Optimizing Anti-HER2 Therapies for HER2 Positive Breast ...gbcc.kr/upload/GBCC Anti-HER2 Therapy...
Transcript of Optimizing Anti-HER2 Therapies for HER2 Positive Breast ...gbcc.kr/upload/GBCC Anti-HER2 Therapy...
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April 26, 2019Global Breast Cancer Conference 2019
Symposium 5
Optimizing Anti-HER2 Therapies for HER2 Positive Breast Cancer
Optimal Sequence of Anti-HER2 Therapy
in the Metastatic Setting
Toshimi Takano, M.D.Department of Medical Oncology,
Toranomon HospitalBreast Cancer Committee,
West Japan Oncology Group (WJOG)
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Conflict of Interest disclosure
Toshimi Takano
• Honoraria:
Daiichi-Sankyo, Kyowa Hakko Kirin, Eisai, Pfizer,
and Eli Lilly
• Research funding:
Daiichi-Sankyo, Kyowa Hakko Kirin, Eisai, Ono,
MSD, Merck Serono, Taiho, Novartis, Chugai
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WJOG9917B (NEWBEAT)
Results will be reported at SABCS 2019
Nivolumab Evaluation With BEvacizumab And paclitaxel
IIT using investigational drugs
MBC 1st lineHER2 negative
N = 51
Nivolumab Paclitaxel
Bevacizumab
Including Luminal MBCSingle-arm phase II trialPrimary endpoint: ORR
PI: Ozaki Y
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・ HR+ HER2- MBC・ No CTx for MBC・ 0 or 1 ET for MBC
N = 53
Phase II trial for Luminal MBC
WJOG11418B (NEWFLAME)
Nivolumab Evaluation With endocrine therapy (Fulvestrant or Letrozole) and AbeMaciclib
Primary endpoint: ORRSecondary endpoint: PFS, OS, Safety
PI: Masuda J
Letrozole cohort
Fulvestrant cohort
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6
Anti-HER2 Therapy
Current Situation
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ET-resistant
Treatment Strategy for MBC
ET #1
ET #2
ET #3
Tra+Per+CT #1
Lapa+CT #2
Tra+CT #3
T-DM1
Non-life-threatening Life-threatening
HR+ HER2+ TNBC HER2+ HER2-HR+/HER2+
Tra+Per+ ETCT #1
CT #2
CT #3
CT #4
ET: endocrine therapy, CT: chemotherapy Takano T: Original
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Non-life-threatening Life-threatening
ET-resistant
Clinical Questions
ET #1
ET #2
ET #3
Tra+Per+CT #1
Lapa+CT #2
Tra+CT #3
T-DM1
HR+ HER2+ TNBC HER2+ HER2-HR+/HER2+
Tra+Per+ ETCT #1
CT #2
CT #3
CT #4
ET: endocrine therapy, CT: chemotherapy Takano T: Original
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1st-generationAnti-HER2 drugs
Trastuzumab
(H: Herceptin)
Lapatinib
(L: Tykerb)
Mode of action HER2 MAb HER2-TKI
Administrationdiv
q3w or q1w
po
Every day
Approval June 2001 April 2009
ToxicityInfusion reaction
Cardiac toxicity
Rash
Diarrhea
Brain mets Less effective ? Effective ?
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Anti-HER2 drugs are needed all the time.
Phase III trials evaluating anti-HER2 drugs in HER2+ MBC
Endocrine therapy
Ana <Ana+H
1st line chemotherapy
PTX<PTX+H
2nd line chemotherapy (beyond PD)
X<X+H
3rd line chemotherapy (beyond PD)
L<L+H
Almost all trials were positive.
X<X+L
Let <Let +L
PTX<PTX+L
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1st line H: H0648g
Slamon DJ: N Engl J Med 344:783, 2001
PTX(or AC)± HMST 25.1 vs 20.3m
P=0.046
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H beyond PD
Cape+H>Cape (GBG-26)
mPFS: 8.2 vs 5.6mP=0.034
von Minckwitz G: J Clin Oncol 27:1999, 2009
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PTX<PTX+HH0648g
Trastuzumab
Trastuzumab to the end?
X<X+HGBG-26
L<L+HEGF104900
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XLX
P=0.00013
4.36.2Median TTP, mo
201198No. of pts
0.57 (0.43, 0.77)HR (95% CI)
Cameron D: Breast Cancer Res Treat 112:533, 2008
(%)100
0
60
(week)9010 20 30 40 50
80
40
20
060 70 80
70
90
50
30
10
Switch to Lapatinib is also effective.
EGF100151: TTP
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Clinical Question
Early switch to Lapatinib
vs.
Trastuzumab beyOnd PD
ELTOP study
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WJOG6110B/ELTOP
Takano T: The Breast 40:67-75, 2018
Previously
treated with
Tmab and
Taxane
HER2(+)MBC
2ndor3rd line
N=170
R
HX “Trastuzumab beyond PD”
Trastuzumab+Capecitabine
LX “Early Switch to Lapatinib”
Lapatinib+Capecitabine
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0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
ELTOP: PFS
Median PFS (months)
LX 7.1
HX 6.1
Hazard ratio 0.81 (90% CI, 0.55 to 1.21)
Log-rank P = .39
Pro
gre
ssio
n-F
ree S
urv
ival (%
)
Time (months)Number at risk
LX HX
43 38 25 14 8 7 7 3 2 1 1 1 0 0 0 043 31 22 10 6 4 3 3 3 3 3 2 2 2 2 0
Takano T: The Breast 40:67-75, 2018
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0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54
Overa
ll S
urv
ival (%
)
Time (months)Number at risk
LX HX
43 42 42 33 26 18 8 5 1 043 40 34 27 18 11 7 5 1 0
ELTOP: OS
Median OS (months)
LX Not reached
HX 31.0
Hazard ratio 0.58 (95% CI, 0.26 to 1.31)
Log-rank P =.18
Takano T: The Breast 40:67-75, 2018
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0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time (months)
Pro
gre
ssio
n-F
ree S
urv
iva
l (%
)
5 3 3 0 0 0 0 0 0 0 0 0 0 0 0 0
14 11 6 4 1 0 0 0 0 0 0 0 0 0 0 03 3 1 1 0 0 0 0 0 0 0 0 0 0 0 0
Number at risk
LX, wild type
HX, wild type
LX, mutant
HX, mutant
13 13 9 5 5 5 5 2 2 1 1 1 0 0 0 0
median PFS (months)
LX, PIK3CA wild type 8.2
HX, PIK3CA wild type 4.9
LX, PIK3CA mutant 4.1
HX, PIK3CA mutant 6.1
Hazard ratio (PIK3CA wild type) 0.38 (95% CI, 0.16 to 0.93)
Hazard ratio (PIK3CA mutant) 0.60 (95% CI, 0.11 to 3.13)
PFS by PIK3CA mutations
Takano T: The Breast 40:67-75, 2018
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0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
5 4 4 2 1 0 0 0 0
14 12 9 6 4 2 1 0 03 3 3 1 0 0 0 0 0
13 13 13 12 11 6 2 1 0Number at risk
LX, wild type
HX, wild type
LX, mutant
HX, mutant
Time (months)
Ove
rall
Su
rviv
al (%
) median OS (months)
LX, PIK3CA wild type Not reached
HX, PIK3CA wild type 18.7
LX, PIK3CA mutant 15.4
HX, PIK3CA mutant 15.7
Hazard ratio (PIK3CA wild type) 0.088 (95% CI, 0.011 to 0.73)
Hazard ratio (PIK3CA mutant) 1.20 (95% CI, 0.20 to 7.32)
OS by PIK3CA mutations
Takano T: The Breast 40:67-75, 2018
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2nd or more-generation anti-HER2 drugs
Pertuzumab
T-DM1
Neratinib or other HER2-TKIs
DS-8201a or other HER2-ADCs
Combinations with other agents
CDK4/6-I
Immune checkpoint inhibitors
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1st line Pertuzumab
CLEOPATRA:HER2+ MBC 1st line
Trastuzumab + Pertuzumab + Docetaxel
Baselga J: N Engl J Med 366:109, 2012
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OS was also improvedSwain SM: N Engl J Med 372:724-34, 2015
MST40.8m → 56.5m
MST of CT alone arm in H0648g was 20.3m
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CLEOPATRA1
n=808
EGF30008 6
n=219
TAnDEM 7
n=208
M770014
n=188
H0648g 5
n=469
HERNATA2
n=284
BCIRG0073
n=263
56.5
40.8
38.8
35.7
37.4
37.1
31.2
22.7
25.1
20.3
33.3
32.3
28.5
23.9
HER+DTX+PER
HER+DTX
HER+VNR
HER+DTX
HER+DTX+CBDCA
HER+DTX
HER+DTX
DTX
HER+CT
CT
LAP+FEM
FEM
HER+ANA
ANA
0 10 20 30 40 50 60
ER and/or
PgR positive
P<0.001
P=0.046
P=0.0325
P=0.98
P=0.99
P=0.113
P=0.325
1) Baselga J, et al. N Engl J Med 2012; 366: 109-119
2) Andersson M, et al. J Clin Oncol 2011; 29: 264-71
3) Valero V, et al. J Clin Oncol 2011; 29: 149-156
4) Marty M, et al. J Clin Oncol 2005; 23: 4265-74
5) Slamon DJ, et al. N Engl J Med 2001; 344: 783-92
6) Johnston S, et al. J Clin Oncol 2009; 27:5538-46
7) Kaufman B, et al. J Clin Oncol 2009; 27:5529-37
HER2+ MBC: MST (1st line)
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T-DM1: 2nd line
EMILIA
Verma S: N Engl J Med 367:1783, 2012
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T-DM1: 1st line
• Stratification factors: World region, Prior neo-/adjuvant therapy (if Yes: prior
trastuzumab/lapatinib), Visceral disease
• Primary end point: PFS by independent review facility (IRF), non-inferiority and superiority
assessed
• Key secondary end points: OS, PFS by investigator, ORR, Safety, Patient-reported outcomes
MARIANNE
• HER2-positive (central) LABC or MBC
• No prior chemotherapy for LABC/MBC
• >6 months from prior neo-/adjuvant vincaalkaloid or taxane chemotherapy
N = 1095
Trastuzumab + docetaxelOR
Trastuzumab + paclitaxel
T-DM1 + placebo
T-DM1 + pertuzumab
Ellis PA, J Clin Oncol, 2015 ASCO Annual Meeting abstr 507
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MARIANNE: PFS T-DM1(+Pmab) was not superior to Tmab+Taxane
Ellis PA, J Clin Oncol, 2015 ASCO Annual Meeting abstr 507
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Standard Tx for HER2+ MBC
1st line
Trastuzumab+Pertuzumab+Taxane
2nd line
T-DM1
3rd or later line
Lapatinib+Capecitabine
Trastuzumab beyond PD+CT
Others
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30
Anti-HER2 Therapy
Clinical Questions
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1st line T-DM1?
T-DM1=Tmab+Taxane<Tmab+Pmab+Taxane
In selected patients, can T-DM1 be an option?
Elderly patients?
Patients with predictive biomarkers (e.g. PIK3CA mutations)?
HER2+ MBC
Elderly Pts65-79yo
R
Tmab+Pmab+DTX
T-DM1
<JCOG1607 (HERB TEA Study)>
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Pertuzumab Beyond PD?
“Trastuzumab beyond PD” is supported by several trials.
Significance of “Pertuzumab beyond PD” is unknown.
HER2+ MBC
R
Tmab+Pmab+
Taxane
T-DM1
T-DM1+Pmab
<Proposed Trial>
PD
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JBCRG-M05 (PRECIOUS)
“Rechallenge of Pertuzumab”
3rd/4th line
R
Tmab + CT
(N=218)
CT: Taxane, Vinorelbine, Eribulin, Capecitabine, or Gemcitabine
Primary endpoint: PFS
Previously treated with Pmab
HER2+ MBC Tmab + Pmab+ CT
Phase III
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Best partner for Tmab + Pmab?
Tmab + Pmab + Cytotoxic agents
DTX (Phase III CLEOPATRA)
PTX (Phase II)
Vinorelbine (Phase II)
Capecitabine (Phase II)
Eribulin (Phase II)
Tmab + Pmab + Endocrine therapy
AI
Fulvestrant
ET+CDK4/6-I
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EMERALD (JBCRG-M06)
HER2+ MBC 1st line, Phase III
HER2+MBC
N=480
Tmab+Pmab+Taxane
R
Tmab+Pmab+Eribulin
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HER2+ ER+ MBC: Options
1st line
Trastuzumab+Pertuzumab+Taxane
2nd line
T-DM1
3rd or later line
Lapatinib+Capecitabine
Trastuzumab beyond PD+CT
Others
Tmab+Pmab+Endocrine Tx
Tmab+Pmab+Endocrine Tx(Maintenance Tx)
Anti-HER2 drug+Endocrine Tx
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PERTAIN: Tmab+Pmab+AI
Rimawi M: J Clin Oncol 36:2826-2835, 2018
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PERTAIN: PFS
Rimawi M: J Clin Oncol 36:2826-2835, 2018
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PERTAIN: PFS (No induction CTx)
Rimawi M: J Clin Oncol 36:2826-2835, 2018
Therapy without CTx yielded a median PFS of 21.7m.
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PATINA: Tmab+Pmab+ET+Palbo
Maintenance Tx after Tmab+Pmab+CT
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Predictive biomarkers?
Biomarkers will guide the selection of anti-HER2 therapy in the future, but not yet.
Many candidates have been suggested.
HER2, HER2-ECD, p95HER2, HER2 mut
HER2/HER3 heterodimers
FcγR polymorphisms
Ligands (e.g. TGFα, Heregulin)
Immunology (e.g. TILs, PD-L1)
PI3K/Akt pathway (e.g. PIK3CA mut, PTEN)
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CLEOPATRA
Baselga J: SABCS 2012 #S5-1
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CLEOPATRA
Baselga J: SABCS 2012 #S5-1
PIK3CA mut is not a predictor of pertuzumab efficacy.
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PIK3CALap + Cap T-DM1
N mPFS N mPFS HR 95% CI
Mutated
Wild-type
39
87
4.3
6.4
40
93
10.9
9.8
0.45
0.740.25–0.82
0.50–1.10
Lap+Cap(PIK3CA mutated)
Lap+Cap(PIK3CA wild-type)
T-DM1(PIK3CA mutated)T-DM1(PIK3CA wild-type)
Time (months)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 280.0
0.2
0.4
0.6
0.8
1.0
EMILIA: PFS by PIK3CA mutations
Baselga J, et al. AACR 2013
EMILIA
PIK3CA mut may be a predictor of T-DM1 efficacy.
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New Antibody-Drug Conjugate
trastuzumab deruxtecan
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Standard Tx will be changed?
1st line
Trastuzumab+Pertuzumab+Taxane
2nd line
T-DM1
3rd or later line
Lapatinib+Capecitabine
Trastuzumab beyond PD+CT
Others
DS-8201a?
DS-8201a?
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DS-8201a is also effective in HER2-low BC
HER2-positive Breast Cancer HER2-low Breast Cancer
Modi S: SABCS2017 PD3-07
This drug will change the concept of HER2 positivity.
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Summary
Tmab+Pmab+Taxane as 1st line and T-DM1
as 2nd line are current standard strategy.
Tmab+Pmab+ET is also an important
option.
We need predictive biomarkers to select
individualized therapy.
Many clinical questions remain to be
solved.
Let’s solve them in inter-group
collaboration!
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Toshimi Takano
Thank you !