No Previous TrastuzumabWhat 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
1 2
Downstream signaling pathways
Cell proliferation Cell survival
21 1 2
TrastuzumabT
LapatinibL L L L L L
Erb receptors
Mechanism of Action of LapatinibCompared to Trastuzumab
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Patients with HER2+ progressive MBC or stage IIIB/IIIC LABC with
T4 lesion and unlimited previous therapies*
Primary endpoint: TTP
Secondary endpoints: OS, PFS, ORR
Primary endpoint: TTP
Secondary endpoints: OS, PFS, ORR
Lapatinib1250 mg/day PO +
Capecitabine 2000 mg/m2/day on
Days 1-14 every 21 days
Lapatinib1250 mg/day PO +
Capecitabine 2000 mg/m2/day on
Days 1-14 every 21 days
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days
*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.
EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Lapatinib + Capecitabine in HER2+ MBC:TTP
Cameron D, et al. Oncologist. 2010;15:924-934.
TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous Trastuzumab Regimen
CapecitabineLapatinib + capecitabine
Cu
mu
lati
ve P
rog
ress
ion
Fre
e (%
)
100
80
60
40
20
00 20 40 60 80
Wks
100
80
60
40
20
00 20 40 60 80
WksC
um
ula
tive
Pro
gre
ssio
n F
ree
(%)
CapecitabineLapatinib + capecitabine
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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
Brain mets as site of first progression,* n (%)[2]
13 (6) 4 (2) -- .045
† n=198 in 2008 study.*Exploratory analysis.
1. Cameron D, et al. Oncologist. 2010;15:924-9342. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.
Lapatinib + Capecitabine in HER2+ MBC: Efficacy
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Combining Lapatinib and Trastuzumab Increases Antitumor Activity
Scaltriti M, et al. Oncogene. 2009;28:803-814. Konecny GE, et al. Cancer Res. 2006;66:1630-1639. Xia W, et al. Oncogene. 2004;23:646-653.
Tu
mo
r V
olu
me
(m
m3)
1600
1400
1200
1000
800
600
400
200
013 16 19 21 23
Days After Injection*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; §P < .01 vs both lapatinib and trastuzumab.
ControlTrastuzumabLapatinibTrastuzumab + lapatinib*
*†‡ †
†
§
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
– 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
In vivo activity was consistent with in vitro data demonstrating the combination as synergistic
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
• Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks
• Steady state of single-agent lapatinib occurs at approximately 7 days
Crossover allowed to lapatinib + trastuzumab if progression after at
least 4 weeks on therapy
Patients with HER2+ (FISH/IHC3+) MBC and
progression on anthracycline, taxane, and
trastuzumab
Lapatinib 1500 mg/day PO(n = 148)
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
Patients with progression after ≥ 4 wks of lapatinib monotherapy allowed to cross over to receive trastuzumab
EGF104900 Phase III Study: Dual HER2 Blockade in MBC
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
EGF104900: OS With Lapatinib ± Trastuzumab in MBC (ITT Population)
OS Outcome L (n = 145)
L + T (n = 146)
Died, n (%) 113 (78) 105 (72)
Median, mos 9.5 14
HR (95% CI) 0.74 (0.57-0.97)
Log-rank P value .026
6 Month OS
80%
70%
12 Month OS
56%
41%
Blackwell KL, et al. SABCS 2009. Abstract 61.
Ali
ve w
ith
ou
t P
rog
ress
ion
(C
um
ula
tive
%)
Patients at Risk, n148148
LL + T
121102
8865
6447
4328
2513
0
20
40
60
80
100
0 5 10 15 20 25 35Mos From Randomization
1
30
LL + T
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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‡
Symptomatic83
32
Therapy related 8 3
Deaths 1§ 0†Defined by ≥ 20% LVEF drop relative to baseline and below institution’s lower limits of normal.‡2 patients had > 1 occurrence.§Cause of death: pulmonary thromboembolism.
Blackwell KL, et al. J Clin Oncol. 2010;28:1124-1130.
Lapatinib ± Trastuzumab in Heavily Pretreated MBC: Selected Adverse Events
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Trastuzumab Beyond Progression in HER2+ MBC: BIG 03-05 Phase III Trial
Patients with progressive MBC orLABC, HER2 overexpression, previous
trastuzumab within 6 wks, and LVEF ≥ 50
(N = 156*)
Primary endpoint: TTP
Secondary endpoints: OS, ORR, safety
Primary endpoint: TTP
Secondary endpoints: OS, ORR, safety
Trastuzumab6 mg/kg every 3 wks +
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days(n = 78)
Trastuzumab6 mg/kg every 3 wks +
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days(n = 78)
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days(n = 78)
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days(n = 78)
*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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
BIG 03-05: Trastuzumab Beyond Progression in HER2+ MBC
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.
PFS1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ilit
y o
f P
FS
0 10 20 30 40Mos
XXHCensoredLog-rank P = .0338
Pts at Risk, nX
XH7477
4055
1529
812
54
33
21
11
11
OS1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ilit
y o
f O
S
0 10 20 30 40Mos
XXHCensoredLog-rank P = .2570
Pts at Risk, nX
XH7477
6668
5059
3347
2127
1015
36
31
21
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Trastuzumab Beyond Progression in HER2+ MBC: Effect of Previous Treatment
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.
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)
von Minckwitz G, et al. J Clin Oncol. 2009;27:1999-2009.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Recap Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabWhat treatment option would you recommend for the 39-year-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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat 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
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat 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)
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Highly potent cytotoxic agent
Cytotoxic agent: DM1
Monoclonal antibody: Trastuzumab
Target expression: HER2
Systemically stable
Linker: SMCCT-DM1
Average drug:antibody ratio ≅ 3.5:1
Trastuzumab-DM1: Novel Antibody-Drug Conjugate
Trastuzumab
MCCDM1
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
T-DM1: Phase II Results in Previously Treated HER2+ MBC Treatment: single-agent T-DM1 3.6 mg/kg every 3 wks
1. Burris HA, et al. J Clin Oncol. 2011;29:398-405. 2. Krop I, et al. SABCS 2009. Abstract 5090.
Outcome 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 --
Grade 3/4 AEs, %
Thrombocytopenia 8.0 5.4
Fatigue 4.5 2.7
Hypokalemia 8.9 --
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Phase II Study of First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC
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
PD
Perez EA, et al. ESMO 2010. Abstract LBA3.
Stratified by region (US vs ROW), previous adjuvant trastuzumab, disease-free interval (≤ 24 mos vs > 24 mos)
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)
Patients with HER2+ MBC or recurrent
LABC and no previous chemo for metastatic disease
(N = 137)
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Prior TreatmentPrevious Treatment, n (%) 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)
Perez EA, et al. ESMO 2010. Abstract LBA3.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Adverse EventsAdverse Event, n (%) 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)
Perez EA, et al. ESMO 2010. Abstract LBA3.
*Resulting in death, life threatening situation, in-patient hospitalization, prolongation of existing hospitalization, persistent or significant disability/incapacity, or birth defects.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
First-line T-DM1 vs Trastuzumab/ Docetaxel in HER2+ MBC: Grade ≥ 3 AEsGrade ≥ 3 AEs, n (%) NCI CTCAE
GradeTrastuzumab + 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 neutropenia3 4
6 (8.8)1 (1.5)
(0)(0)
Pneumonia3 4
1 (1.5)0 (0)
3 (4.5)0 (0)
Hypercalcemia3 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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
First-line T-DM1 vs Trastuzumab/Docetaxel in HER2+ MBC: Efficacy Summary
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Phase III MARIANNE Study: T-DM1 ± Pertuzumab in HER2+ MBC
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, DORClinicalTrials.gov. NCT01120184.
PD
Trastuzumab + Taxane(n = 364)
T-DM1 + Pertuzumab(n = 364)
T-DM1 + Placebo(n = 364)
Patients with HER2+, previously untreated MBC
(N = 1092)
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
EMILIA (TDM4370g) Phase III Study: T-DM1 vs Lapatinib/Capecitabine in HER2+ MBC
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
PD or unacceptable toxicity
ClinicalTrials.gov. NCT00829166.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes
Hubbard SR. Cancer Cell. 2005;7:287-288.
Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex
PertuzumabDimerization domain
TrastuzumabIII
II
I
Inhibits HER2 dimerization with other HER family receptors (particularly HER3)
Activates ADCC
Inhibits multiple HER-mediated signaling pathways
Activates ADCC
Inhibits HER-mediated signaling pathways
Prevents HER2 domain cleavage
III
II
I
IV IV
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Phase II Trial of Pertuzumab + Trastuzumab in HER2+ MBC: Efficacy
Responses were durable:
Median duration of response: 5.8 mos
Median PFS (all patients): 5.5 mos
Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.
60
50
30
20
10
0
Pat
ien
ts (
%)
All Patients (N = 66)
40
SDPRCR
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
CLEOPATRA Phase III Trial: Trastuzumab + Docetaxel ± Pertuzumab in HER2+ MBC
Primary endpoint: PFS (IRF evaluation)
Secondary endpoints: OS, incidence of CHF and LVEF events, safety
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
ClinicalTrials.gov. NCT00567190.
mTOR Inhibitors
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.
mTOR
AKT
AMPKTSC1 TSC2
PTENLKB1
PI3K
RHEB
IGF-1R EGFR/HER2Increased signaling through IGF-1R
Constitutive PI3K/AKT activation
Elevated AKT or pAKT
Absent or low PTEN
Truncated HER2
Nutrients
mTOR inhibitorGrowth &
proliferation
Angiogenesis Cellmetabolism
Downstream inhibition with mTOR inhibitor counters these resistance mechanisms
Synergy of mTOR inhibition and trastuzumab in vitro and in vivo
mTOR Inhibition May Overcome Trastuzumab Resistance
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Andre F, et al. J Clin Oncol. 2010;28:5110-5115.
Women with HER2-overexpressing MBC and progression after trastuzumab, WHO PS 0-1
– Previous exposure to lapatinib allowed
– Unrestricted number of previous antineoplastic therapy lines
(N = 33)
Endpoints: safety, tumor
response, cardiac toxicity
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
Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC (J2101 Phase I Study)
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC: Baseline Characteristics
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC (J2101): Antitumor Activity
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Everolimus, Trastuzumab, and Paclitaxelin HER2+ MBC (J2101): PFSRegimen 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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
BOLERO-1 Phase III Study: Paclitaxel + Trastuzumab Everolimus in HER2+ MBC
Patients with HER2-overexpressing, unresectable locally advanced or metastatic
breast cancer, no previous trastuzumab or chemotherapy
within 12 mos for advanced disease
(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
Stratification by previous adjuvant or neoadjuvant trastuzumab
and presence of visceral metastases
ClinicalTrials.gov. NCT00876395.
2:1
28-day cycle
Targeting Angiogenesis
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Angiogenesis in MCF-7 Spheroids: Day 14
MCF-7 Neo:3.5 x mag.
Mature vasculature No vessel buds
Development stopped
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
MCF-7 HER-2/neu:10 x mag.
High number mature vessels Vessel buds in center of tumor
Vasculature still growing
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Pegram MD, et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124.
Phase I/II Trial of Trastuzumab + Bevacizumab in Relapsed/MBC
Investigator-initiated, investigator held IND
First report of 2 humanized MAbs in human subjects
Primary endpoints: PK and safety
Phase ICohort 1 (n = 3)
Trastuzumab qw +Bevacizumab 3 mg/kg on Day 7, then q2w
Cohort 2 (n = 3)Trastuzumab qw +
Bevacizumab 5 mg/kg on Day 7, then q2w
Cohort 3 (n = 3)Trastuzumab qw +
Bevacizumab 10 mg/kg on Day 7, then q2w**RP2D
HER2+ (FISH+)
(N = 9)
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Trastuzumab 4 mg/kg 2 mg/kg qw+
Bevacizumab q14d
Trastuzumab 4 mg/kg 2 mg/kg qw+
Bevacizumab q14d
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 dose escalation (n = 24) 3 mg/kg 5 mg/kg 10 mg/kg IV on Day 7,
then q14d
Phase I/II Trial of Trastuzumab and Bevacizumab in Relapsed/MBC (TORI B03)
Inclusion Criteria: LABC or MBC HER2+ by FISH ECOG 0-1 > 18 yrs of age LVEF WNL
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
Study endpoints
1. Clinical safety
2. Pharmacokinetics
3. Efficacy
Pegram MD, et al. SABCS 2006. Abstract 301.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
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.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Locally recurrent or MBC, HER2+
No previous chemotherapy for MBC
RT for metastatic bone pain relief only
(N = 407)
Primary endpoint: PFS
Secondary outcomes: OS, OR, DR, TTF, QoL, safety/tolerability
Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w +
Docetaxel 100 mg/m2 IV q3w
Trastuzumab 8 mg/kg IV loading dose, 6 mg/kg IV q3w +
Bevacizumab 15 mg/kg IV q3w +Docetaxel 100 mg/m2 IV q3w
ClinicalTrials.gov. NCT00391092.
AVEREL Phase III Study: Trastuzumab ± Bevacizumab in 1st-line HER2+ MBC
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
6 x docetaxel and carboplatin
1 yr of trastuzumab
TCHB(Group 1B)
1 yr of bevacizumab
RT
6 x docetaxel and carboplatin
1 yr of trastuzumab
TCH(Group 1A) RT
BETH Phase III Study: Chemotherapy + Trastuzumab ± Bevacizumab
Primary endpoint: IDFS
Secondary endpoints: DFS, OS, RFI, DRFI, toxicity
HER2+, N+ or high-risk N-
Stratified by Ns and HRS
(N ~ 3500)
ClinicalTrials.gov. NCT00625898.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
P
P
P
P
Cell growth, proliferation, survival, metastasis, angiogenesis
Akt/PKB
mTOR
S6K1
PI3-K
Lapatinibphase III
Gefitinibphase II
Everolimusphase III
EGFR HER2
4E-BP1
elF-4E
Protein synthesis
Neratinibphase III
Pertuzumabphase III
Trastuzumab
T-DM1 phase III
P
P
P
P
PTEN
VEGFRSunitinibphase II
Bevacizumabphase III VEGF
Targeted Agents for HER2+ Breast Cancer
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Recap Case 3: Woman With HER2+ MBC, Relapse Following Trastuzumab/LapatinibWhat 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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