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Sponsored By:
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SABCS 2011 Review:HER2-Directed Therapy in
Breast CancerChau Dang, MD
Assistant Professor of Medicine
Weill Cornell Medical College
Breast Cancer Medicine Service
Memorial Sloan-Kettering Cancer Center
January 28, 2012
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Objectives• Overview on Trastuzumab• Lapatinib
– Goss et al (abstract # S4-7)
• Neratinib– Martin et al (abstract # S5-7)
• Pertuzumab– Baselga et al (abstract # S5-5)– Schneeweiss et al (abstract # S5-6)
• pCR as predictor of outcomes– Loibl et al (abstract # S5-4)
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HER2-“Positive” Breast Cancer• 20-25% of invasive breast cancers• Overexpression can activate signaling• Promotes cell proliferation and survival
Hudis NEJM 2007
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Studies Slamon et al,
20011
Vogel et al,
20022
Burstein et al, 20033
Marty et al, 20054
Kaufman et al, 20095
Valero et al 20116
N 469 114 54 186 207 263
Treatment AC/EC + H or T+H vs chemo
H VH D+H vs
D
Anas + H vs
Anas DCbH vsD+H
Response Rate
50% vs 32%* 35% (IHC 3+)
34% (FISH+)68% 61% vs
34%*20.3% vs 6.8%*
72% vs 72%
Median TTP
7.4 vs 4.6 mo*
3.8 mo (H at 4 mg/kg)
3.5 mo
(H at 2 mg/kg)
NR 11.7 vs 6.1 mo*
4.8 vs
2.4 mo*10.3 vs 11.1 mo
Median PFS
NR NR NR NR 4.8 vs
2.4 mo*NR
Median OS 25.1 vs 20.3 mo*
24.4 mo NR 31.2 vs 22.7 mo*
28.5 vs 23.9 mo
37.4 vs 37.1 mo
Trastuzumab in First-Line Treatment
AC, anthracycline + cyclophosphamide; Anas, anastrozole; T, paclitaxel; D, docetaxel; EC, epirubicin + cyclophosphamide; H, trastuzumab; mo, months; PFS, progression-free survival; OS, overall survival; RR, response rate; TTP, time to progression; VH, vinorelbine + trastuzumab; *statistically significant1Slamon DJ et al. N Engl J Med. 2001:344(11):783-792; 2Vogel CL et al. J Clin Oncol. 2002;20:719-726; 3Burstein HJ et al. J Clin Oncol. 2003;21(15):2889-2895; 4Marty M et al. J Clin Oncol. 2005;23(19):4265-4274; 5Kaufman B et al. J Clin Oncol. 2009;27(33):5529-5537; 6Valero V et al. J Clin Oncol. 2011;29:149-156.
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6
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“Other” HER Targeted Strategies
HER dimerizationinhibitors
pertuzumab
Anti-EGFRblocking
antibodies
cetuximab
Anti-ligandblocking
antibodiesTyrosinekinase
Inhibitors
neratiniblapatiniberlotinib gefitinib
Ligand- or Ab-toxin
conjugates
T-DM1Adapted from Noonberg and Benz. Drugs. 2000;59:753.
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Lapatinib
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Lapatinib
• Targets intracellular kinase domain of HER1 and HER2
• Reversible inhibition of HER1 and HER2 homo and heterodimer formation
• Inhibits growth in trastuzumab conditioned cell lines
1+1 2+2 1+2
Courtesy of E. Winer
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Clinical Activity of Lapatinib in HER2+ MBC
ORR
Monotherapy in trastuzumab-refractory MBC1,2
4-8%
Monotherapy in trastuzumab-naive MBC3
≈24%
With chemo (capecitabine) in chemo & trastuzumab-refractory MBC4,5
24% (vs 14% with X alone)
With chemo (paclitaxel) in first-line MBC setting6
63% (vs 38% with T alone)
1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4Geyer NEJM 2006; 5Cameron BrCancerResTreat 2008; 6Di leo JCO 2008
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TEACH trial: Tykerb Evaluation After
Chemotherapy• Randomized, double-blind, placebo-controlled, phase III
trial to evaluate the effects of delayed adjuvant lapatinib monotherapy
• More than 3000 women– completed neo-adjuvant or adjuvant chemotherapy, – did not receive trastuzumab and – NED
• Randomized to lapatinib or placebo for up to 12 months or until a DFS event
• Median time from diagnosis to study entry: 3 years
Goss abs S4-7
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Delayed Adjuvant Lapatinib Results
• Median follow up of 4 years
• DFS events were 13% vs. 17% in favor of lapatinib vs placebo (HR = 0.83 95% CI, 0.70 to 1.00; 2 sided p=0.053), but not statistically significant.
• No role for “delayed” lapatinib in the adjuvant setting !
• What about “upfront” lapatinib in ALTTO ?
Goss abs S4-7
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•Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 yearsafter the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years• Radiotherapy if indicatedRadiotherapy if indicated
ALTTOALTTO
TH (12 wks)TH (12 wks)
H (40 wks)H (40 wks)
TL (12 wks)TL (12 wks)
L (40 wks)L (40 wks)
(L =1500 mg qd) (L =1500 mg qd)
TH (12 wks)TH (12 wks) THL (12 wks)THL (12 wks)
HL (40 wks)HL (40 wks)
(L =1000 mg qd)(L =1000 mg qd)
Washout (6 wks)Washout (6 wks)
L (34 wks)L (34 wks)
(L =1500 mg qd)(L =1500 mg qd)
Adjuvant Lapatinib and/or Trastuzumab Treatment
Optimization
Neo (adj) anthracycline-based chemo
T=paclitaxel, H=trastuzumab, L=lapatinib
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Neratinib
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Lapatinib vs Neratinibin HER2+ MBC
Lapatinib ORR Neratinib ORR
Monotherapy in H-refractory MBC
4-8%1,2 24%4
Monotherapy in H-naive MBC
≈24%3 56%4
1Blackwell 2004 (abs 103); 2Burstein Ann Oncol 2008; 3Gomez JCO 2008; 4 Burstein JCO 2010
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Phase 2, open-label trial in HER2+ locally
advanced or metastatic BC
patients
Neratinib 240 mg/day
n = 117
L + CL 1,250 mg/day +
C 2,000 mg/m2 per day n = 116
RANDOMIZE
Study Design
Neratinib was administered orally at 240 mg/day continuously
L 1,250 mg/day was administered orally continuously;
C 2,000 mg/m2 was administered orally on D1 to 14 of each 21-day cycle
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Martin et al, SABC 2011 abstract # S5-7
1○- PFS2○ - ORR, CBR, OS, Safety G 3/4 Diarrhea and PPE
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Key Eligibility Criteria• Women with HER2+ locally advanced or metastatic BC not
amenable to curative therapy
• Disease progression on or following 1 to 2 prior trastuzumab-based regimens
• Prior treatment with a taxane regimen
• Prior anthracycline treatments at or below the maximum cumulative dose of 400 mg/m2 for doxorubicin, 800 mg/m2 for epirubicin, or equivalent dose for other anthracycline derivatives
• Measurable disease (≥1 measurable lesion), as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
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Baseline Characteristics
CharacteristicNeratinib(n = 117)
L + C(n = 116)
Median age (range), y 52 (28–79) 56 (30–79)ER–positive, %b 44 40PR–positive, %c 27 28No. of prior anti-cancer regimens, % 1 14 14 2 33 33 ≥3 53 53Prior trastuzumab therapy, % Adjuvant/neoadjuvant settings 20 32 Metastatic setting 79 68
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
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0 305 10 15 20 250
10203040506070809010
0
PFS: ITT Population
n Median PFS 95% CI P valueNeratinib 117 4.5 mo 3.1–5.7 mo
0.231L + C 116 6.8 mo 5.9–8.2 moL, lapatinib; C, capecitabine; PFS, progression-free survival; CI, confidence interval.
Time since randomization (mo)
Pro
babi
lity
of P
FS
(%
)NeratinibL + C
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Non-inferiority of neratinib vsL+C could not be demonstrated.
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010203040506070809010
0
0 5 10 15 20 25 30
Overall Survival: ITT Population
n Median OS 95% CI P valueNeratinib 117 19.7 mo 18.2 mo–NE
0.280L + C 116 23.6 mo 18.0 mo–NEL, lapatinib; C, capecitabine; OS, overall survival; CI, confidence interval; NE, not estimable.
Time since randomization (mo)
Pro
babi
lity
of O
S (
%)
NeratinibL + C
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
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Best Overall Response: ITT
NeratinibN = 117
L + CN = 116
CR 2% 4%
PR 27% 36%
SD > 24 wks 15% 23%
SD < 24 wks 29% 24%
POD 17% 7%
Unknown/missing 9% 5%
L=lapatinib, C=capecitabine
The ORR was 40% in L+C arm vs 29% in neratinib arm.The CBR was 63% in L+C arm vs 44% in neratinib arm.
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Selected Treatment-related AEs (All Grades)
Neratinib (n = 116)
L + C (n = 115)
Adverse event, %
Diarrhea
85%
(28% G 3/4)
68%
(10% G 3/4)
PPE
5%
(0% G 3/4)
65%
(14% G 3/4)
Nausea 35% 38%Vomiting 24% 17%Rash 19% 34%Fatigue 16% 23%Hyperbilirubinemia 1% 23%Increased ALT 7% 13%Neutropenia 5% 12% There was a low incidence of cardiac events in both treatment arms:
neratinib, 7%; L + C, 6%
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
This presentation is the intellectual property of the authors/presenter. Contact them at mmartin@geicamorg for permission to reprint and/or distribute.
Diarrhea was transient and manageable.
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Conclusions• Neratinib did not demonstrate non-inferiority for PFS
against L+C.
• Med PFS was numerically (not statistically) superior with L+C (6.8 mo vs 4.5 mo).
• Diarrhea was the most frequently reported AE.
• The ORR of neratinib in heavily pretreated patients was 29%, consistent with results from the preceding single-arm trial.1
• Continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC ?
1. Burstein HJ, et al. J Clin Oncol. 2010;28(8):1301-1307.
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 6–10, 2011
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Pertuzumab
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HER2-Targeted Therapy with Pertuzumab
• Monoclonal antibody and pan-HER inhibitor
• Binds to a distinct epitope on the HER2 extracellular domain
• Prevents dimerization
Trastuzumab Pertuzumab
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Pertuzumab Activity
1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022
With trastuzumabN= 661
Monotherapy N= 292
% %
Best Objective Response
CR 8% 0%
PR 17% 7%
SD 6 months
26% 4%
ORR 24% 7%
Clinical Benefit Rate
50% 11%
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Pertuzumab ActivityWith
trastuzumabN= 661
Monotherapy N= 292
Trastuzumab added back in
N=142
% % %
Best Objective Response
CR 8% 0%
PR 17% 7% 14%
SD 6 months
26% 4%
ORR 24% 7% 14%
Clinical Benefit Rate
50% 11%
1. Baselga, JCO 2010; 2. Cortés, ASCO 2009 Abst # 1022
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CLEOPATRACLEOPATRA: CLinical Evaluation Of
Pertuzumab And TRAstuzumab
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Eligibility Criteria
• Centrally confirmed HER2+ (IHC 3+ and/or FISH > 2.0)• Locally recurrent, un-resectable, or MBC• Measurable and/or non-measurable• 1 prior hormone Rx for MBC allowed• Prior neoadj/adj chemo and trastuzumab allowed if DFI >
12 mo• LVEF > 50%• No h/o CHF or LVEF < 50% during/after prior
trastuzumab
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Patient CharacteristicsPlacebo +
trastuzumab + docetaxel(n = 406)
Pertuzumab + trastuzumab +
docetaxel(n = 402)
Median age, years 54y 54y
ER- and/or PR-positive
199 (49%) 189 (47%)
Prior (neo)adjuvant chemotherapy
192 (47%) 184 (46%)
Components of neoadj/adj therapy Anthracycline Hormones Taxane Trastuzumab
164 (40%)97 (24%)94 (23%)41 (10%)
150 (37%)106 (26%)91 (23%)47 (12%)
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Baselga abs #S5-5
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PFS in predefined subgroups
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Baselga abs #S5-5
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Data immature but
Baselga abs #S5-5
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Grade 3/4 Adverse Events(incidence > 5%)
Adverse Events Placebo + Trastuzumab +
DoceN=397
Pertuzumab + Trastuzumab +
DoceN=407
Neutropenia 182 (45.8%) 199 (48.9%)
Febrile neutropenia 30 (7.6%) 56 (13.8%)
Leukopenia 58 (14.6%) 50 (12.3%)
Diarrhea 20 (5.0%) 32 (7.9%)
G 3/4 diarrhea was low !
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Cardiac Safety
Placebo + Trastuzumab + Doce
Pertuzumab + Trastuzumab + Doce
Investigator-assessedsymptomatic LVSD*
1.8% 1.0%
Independently adjudicatedsymptomatic LVSD*
1.0% 1.0%
Decline in LVEF to < 50% and by > 10% from baseline
6.6% 3.8%
*LVSD=left ventricular systolic dysfunction, defined as NYHA class III/IV
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Conclusions• CLEOPATRA met its primary endpoint w/ a statistically
significant PFS improvement from 12.4 to 18.5 months w/ addition of pertuzumab (HR 0.62, p < 0.0001).
• OS data immature
• Pertuzumab well tolerated
• No increased cardiac toxicity
• May be practice changing !
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Questions
• Safe in combination with other chemotherapy foundations?
• Adjuvant/neoadjuvant studies ?
• Continuation beyond progression ?
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MSKCC IRB# 10-142THP Schema
Accrual Goal = 69 patients
♥ ♥ every 4 cycles………………….. TNI, BNP, NRG-1ß every 2 cycles…………………………
q week ……………………………
q 3 weeks………………………….
q 3 weeks………………………….
Paclitaxel at 80 mg/m2
Pertuzumab at 840mg load → 420 mg q 3 w
Trastuzumab at 8 mg/kg load → 6 mg/kg q 3 w
N = 69HER2 +0-1 prior RxTissue bx optional1° endpoint=6 mo PFS
♥ ECHO w/strain imaging
PI: Dang
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APHINITY: Adjuvant PertuzumabAnthracycline-Based
S R
FOLLOWUP
10yrs
T x 3-4AC/EC x 4 orFEC/FEC x 3-4
Trastuzumab q 3 wks x 52 wks
Pertuzumab q 3 wks x 52 wks
AC/EC x 4 orFEC/FEC x 3-4
T x 3-4
Trastuzumab q 3 wks x 52 wks
Placebo q 3 wks x 52 wks
SURGERY
RANDOMIZE
CentrallyConfirm HER2
Randomize w/i 7 wks of surgeryStart w/i 1 wk of randomization
Breast/chest RT and endocrine Rx as appropriate after chemo completion
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APHINITY: Adjuvant PertuzumabNon-Anthracycline Based
S R
FOLLOWUP
10yrs
TC x 6
Trastuzumab q 3 wks x 52 wks
Pertuzumab q 3 wks x 52 wks
TC x 6
Trastuzumab q 3 wks x 52 wks
Placebo q 3 wks x 52 wks
SURGERY
RANDOMIZE
CentrallyConfirm HER2
Randomize w/i 7 wks of surgeryStart w/i 1 wk of randomization
Breast/chest RT and endocrine Rx as appropriate after chemo completion
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Can HER2-targeted antibody therapies be administered
safely with anthracyclines?
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TRYPHAENA
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Study Endpoints• Primary endpoint:
– Cardiac safety• Symptomatic LVSD (grade ≥3)• LVEF declines (≥10 percentage points and below
50%)• Secondary endpoints:
– Toxicity
– pCR
– Clinical response rate
– Rate of BCS
– DFS, OS
– Biomarker evaluation
Schneeweiss abs #S5-6
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Eligibility Criteria
• Centrally confirmed HER2-positive locally advanced, inflammatory, or early-stage breast cancer
• Primary tumor ≥2 cm• Baseline LVEF ≥55%• ECOG PS 0 or 1• No previous anticancer therapy or radiotherapy
for any malignancy• Adequate bone marrow, liver, and renal function
Schneeweiss abs #S5-6
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Baseline CharacteristicsFEC/HP →THP
N=72FEC →THP
N=75TCHPN=76
Med age, yrs (range) 49 (27-77) 49 (24-75) 50 (30-81)
ECOG 0 65 (91.5%) 66 (88.0%) 67 (88.2%)
ECOG 1 6 (8.5%) 9 (12.0%) 9 (11.8%)
ER and/or PR + 39 (53.4%) 35 (46.7%) 40 (51.9%)
ER and/or PR- 34 (46.6%) 40 (53.3%) 36 (48.1%)
Disease Type
Operable 53 (72.6%) 54 (72.0%) 49 (63.6%)
LABC 15 (20.5%) 17 (22.7%) 24 (31.2%)
IBC 5 (6.8%) 4 (5.3%) 4 (5.2%)
HER2 IHC 0 and 1+ 1 (1.4%) 0 (0.0%) 0 (0.0%)
HER2 IHC 2+ 5 (6.8%) 1 (1.3%) 2 (2.6%)
HER2 IHC 3+ 67 (91.8%) 74 (98.7%) 75 (97.4%)
HER2 FISH + 69 (94.5%) 69 (92.0%) 73 (94.8%)
HER2 FISH- 0 (0.0%) 1 (1.3%) 2 (2.6%)
HER2 unknown 4 (5.5%) 5 (6.7%) 2 (2.6%)
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Schneeweiss abs #S5-6
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Other Notable G 3/4 AEs
Adverse events
FEC/HP →THPN=72
FEC →THPN=75
TCHPN=76
Neutropenia 34 (47.2%) 32 (42.7%) 35 (46.1%)
Febrile neutropenia
13 (18.1%) 7 (9.3%) 13 (17.1%)
Leukopenia 14 (19.4%) 9 (12.0%) 9 (11.8%)
Diarrhea 3 (4.2%) 4 (5.3%) 9 (11.8%)
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Breast Conserving Surgery When Mastectomy Was Planned*
FEC/HP →THPN=46
FEC →THPN=36
TCHPN=37
Achieved(95% CI)
10 (21.7%)(10.9-36.4)
6 (16.7%)(6.4-32.8)
10 (27.0%)(13.8-44.1)
Not Achieved 36 (78.3%) 30 (83.3%) 27 (73.0%)
* Patients in ITT population w/ T2-3 tumors for whom mastectomy was planned.
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Conclusions• Low incidence of symptomatic/asymptomatic LVSD across
all arms:– Concurrent admin of HP w/ Epi resulted in similar cardiac
tolerability compared with sequential admin or the anthracycline-free regimen
• Neutropenia, FN, leukopenia, and diarrhea were the most frequent G 3/4 AEs across all arms.
• High pCR rates (57- 66%) w/ HP, regardless of chemotherapy chosen
• TRYPHAENA supports ongoing APHINITY study, a Phase III trial to evaluate HP + standard chemo in adjuvant setting.
Schneeweiss abs #S5-6
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Comparison of OS according to pCR in Pts w/ HER2+ BCA
Receiving Neoadjuvant Chemo w/ and w/o Trastuzumab Compared
w/ Pts w/ HER2- Tumors
Loibl et al for GBG and AGO-B Study groups
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pCR in HER2 + BCA
• pCR is a surrogate for DFS and OS in pts w/ HER2+ BCA treated w/ neoadjuvant chemo w/ or w/o trastuzumab.1
• Pts w/ pCR after neoadjuvant chemo + trastuzumab have excellent DFS and OS.2
1. Gianni, Lancet 2010; 2. Untch, JCO 2011
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Objectives
• Define 3 subgroups:– HER2+ w/ trastuzumab– HER2+ w/o trastuzumab– HER2-
• Compare DDFS and OS in these subgroups– pCR vs no pCR– Hormone receptor + vs -tumors
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Patients’ Characteristics
Age 49 (22-81) yrs
cT1-3 87%
cN+ 53%
IDC 82%
Grade 3 40%
Hormone Receptor + 66%
HER2- 70%
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pCR > No pCR
• DDFS and OS were better in pCR vs no pCR groups in all 3 subgroups:
– HER2+ w/ tras– HER2+ w/o tras– HER2-
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Loibl abs #S5-4
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Author’s Conclusions• HER2+ pts w/ tras + chemo had higher pCR.
• DDFS and OS was better in pCR group than no pCR group in all 3 subgroups (HER2+ w/ tras, HER2+ w/o tras, HER2-).
• In pCR pts, OS was better in HER2+ pts w/ tras than HER2+ pts w/o tras.
• In hormone receptor- group, HER2+ pts w/ tras have better outcomes than HER2+ w/o tras and HER2- groups. Trastuzumab is effective !
• pCR can be surrogate marker for HER2+ disease.
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Summary• No role for “delayed” adjuvant lapatinib
– ALTTO may define role of lapatinib ?
• Neratinib did not demonstrate non-inferiority for PFS against L+C. – Main toxicity was diarrhea.
• Pertuzumab added to standard docetaxel + trastuzumab improves PFS ! – Maybe new standard of care !
– Adjuvant study APHINITY open !
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Summary
• No increased cardiac toxicity when HP given concurrently w/ epi-taxane Rx and carbo-taxane Rx.– However, concurrent anthracycline with trastuzumab
or pertuzumab should not be given outside of clinical trial.
• What to do for those w/ no PCR?– Need trials designed to assess utility of novel or
optimal Rx for those w/o pCR
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Thank You !
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