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Welcome!Please take a moment to complete the short
pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.
Faculty Disclosures
The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:• Presenter, MD: Research: Pharma Company; Consultant:
Pharma CompanyTO BE FILLED IN BY
PRESENTING PHYSICIAN(S)Off-label discussion disclosure: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.
Steering Committee Disclosures
The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:• Debu Tripathy, MD: Consultant: Clovis Oncology; Clinical Investigator:
Piramal Pharmaceuticals
• Kathy Miller, MD: Speaker/Consultant: Genentech/Roche; Consultant: AstraZeneca, Bristol-Myers Squibb
Non-faculty Disclosures
Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz: Nothing to Disclose
Michelle Melisko, MD: Speaker: Agendia,Genentech/Roche, Novartis, Bristol-Myers Squibb. Clinical Investigator: Amgen, AstraZeneca, Celldex.
Educational Objectives
At the conclusion of this activity, participants should be able to demonstrate the ability to:
• Review the recently updated clinical practice guidelines for HER2-positive breast cancer
• Discuss recent data with HER2-targeted agents in the neoadjuvant and adjuvant settings and choose the optimal treatment for patients with early-stage HER2-positive breast cancer and patients with abnormal cytogenetics
• Assess the various treatment strategies for patients with locally advanced or metastatic HER2-positive breast cancer
• Identify eligibility criteria and the status of currently accruing clinical trials in HER2-positive breast cancer and counsel patients accordingly
Paper Audience Response Questions• During the course of the
program Audience Response Questions will be asked to determine the current knowledge of the audience
• These questions will not be graded and are for outcomes purposes only
• Please record your answers on your evaluation form located in your packet
HER2 Oncogene: A Biological Target
• Increased Aggressiveness
• Shortened Survival
• Hormonal Resistance
HER2 protein overexpression
HER2 gene amplification
HER1/EGFR
HER2 HER3
HER4
PI3K/AKTRas/MEK/MAPK
(STAT)
TFCoA
CoR
ProliferationMigrationDifferentiationApoptosis
P
EGF
TGF
AR
HRGHRG
TK
TK
TK
X
HER Family Ligands and Signaling
P
EARLY STAGE/ADJUVANT THERAPY
Adjuvant Trastuzumab Trial Designs
Summary of Trastuzumab AdjuvantTrial DFS Benefits
Study FU, yrs N
HERA1 3,387
2 3,401
NSABP B-31/NCCTG 9891
2 3,351
4 3,833
BCIRG 006 3 3,222
FinHer 3 231
PACS 04 4 528
0 1 2In favor of T In favor of Obs.
HR0.54
0.64
0.48
0.52
0.64
0.42
0.86
Dahabreh IJ, et al. The Oncologist 2008 ;13(6): 620-630
NSABP/NCCTG Update – Disease-Free Survival
Years From RandomizationPerez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.
Median F/U 3.9 years
HR=0.52, P<.001
NSABP/NCCTG Update – Overall Survival
Years From RandomizationPerez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.
Median F/U 3.9 years
HR=0.61, P<.001
BCIRG 006 Study – Final Analysis
Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX;Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.
Concurrent vs Sequential Therapy: N9831 Trial
Perez EA, et al. J Clin Oncol. 2011;29(25):3366-3373.
HERA Trial Update – Median F/U 4 YearsDisease-Free Survival, Censored for Crossover
Gianni L, et al. Lancet Oncol. 2011;12(3):236-244.
Unadjusted HR censored for crossover = 0.69P<.0001
Trial
HERA
B31
N9831
BCIRG 006
FinHer
Arm
Control H 1 year
ACPACPH
ACP ACPH
ACPH
ACDACDH
TCH
No HH
BaselineLVEF, %
>55
>50
>50
>50
CHF, %
Cardiacdeath, n
10
10
110
000
00
Smith I, et al. Lancet. 2007;369(9555):29-36; Perez EA, et al. J Clin Oncol. 2008;26(8):1231-1238; Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.; Rastogi S, et al. Cardiovasc Drugs Ther. 2007;21(6):415-422; Rastogi S, et al. J Clin Oncol. 2007; 25 (964S; LBA513)
02.1
0.83.80.32.8 3.3
0.62.00.4
10
Clinical Cardiomyopathy FromTrastuzumab Adjuvant Trials
H = Trastuzumab; A = Doxorubicin; C = Cyclophosphamide; P = Paclitaxel; D = Docetaxel.
Any Chemo
Case
A 59-year-old postmenopausal woman undergoes a left lumpectomy and sentinel node biopsy for a 2.2-cm grade II infiltrating ductal cancer that is ER/PR+ and HER2+ (FISH ratio 3.7). Neither of 2 sentinel nodes examined contain tumor. Chest x-ray and serum chemistries including liver function test are normal. A cardiac ejection fraction by MUGA scan is normal at 56%.
What would you recommend for this patient?
A. An aromatase inhibitor (AI) for 5 years plus trastuzumab for 1 year
B. Docetaxel and cyclophosphamide for 4 cycles followed by an AI for 5 years
C. Docetaxel, carboplatin, and trastuzumab for 6 cycles with trastuzumab for 1 year and an AI for 5 years
D. Doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab, with trastuzumab for 1 year and an AI for 5 years
ARS Question 1
ARS Question 1 Response
What would you recommend for this patient?
A. An aromatase inhibitor (AI) for 5 years plus trastuzumab for 1 year
B. Docetaxel and cyclophosphamide for 4 cycles followed by an AI for 5 years
C. Docetaxel, carboplatin, and trastuzumab for 6 cycles with trastuzumab for 1 year and an AI for 5 years–Reasonable choice
D. Doxorubicin plus cyclophosphamide followed by paclitaxel with trastuzumab, with trastuzumab for 1 year and an AI for 5 years
• HERA and BCIRG 006 trials enrolled patients with node-negative HER2+ breast cancer
• In the HERA study, patients had to have tumor >1cm if node-negative (one third of all patients)
• In the BCIRG 006 study, high-risk node negative cases were enrolled, defined as tumor >2 cm, or ER- and PR-negative or histologic grade 2 or 3 (29% of patients enrolled)
• Subset analysis of these trials have shown a statistically significant reduction in risk of recurrence in node-negative patients, but as expected, the absolute magnitude of risk reduction is lower compared to that of node-positive patients.
• In this case, the patient would have been eligible for either of these trials and therefore would be expected to derive a benefit from chemotherapy plus trastuzumab. Given the smaller benefit, the regimen with lower cardiac toxicity (TCH) would be preferable.
0.0 0.5 1.0 1.5HR
Europe, Canada, SA, Australia, NZ (2438) 161 vs 235 0.66 (0.54, 0.81)Asia Pacific, Japan (405) 21 vs 37 0.53 (0.31, 0.90)Eastern Europe (369) 23 vs 36 0.54 (0.32, 0.91)
Region of the world
<35 years (253) 19 vs 31 0.57 (0.32, 1.01)35-49 years (1508) 89 vs 150 0.54 (0.42, 0.70)50-59 years (1096) 71 vs 97 0.71 (0.52, 0.97)>60 years (544) 39 vs 43 0.91 (0.59, 1.41)
Premenopausal (491) 43 vs 49 0.80 (0.53, 1.21)Uncertain (1373) 70 vs 135 0.48 (0.36, 0.64)Postmenopausal (1535) 105 vs 137 0.75 (0.58, 0.97)
Neoadjuvant CT (372) 39 vs 50 0.66 (0.43, 1.00)Negative (1099) 34 vs 58 0.59 (0.39, 0.91)1-3 positive nodes (976) 50 vs 80 0.61 (0.43, 0.87)
Nodal status
Menopausal status at randomisation
Age at randomisation
No. eventsT vs obs
HR (95% CI)Subgroup (No. patients)
>4 positive nodes (953) 95 vs 132 0.64 (0.49, 0.83)
Central + South America (189) 13 vs 13 0.98 (0.45, 2.11)
All patients (3401) 218 vs 321 0.64 (0.54, 0.76)
Overall ResultSmith I, et al. Lancet. 2007;369(9555):29-36.
Exploratory DFS Subgroup Analysis (ITT):1-year Trastuzumab vs Observation – HERA Trial
BCIRG 006 Trial, Node-Negative SubsetDisease-Free Survival
Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX (Abstr 62);Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.
BCIRG 006 Trial, Node-Negative SubsetOverall Survival
Slamon D, et al. Presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 2009; San Antonio, TX (Abstr 62);Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.
The patient is treated with AC → paclitaxel with trastuzumab and completes the chemotherapy portion of therapy without any problems. Trastuzumab is planned for a total trastuzumab duration of 1 year.
What would you recommend at this point?
A. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after radiation
B. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after trastuzumab
C. Initiation of radiation therapy to the left breast and resumption of trastuzumab and hormonal therapy after radiation
D. Initiation of radiation therapy to the left breast and resumption of trastuzumab after radiation, with hormonal therapy after trastuzumab
ARS Question 2
What would you recommend at this point?
A. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after radiation–Reasonable choice
B. Initiation of radiation therapy to the left breast and continuation of trastuzumab, with hormonal therapy after trastuzumab
C. Initiation of radiation therapy to the left breast and resumption of trastuzumab and hormonal therapy after radiation
D. Initiation of radiation therapy to the left breast and resumption of trastuzumab after radiation, with hormonal therapy after trastuzumab
ARS Question 2 Response
• The NCCTG N9831 and NSABP B-31 trials were designed to allow radiation following chemotherapy as indicated by standard of care to overlap with the administration of trastuzumab
• Hormonal therapy was to be given as standard of care following chemotherapy and to overlap with the administration of trastuzumab
This patient would receive radiation as standard of care following a lumpectomy and hormonal therapy based on ER and PR positivity. Analysis of adverse events based on radiation therapy in the N9831 did not show a difference in cardiac adverse events or other adverse events.
Cardiac Adverse Events With or Without RT: N9831
HR RT vs No RT/Unknown = 0.7; P=.21
Halyard MY, et al. J Clin Oncol. 2009;27(16):2638-2644.
Three months after completion of chemotherapy as trastuzumab therapy is ongoing, a follow-up cardiac ejection fraction (EF) is found to be 45%. The patient has no cardiac symptoms and has a normal cardiac examination along with an excellent performance status.
What would you recommend?
A. Permanent discontinuation of trastuzumabB. Continuation of trastuzumab with a recheck of EF in 1 monthC. Continuation of trastuzumab with the addition of a beta blocker and
angiotensin converting enzyme inhibitor with a recheck of EF in 1 monthD. Discontinuation of trastuzumab with a recheck of EF in 1 month and
restarting trastuzumab if EF recovers to more than 50%
ARS Question 3
What would you recommend?A. Permanent discontinuation of trastuzumabB. Continuation of trastuzumab with a recheck of EF in 1
monthC. Continuation of trastuzumab with the addition of a beta
blocker and angiotensin converting enzyme inhibitor with a recheck of EF in 1 month
D. Discontinuation of trastuzumab with a recheck of EF in 1 month and restarting trastuzumab if EF recovers to more than 50%–Reasonable choice
ARS Question 3 Response
Cardiac dysfunction is seen at a rate of 3-10% and is usually subclinical, with clinical signs of congestive heart failure seen at a rate of 0.5-3.8%. Cardiac function usually recovers over time and the long-term consequences are still unknown. The guidelines for evaluating cardiac status is empiric and based on the design of most adjuvant trials. These trials required normal EF prior to initiation of trastuzumab (usually defined as EF >50%), and monitoring every 3 months. For clinical congestive heart symptoms, immediate EF evaluation is recommended to verify cardiac cause, with permanent discontinuation of trastuzumab. For asymptomatic decreases in cardiac function, guidelines are recommended (see next slide) that the trials used for holding trastuzumab and rechecking, with restarting once criteria for continuation are met.
Within Normal Limits
1-5% below LLN
6% below LLN
Cont.
Hold *
Hold *
Relationship of LVEF to LLN
Absolute Decreaseof <10%
Absolute Decrease of 10-15%
Absolute Decrease of 16%
Hold *
Hold *
Hold *
Cont.
Cont.
Cont.*
* Repeat LVEF assessment after 4 weeks - If criteria for continuation met – resume trastuzumab
- If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab
Asymptomatic PatientsRules for Trastuzumab Continuation Based on Serial LVEF Used in Trials
Romond EH, et al. N Engl J Med. 2005; 353: 1673-84; Russell S, et al. J Clin Oncol. 2010;28(21):3416-3421; Procter M, et al. J Clin Oncol. 2010;28(21):3422-3428.
METASTATIC BREAST CANCER
1.0
0.0
0.2
0.4
0.6
0.8
P<.001
0 5 10 15 20 25Months
Trast + CT (n=235) Median TTP = 7.4 mon
CT alone (n=234) Median TTP = 4.6 mon
Prob
abili
ty
Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.
Trastuzumab Increases Time to Progression in HER2(+) MBC
Trastuzumab Added to ChemoRxImproves Survival in MBC
Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.
RR=0.76P=.025
Lapatinib Increases Time to ProgressionAfter Trastuzumab
* Censors 4 patients who died due to causes other than breast cancer.
70
10
20
30405060708090
0
100
10 20 30 40 50 600Time (weeks)
CapecitabineLapatinib +
capecitabine
.00016P value (log-rank, 1-sided)
69 (43%)45 (28%)Progressed or died*19.736.9Median TTP, wk
161160No. of pts
0.51 (0.35, 0.74)Hazard ratio (95% CI)
% o
f pat
ient
s fre
e fro
m p
rogr
essi
on*
Geyer CE, et al. N Engl J Med. 2006;355(26):2733-2743.
X XH0
10
20
30
40
50
60
70
80
90
100
% o
f pts
54 (42.1-65.7)
75.3%(64.2-84.4)
27.0 (17.3-38.6)
48.0 (36.5-59.7)
2-sided p:OR: 0.011CB: 0.0068
CR+PR
NC>24wks
CR: 7.7%PR: 40.3%
CR: 2.7%PR: 24.3%
Trastuzumab Remains Effective After Disease Progression
von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.
Combined HER2 Blockade Improves PFS After Progression on Trastuzumab
L N=145
L+T N=146
Progressed or Died, n 128 127
Median, wks 8.1 12.0
Hazard ratio (95% CI) 0.73 (0.57, 0.93)
P value .008
Cum
ulat
ive
% A
live
with
out
Prog
ress
ion
LL+T 13%
28%
0
20
40
60
80
100
0 10 20 30 40 50 60Time from Randomization (wks)
Lapatinib Lapatinib + Trastuzumab Odds Ratio P Value
Response Rate 6.9 10.3 1.5 0.46
CBR 12.4 24.7 2.2 0.01
Blackwell KL, et al. J Clin Oncol. 2010; 28 (7): 1124-30.
Blackwell KL, et al. J Clin Oncol. 2012 Jun 11 [Epub ahead of print].
Updated Overall Survival in ITT
Novel Agents: HER2HER1/2 TKI HKI-272, BIBW 2992, PKI-166, EKB-569Pan HER TKI Canertinib, BMS-599626HER1/2/VEGFR TKI XL647, AEE788HER2 dimerization inhibitor PertuzumabBispecific antibody Ertumaxomab, MM111Conjugated antibodies Trastuzumab-MCC-DM1, trastuzumab-A-Z-CINN
310-paclitaxelTargeted nanoparticles MM302HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922,
SNX5422IGF-1R inhibitors (mAb, TKI) CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-18HDAC inhibitors Vorinostat, LBH589, PXD101, NVP-LAQ824, depsipeptide, CI-
994, MS-275 PI3K inhibitors SF1126, BEZ235, XL147, XL765, GDC-0941Akt inhibitors Perifosine, XL418mTOR inhibitors Rapamycin (sirolimus), temsirolimus, everolimus,
deforolimusHER2 vaccines
Investigating T-DM1 (EMILIA): Study Design• Primary endpoints: PFS (independently assessed), OS, safety• Secondary endpoints: PFS (investigator assessment), ORR, OS,
duration of response, time to symptom progression
Women with HER2+
unresectable LABC or MBC(N=991)
Trastuzumab-DM1 3.6 mg/kg q3w IV
(n=495)
Capecitabine 1,000 mg/m2 orally bid, days 1-14, q3w
+Lapatinib
1,250 mg/day orally qd(n=496)
Treatment until disease
progression or unacceptable
toxicity
Stratified by World region, number of prior chemo regimens for MBC, or unresectable
LABC, presence of visceral disease
T-DM1= Trastuzumab-DM1Blackwell KL, et al. Presented at: 2012 Annual ASCO meeting; Abstract LBA1, Abstract S5-5.
T-DM1 Demonstrated Improved Efficacy over Capecitabine + Lapatinib
CAP + LAP(n=495)
T-DM1(n=495)
PFS by Independent Review
6.4 months 9.6 months
HR=0.650; P<0.0001OS (Interim analysis) 23.3 months NRORR 30.8% 43.6%DOR 6.5 months
(95% CI: 5.5,7.2)12.6 months
(95% CI: 8.4,20.8)
Blackwell KL, et al. Presented at: 2012 Annual ASCO meeting; Abstract LBA1, Abstract S5-5.
Case
38-year-old patient presented with inflammatory ER-negative/PgR-negative/HER2-positive breast cancer. She was treated with neoadjuvant AC >TH followed by mastectomy (achieved a pCR) and radiation therapy. She completed 1 year of trastuzumab.
Now, 2 years later, she has disease progression with lung metastases. Biopsy of the largest lesion (2.5 cm) confirms recurrent disease that remains ER-/PgR-/HER2+ by FISH with ratio 8.9. She has a cough but is not SOB. ECOG PS = 1.
Her main goal in therapy is to maximize response and PFS.
Which treatment would you recommend?A. Rechallenge with trastuzumab + capecitabineB. Lapatinib + capecitabineC. Lapatinib + paclitaxelD. Trastuzumab + lapatinibE. Trastuzumab + pertuzumab + docetaxel
ARS Question 4
Which treatment would you recommend?
A. Rechallenge with trastuzumab + capecitabine–Reasonable choice
B. Lapatinib + capecitabine–Reasonable choice
C. Lapatinib + paclitaxel–Incorrect answer
D. Trastuzumab + lapatinib–Reasonable choice
E. Trastuzumab + pertuzumab + docetaxel–Reasonable choice. On June 8, 2012, the FDA approved pertuzumab for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease
ARS Question 4 Response
Pertuzumab and Trastuzumab: Complementary Mechanisms of Action
Trastuzumab:• Inhibits ligand-independent HER2
signaling• Activates ADCC• Prevents HER2 ECD shedding
Pertuzumab:• Inhibits ligand-dependent HER2 dimerization and
signaling• Activates ADCC
Baselga J, et al. Presented at: 34th Annual San Antonio Breast Cancer Symposium; December 6-11, 2011; San Antonio, TX. Abstract S5-5; Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.
HER 1/3/4
HER2
Trastuzumab Pertuzumab
Dimerization domain
Subdomain IV
Pertuzumab Activity:
With trastuzumab
n=66
Monotherapy n=29
% %Best Objective Response
CR 8 0PR 17 7SD 6 months 26 4
ORR 24 7Clinical Benefit Rate 50 11
Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.
CLEOPATRA: Study Design
• Primary endpoint: PFS (independently assessed)• Secondary endpoints: PFS (investigator assessment), ORR, OS, Safety
Women with previously untreated, HER2-
positive locally recurrent/metastatic breast
cancer
(N = 808)
Trastuzumab 6 mg/kg q3w* +Docetaxel 75-100 mg/m2 q3w† +
Pertuzumab 420 mg q3w‡
(n = 402)
Trastuzumab 6 mg/kg q3w* +Docetaxel 75-100 mg/m2 q3w† +
Placebo q3w (n = 406)
Treatment until disease progression or
unacceptable toxicity
Stratified by geographic regionand previous (neo)adjuvant chemotherapy
* Trastuzumab 8 mg/kg loading dose given. † Minimum of 6 docetaxel cycles recommended; <6 cycles permitted for unacceptable toxicity or PD.‡ Pertuzumab 840 mg loading dose given.
Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.
CLEOPATRA: Independently Assessed PFS
100
90
80
70
60
50
40
30
20
10
0
Prog
ress
ion-
free
surv
ival (
%)
Time (months)
0 5 10 15 20 25 30 35 40
Ptz + T + D: median 18.5 monthsPbo + T + D: median 12.4 months
HR = 0.6295% CI 0.51-0.75
P<.0001
Stratified by prior treatment status and region.
No. at riskPtz + T+ DPbo + T + D
402406
00
345311
287209
13993
8842
3217
107
00
Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.
CLEOPATRA: Independently Assessed PFS by Predefined Subgroups
Favorspertuzumab
Favorsplacebo
Unstratified analyses.
n
80843237630613511425368112778919480302613763017838840812721767
HR
0.630.630.610.720.510.460.680.650.520.640.550.620.640.680.390.550.960.720.55
0.600.64
95% CI
0.52-0.760.49-0.820.46-0.810.53-0.970.31-0.840.27-0.780.48-0.950.53-0.800.31-0.860.53-0.780.12-2.540.49-0.800.23-1.790.49-0.950.13-1.180.45-0.680.61-1.520.55-0.950.42-0.72
0.49-0.740.53-0.78
AllNo
YesEurope
North AmericaSouth America
Asia<65 years≥65 years<75 years≥75 years
WhiteBlackAsianOther
Visceral diseaseNonvisceral disease
PositiveNegative
IHC 3+FISH-positive
Unknown
0.20 0.4 0.6 1 2
Prior (neo)adjuvant chemotherapy
Region
Age group
Race
Disease type
ER/PgR status
HER2 status
Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.
CLEOPATRA: Response Data
1.5 1.53.8 8.314.6
20.8
74.665.2
5.5 4.2
0
10
20
30
40
50
60
70
80
90
100
Trastuzumab + Docetaxel + Pertuzumab
(n = 343)
Trastuzumab + Docetaxel + Placebo
(n = 336)
CR
PR
SD
PD
Not evaluable
Patie
nts
(%) ORR:
80.2%
ORR: 69.3%
Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.
CLEOPATRA: Safety
Adverse Events,* %Trastuzumab + Docetaxel + Pertuzumab
(n = 407)Trastuzumab + Docetaxel + Placebo
(n = 397)
All Grades Grade 3/4 All Grades Grade 3/4Diarrhea 66.8 7.9 46.3 5.0Alopecia 60.9 NR 60.5 NRNeutropenia 52.8 48.9 49.6 45.8Nausea 42.3 NR 41.6 NRFatigue 37.6 NR 36.8 NRRash 33.7 NR 24.2 NRDecreased appetite 29.2 NR 26.4 NRMucosal inflammation 27.8 NR 19.9 NRAsthenia 26.0 NR 30.2 NRPeripheral edema 23.1 NR 30.0 NRConstipation 15.0 NR 24.9 NRFebrile neutropenia 13.8 13.8 7.6 7.6Dry skin 10.6 NR 4.3 NRLeukopenia NR 12.3 NR 14.6
Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.
CLEOPATRA: Conclusions
• Adding pertuzumab to first-line trastuzumab/docetaxel in HER2+ locally recurrent or MBC improves PFS
• Median PFS prolonged 6.1 months according to IRF– PFS improvement consistent across nearly all patient subgroups
– ORR higher with addition of pertuzumab to trastuzumab/docetaxel
• Pertuzumab associated with increased incidence of mild and manageable diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin
• Incidence of cardiac toxicities comparable between treatment arms
Baselga J, et al. N Engl J Med. 2012; 366 (2): 109-19.
Case Discussion(Continued)
• She was treated with combined trastuzumab and docetaxel plus pertuzumab on the CLEOPATRA trial. She had an excellent response.
• Docetaxel was discontinued due to increased fatigue and worsening neuropathy after 8 cycles.
• She continued trastuzumab and pertuzumab for another 8 months until she developed increasing headaches associated with nausea.
• Imaging found multiple cerebral lesions with surrounding edema. Systemic disease remained stable.
In addition to steroids and radiation therapy, what would you recommend for this patient at this point?A. No change in therapy B. Discontinue pertuzumab, continue trastuzumab with
lapatinibC. Discontinue pertuzumab, continue trastuzumab with
capecitabineD. Discontinue trastuzumab and pertuzumab. Begin
lapatinib and capecitabine
ARS Question 5
What would you recommend for this patient at this point?A. No change in therapy B. Discontinue pertuzumab, continue trastuzumab with
lapatinibC. Discontinue pertuzumab, continue trastuzumab with
capecitabineD. Discontinue trastuzumab and pertuzumab. Begin
lapatinib and capecitabine–Reasonable choice
ARS Question 5 Response
High Risk of Brain Metastases in Patients With HER2+ MBC
Study IncidenceBendell et al, 2003 34%
Clayton et al, 2004 39%
Stemmler et al, 2006 31%
Kennecke et al, 2010 29% (ER-)15% (ER+)
CNS-Specific Goals for Patients With HER2+ Breast Cancer
• Improve/maintain quality of life– Relieve symptoms– Prevent symptomatic progression– Minimize impact of treatment-related toxicity
• Prolong survival
• Prevention
Studies of Lapatinib + Capecitabine for HER2+ Breast Cancer Brain Metastases
Study Regimen N Prior chemo Prior RT Response criteria
CNS ORR
TTP/PFS OS
Lin et al,CCR 2009*
L + cape 50 81% with >2 T+chemo; PD
on lapatinib monotherapy
100% 50% volNSS, steroids,
lack of non-CNS PD
20% 3.6 mo NR
Boccardo et al, ASCO 2008 (LEAP)
L + cape 138 Prior T required NR Investigator-assessed on
survey
18% Median time on study 2.8
mo
NR
Sutherland et al, Br J Ca 2010 (LEAP)
L + cape 34 82% with >2 chemo for MBC; prior T required
94% RECIST 21% 5.1 mo NR
Metro et al, Ann Oncol 2011
L + cape 22 Median of 2 prior T-based tx for
MBC
86% WHO 32% 5.1 mo 27.9 mo
Lin et al, 2011submitted*
L+ cape 13 Prior T required 100% 50% vol, NSS, steroids, lack of non-CNS
PD
38% NR NR
Bachelot et al, ASCO 2011*
L + cape 45 22% with >2 T+chemo
(31%: no prior T for MBC)
0% 50% vol, NSS, steroids, lack of non-CNS
PD
67% 5.5 mo 91% alive at 6 mo
Her headaches and nausea resolved with steroids. She completed WBRT and began capecitabine and lapatanib.
You explain that the most common toxicity of this combination is: A. AlopeciaB. NauseaC. Hand-foot syndromeD. DiarrheaE. Neutropenia
ARS Question 6
The most common Toxicity of this combination is:A. AlopeciaB. NauseaC. Hand-foot syndromeD. Diarrhea–Correct answerE. Neutropenia
ARS Question 6 Response
Most Frequent Adverse Events (All Grades)
Gr 3
Gr 2
SeverityGr 4
Gr 1
Diarrhea Rash and/or Skin Reaction
% o
f Pat
ient
s
PPE
L+C
L+C
L+CCC
C
10
20
30
40
50
60
70
80
90
100
0
26
19
121
13
15
11
9
28
6
9
20
5
19
132.5
12
117
L = lapatinib; C = capecitabine.
Geyer CE, et al. N Engl J Med. 2006;355(26):2733-2743.
Question and AnswerSession
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