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HER2+ breast cancer:HER2+ breast cancer:Progress and PromisesProgress and Promises
Ana Maria GonzalezAna Maria Gonzalez--Angulo, M.D.Angulo, M.D.Associate ProfessorAssociate ProfessorAssociate ProfessorAssociate Professor
Breast Medical OncologyBreast Medical OncologySystems BiologySystems Biology
ProgressProgress
•• Dual targeting of HER2 is better than Dual targeting of HER2 is better than HERHER--2 targeting single agents2 targeting single agents–– the evolving story with the evolving story with trastuzumabtrastuzumab//pertuzumabpertuzumab
–– role for role for trastuzumabtrastuzumab//lapatiniblapatinib–– role for role for trastuzumabtrastuzumab//lapatiniblapatinib
–– role for role for trastuzumabtrastuzumab//bevacizumabbevacizumab ??
•• DDuration of effective treatmenturation of effective treatment–– role in MBCrole in MBC
–– role in adjuvant ?role in adjuvant ?
PPertuzumabertuzumab and and trastuzumabtrastuzumab target target different HER2 receptor domainsdifferent HER2 receptor domains
HER2HER2
PertuzumabPertuzumab
HER1/3/4HER1/3/4
TrastuzumabTrastuzumab
DimerizationDimerizationdomaindomain
Subdomain IVSubdomain IV
TrastuzumabTrastuzumab::
•• Inhibits ligandInhibits ligand--independent HER2 independent HER2 signalingsignaling
•• Activates ADCCActivates ADCC
•• Prevents HER2 ECD sheddingPrevents HER2 ECD shedding
PertuzumabPertuzumab::
•• Inhibits ligandInhibits ligand--dependent HER2 dependent HER2 dimerization and signalingdimerization and signaling
•• Activates ADCCActivates ADCC
KPL-4
400
450
500
550
600
650[m
m3 ] ±
SE
M
Vehicle control
Pertuzumab (30/15 mg/kg/w i.p.)
Trastuzumab (30/15 mg/kg/w i.p.)
PertuzumabPertuzumab + + trastuzumabtrastuzumabcombination in a HER2combination in a HER2--positive positive breast cancer breast cancer xenograftxenograft modelmodel
0
50
100
150
200
250
300
350
400
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80Treatment period [d]
Mea
n tu
mor
vol
ume
[
Pertuzumab + Trastuzumab
6/10 animals cured
Friess et al. ESMO 2006
KPL-4
900
1000
1100
1200
1300
1400
[mm
3 ] ± S
EM
Vehicle control
Trastuzumab (15 mg/kg/w i.p.)
Trastuzumab + Pertuzumab
PertuzumabPertuzumab in a breast cancer in a breast cancer xenoxeno--graft model progressing under graft model progressing under
trastuzumabtrastuzumab alonealone
Unpublished data: W. Scheuer, Roche Pharma Research Penzberg
0
100
200
300
400
500
600
700
800
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85Treatment period [d]
Mea
n tu
mor
vol
ume
[
Phase II trial of Phase II trial of pertuzumabpertuzumab + + trastuzumabtrastuzumab in in HER2HER2--positive MBC patients progressing during positive MBC patients progressing during
trastuzumabtrastuzumab--based therapybased therapy
Pertuzumab + Pertuzumab + trastuzumabtrastuzumab
Cohorts Cohorts 1 and 21 and 2
HER2HER2--positive MBC positive MBC progressing on progressing on
15 patients received15 patients receivedpertuzumabpertuzumabPDPD
HER2HER2--positive MBC positive MBC progressing on trastuzumab progressing on trastuzumab
+ chemotherapy + chemotherapy (Cohort 1, n=24;(Cohort 1, n=24;Cohort 2, n=42)Cohort 2, n=42)
•• Primary objectivesPrimary objectives–– safety (evaluate safety of combined antibody treatment)safety (evaluate safety of combined antibody treatment)
–– efficacy (response rate + stabilization of disease = CBR)efficacy (response rate + stabilization of disease = CBR)
•• Heavily Heavily pretreatedpretreated populationpopulation–– median 3 prior lines of therapy in the metastatic settingmedian 3 prior lines of therapy in the metastatic setting
Baselga et al. J Clin Oncol 2010
progressing on progressing on trastuzumab + trastuzumab +
chemotherapy (n=29)chemotherapy (n=29)
pertuzumabpertuzumab+ +
trastuzumabtrastuzumabCohort 3Cohort 3
PertuzumabPertuzumabPDPD
PertuzumabPertuzumab / / trastuzumabtrastuzumab combination combination therapy more active than treatment with therapy more active than treatment with
either agent aloneeither agent alone
Cohorts 1 and 2Cohorts 1 and 2(P + T) (P + T) (n=66)(n=66)
Cohort 3 Cohort 3 (P)(P)
(n=27(n=27aa))
Cohort 3 Cohort 3 (P (P →→→→→→→→ P + T)P + T)
(n=11(n=11bb))
CR, %CR, % 7.67.6 0.00.0 0.00.0
PR, %PR, % 16.716.7 3.43.4 21.421.4
ORR, %ORR, % 24.224.2 3.43.4 21.421.4
SD SD >>6 months, %6 months, % 25.825.8 6.96.9 21.421.4
CBR, % CBR, % (CR + PR + SD (CR + PR + SD >>6 months)6 months) 50.050.0cc 10.310.3 37.537.5
PD, %PD, % 50.050.0 82.882.8 57.157.1
Baselga et al. J Clin Oncol 2010
CLEOPATRA: a Phase III trial of CLEOPATRA: a Phase III trial of trastuzumabtrastuzumab + + pertuzumabpertuzumab in the in the
1st1st--line settingline setting
1:1 1:1 HER2HER2--positivepositiveMBC (n=800MBC (n=800aa))
Docetaxel + trastuzumab + placeboDocetaxel + trastuzumab + placebo
Docetaxel + trastuzumab Docetaxel + trastuzumab + pertuzumab + pertuzumab
An international, Phase III, randomised, doubleAn international, Phase III, randomised, double--blind, blind, placeboplacebo--controlled study (~250 sites worldwide)controlled study (~250 sites worldwide)
•• End pointsEnd points
–– PFS and OSPFS and OS
–– quality of lifequality of life
–– biomarker analysisbiomarker analysis
Docetaxel + trastuzumab Docetaxel + trastuzumab + pertuzumab + pertuzumab
Baselga et al, N Engl J Med 2011
Cleopatra: Independently Cleopatra: Independently assessed PFSassessed PFS
n = 433 PFS eventsn = 433 PFS events
60
70
80
90
100 Ptz + T + D: median 18.5 months
Pla + T + D: median 12.4 months
free s
urviva
l (%
)
402 345 267 139 83 32 10 0 0Ptz + T + D
406 311 209 93 42 17 7 0 0Pla + T + D
Time (months)0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
HR = 0.6295% CI 0.51‒0.75
p<0.0001
Prog
ress
ion-
free s
urviva
l (%
)
Stratified by prior treatment status and regionBaselga et al, N Engl J Med 2011
Exposure to study treatment in Exposure to study treatment in CleopatraCleopatra
PlaceboPlacebo+ + trastuzumabtrastuzumab+ + docetaxeldocetaxel((nn = 397)= 397)
PertuzumabPertuzumab+ + trastuzumabtrastuzumab+ + docetaxeldocetaxel((nn = 407)= 407)
Study treatmentStudy treatmentTime on any treatment (median), monthsTime on any treatment (median), months 11.811.8 18.118.1
Study treatmentStudy treatmentTime on any treatment (median), monthsTime on any treatment (median), months 11.811.8 18.118.1
DocetaxelDocetaxelDose intensity (median), mg/mDose intensity (median), mg/m22/week/weekNumber of cycles administered, median Number of cycles administered, median
(range)(range)
24.824.88 (18 (1‒‒41)41)
24.624.68 (18 (1‒‒35)35)
Baselga et al, N Engl J Med 2011
NeoSphereNeoSphere: study design: study design
THP (THP (nn=107)=107)docetaxeldocetaxel + + trastuzumabtrastuzumab ++pertuzumabpertuzumab
HP (n=107)HP (n=107)
SS
UU
RR
GG
FEC q3w x 3FEC q3w x 3trastuzumab q3w cycles 5trastuzumab q3w cycles 5––1717
FEC q3w x 3FEC q3w x 3trastuzumab q3w cycles 5trastuzumab q3w cycles 5––1717
TH (n=107)TH (n=107)docetaxel + docetaxel + trastuzumab trastuzumab
Patients with Patients with operable or operable or locally advanced locally advanced /inflammatory* /inflammatory* HER2HER2--positive positive BCBC
HP (n=107)HP (n=107)trastuzumab + trastuzumab + pertuzumab pertuzumab
TP (n=96)TP (n=96)docetaxel + docetaxel + pertuzumab pertuzumab
EE
RR
YY
docetaxel q3w x 4docetaxel q3w x 4→→FEC q3w x 3 FEC q3w x 3 trastuzumab q3w cycles 5trastuzumab q3w cycles 5––1717
FEC q3w x 3FEC q3w x 3trastuzumab q3w cycles 5trastuzumab q3w cycles 5––2121
Study dosing: q3w x 4Study dosing: q3w x 4
ChemoChemo--nanaïïve & ve & primary tumors primary tumors >2cm (>2cm (N=417)N=417)
BC, breast cancer; FEC, 5BC, breast cancer; FEC, 5--fluorouracil, fluorouracil, epirubicinepirubicin and and cyclophosphamidecyclophosphamide*Locally advanced=T2*Locally advanced=T2––3, N23, N2––3, M0 or T4a3, M0 or T4a––c, any N, M0; operable=T2c, any N, M0; operable=T2––3, N03, N0––1, M0; inflammatory = T4d, 1, M0; inflammatory = T4d, any N, M0any N, M0H, H, trastuzumabtrastuzumab; P, ; P, pertuzumabpertuzumab; T, ; T, docetaxeldocetaxel
Gianni L et al. SABCS 2010
NeoSphereNeoSphere pCRpCR rates: rates: ITTITT
P=0.0141P=0.01415050
4040
3030
95% C
I95% C
IP=0.0198P=0.0198
P=0.003P=0.003
45.845.83030
2020
1010
00THTH THPTHP HPHP TPTP
pCR
pCR, %
, % ±± ±± ±± ±±
95% C
I95% C
I
29.029.0
45.845.8
16.816.8
24.024.0
Gianni L et al. SABCS 2010
4040
5050
6060
7070
ER or PR posER or PR posER and PR negER and PR neg
pCRpCR and hormone receptors and hormone receptors statusstatus
63.263.2
95% C
I95% C
I
00
1010
2020
3030
4040
THTH THPTHP HPHP TPTP
20.020.0
26.026.0
17.417.4
36.836.8
29.129.1 30.030.0
5.95.9
pCR
pCR, %
, % ±± ±± ±± ±±
95% C
I95% C
I
Gianni L et al. SABCS 2010
Heavily pretreated patients Heavily pretreated patients with HER2with HER2--positive positive
metastatic breast cancer metastatic breast cancer
Lapatinib 1500 mg PO QDLapatinib 1500 mg PO QD(n = 148)(n = 148)
Optional crossover to Optional crossover to trastuzumab arm if trastuzumab arm if
PD after 4 wks (n = 77)PD after 4 wks (n = 77)
Updated Analysis: Phase III Trial of Updated Analysis: Phase III Trial of LapatinibLapatinib ±± TrastuzumabTrastuzumab in HER2+ MBC. in HER2+ MBC.
Primary endpoint:Primary endpoint:PFSPFS
Secondary endpoints:Secondary endpoints:metastatic breast cancer metastatic breast cancer
and progression on and progression on trastuzumabtrastuzumab
(N = 296)(N = 296)
Stratified by visceral disease Stratified by visceral disease and hormone receptor statusand hormone receptor status
Lapatinib 1000 mg PO QD +Lapatinib 1000 mg PO QD +Trastuzumab 4 mg/kg loading Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV wklydose, then 2 mg/kg IV wkly
(n = 148)(n = 148)
PD after 4 wks (n = 77)PD after 4 wks (n = 77) Secondary endpoints:Secondary endpoints:OSOSORRORRCBRCBR
Blackwell K, et al. J Clin Oncol 2010
ProgressionProgression--Free Survival in ITTFree Survival in ITT
L L N = 145N = 145
L+T L+T N = 146N = 146
Progressed or Died, NProgressed or Died, N 128128 127127
Median, weeksMedian, weeks 8.18.1 12.012.0
Hazard ratio (95% CI)Hazard ratio (95% CI) 0.73 (0.57, 0.93)0.73 (0.57, 0.93)
LogLog--rank P rank P valuevalue .008.008
Cum
ulative
% A
live
withou
t Pr
ogre
ssion
Cum
ulative
% A
live
withou
t Pr
ogre
ssion
28%28%4040
6060
8080
100100
6 Month PFS6 Month PFS
Cum
ulative
% A
live
withou
t Pr
ogre
ssion
Cum
ulative
% A
live
withou
t Pr
ogre
ssion
Patients At RiskPatients At Risk
148148148148
LLL+TL+T
53537373
21214242
13132727
5588
0022
13%13%
28%28%
00
2020
4040
00 1010 2020 3030 4040 5050 6060Time from Randomization (weeks)Time from Randomization (weeks)
Blackwell K et al. J Clin Oncol 2010
Updated Overall Survival in ITTUpdated Overall Survival in ITT
L L N =145N =145
L+T L+T N =146N =146
Died, N (%)Died, N (%) 113 (78)113 (78) 105 (72)105 (72)
Median, monthsMedian, months 9.59.5 1414
Hazard ratio (95% CI)Hazard ratio (95% CI) 0.74 (0.57, 0.97)0.74 (0.57, 0.97)
LogLog--rank P rank P valuevalue .026.026
6 Month 6 Month OSOS
80%80%
70%70% 56%56%
6 Month 6 Month OSOS
12 Month 12 Month OSOS
41%41%
Blackwell K et al. J Clin Oncol 2010
NeoNeo--ALTTO trial (BIG 01ALTTO trial (BIG 01--06)06)
Invasive operableInvasive operableHER2+ BCHER2+ BCT > 2 cm T > 2 cm (IBC excluded)(IBC excluded)LVEF LVEF ≥≥≥≥≥≥≥≥ 50%50%
lapatiniblapatinib
trastuzumabtrastuzumab
FFEEC C
SSUURR
RRAANNDD
lapatinib lapatinib
trastuzumabtrastuzumab
paclitaxel paclitaxel
paclitaxel paclitaxel
Stratification:Stratification:•• T≤5 cm vs. T>5 cmT≤5 cm vs. T>5 cm•• ER or ER or PgRPgR + vs. + vs.
ER & ER & PgRPgR ––•• N 0N 0--1 vs. N 1 vs. N ≥ 2≥ 2•• BCS or notBCS or not
LVEF LVEF ≥≥≥≥≥≥≥≥ 50%50%N=450 N=450
34 weeks34 weeks
52 weeks of anti52 weeks of anti--HER2 therapyHER2 therapy
trastuzumabtrastuzumab
lapatiniblapatinibtrastuzumabtrastuzumab
C C
XX
33
RRGGEERRYY
DDOOMMIIZZEE
lapatiniblapatinibtrastuzumabtrastuzumab
paclitaxel paclitaxel
paclitaxelpaclitaxel
+ 12 wks+ 12 wks6 wks6 wks
Baselga J et al. SABCS 2010
Efficacy Efficacy –– pCRpCR and and tpCRtpCR
Baselga J et al. SABCS 2010
pCRpCR by Hormone Receptor Statusby Hormone Receptor Status
Baselga J et al. SABCS 2010
TrastuzumabTrastuzumab plus plus BevacizumabBevacizumab: : synergy in a breast cancer synergy in a breast cancer
xenograftxenograft modelmodel
Mean
tumou
r vo
lume
Mean
tumou
r vo
lume
SEM
SEM
650650600600550550500500450450400400350350
ControlControl
TrastuzumabTrastuzumab (30/15mg/kg every week (30/15mg/kg every week i.pi.p.).)
BevacizumabBevacizumab (5mg/kg every 2 weeks (5mg/kg every 2 weeks i.pi.p.).)
BevacizumabBevacizumab + + TrastuzumabTrastuzumab
TrastuzumabTrastuzumab + + BevacizumabBevacizumab
Scheuer W et al. EORTC-NCI-AACR 2006
SEM = standard error of meanSEM = standard error of mean
Treatment period (days)Treatment period (days)
Mean
tumou
r vo
lume
Mean
tumou
r vo
lume
(mm
(mm
33) ) ±± ±± ±± ±±
SEM
SEM
350350300300250250200200150150100100505000
00 1010 2020 3030 4040 5050 6060 7070 8080
TrastuzumabTrastuzumab + + BevacizumabBevacizumab
•• AEsAEs
–– one grade 4 one grade 4 LVEF declineLVEF decline
–– seven grade 3 seven grade 3
Patient
s (%
)Pa
tient
s (%
)
5151
6060
5050
4040
Phase II trial of Phase II trial of TrastuzumabTrastuzumab with with BevacizumabBevacizumab in firstin first--line MBCline MBC
ORR 54%ORR 54%
–– seven grade 3 seven grade 3 hypertensionhypertension
–– one grade 3 one grade 3 proteinuriaproteinuria
–– one grade 3 one grade 3 dyspnoeadyspnoea
Patient
s (%
)Pa
tient
s (%
)
33
3030
1616
Clinical response (n=37)Clinical response (n=37)
Pegram M et al. Semin Oncol 2006
4040
3030
2020
1010
00
CRCR PRPR SDSD PDPD
AVEREL AVEREL Study schemaStudy schema
Previously untreated Previously untreated HER2HER2--positive LR/mBCpositive LR/mBC
•• Centrally confirmed IHC 3+ or Centrally confirmed IHC 3+ or IHC 2+ and FISH/CISH+IHC 2+ and FISH/CISH+
•• Measurable or evaluable Measurable or evaluable diseasedisease
•• ECOG PS 0/1ECOG PS 0/1No CNS metastasesNo CNS metastases
H: 8H: 8→→6 mg/kg6 mg/kgDOC: 100 mg/mDOC: 100 mg/m22
both q3wboth q3w
H: 8H: 8→→6 mg/kg6 mg/kgDOC: 100 mg/mDOC: 100 mg/m22
BEV: 15 mg/kg BEV: 15 mg/kg
RR
•• ECOG PS 0/1ECOG PS 0/1•• No CNS metastasesNo CNS metastases
DOC: 100 mg/mDOC: 100 mg/mBEV: 15 mg/kg BEV: 15 mg/kg
all q3wall q3wStratification variablesStratification variables•• Prior (neo)adjuvant Prior (neo)adjuvant taxanetaxane (yes (yes vsvs no no
[no chemotherapy/relapse <12 months [no chemotherapy/relapse <12 months vsvs ≥12 months since last ≥12 months since last chemotherapy])chemotherapy])
•• Adjuvant H (yes Adjuvant H (yes vsvs no)no)
•• ER/ER/PgRPgR status (positive status (positive vsvs negative)negative)
•• Measurable disease (yes Measurable disease (yes vsvs no)no)
•• H and BEV continued to PD or H and BEV continued to PD or unacceptable toxicityunacceptable toxicity
•• DOC given until PD or unacceptable DOC given until PD or unacceptable toxicity (planned minimum of 6 toxicity (planned minimum of 6 cycles)cycles)
Gianni L et al. SABCS 2011
IRCIRC--assessed PFS assessed PFS Est
imate
d p
robability
Est
imate
d p
robability
1.01.0
0.80.8
0.60.6
H + DOCH + DOC(n=208)(n=208)
H + DOC + BEVH + DOC + BEV(n=216)(n=216)
Events, n (%)Events, n (%) 114 (54.8)114 (54.8) 111 (51.4)111 (51.4)
Median PFS, monthsMedian PFS, months(95% CI)(95% CI)
13.913.9(11.2(11.2‒‒16.7)16.7)
16.816.8(14.1(14.1‒‒19.5)19.5)
HR, unstratifiedHR, unstratified(95% CI)(95% CI)
0.760.76
(0.59(0.59‒‒0.99)0.99)
LogLog--rank prank p--valuevalue 0.04140.0414
HR, stratifiedHR, stratifiedaa
(95% CI)(95% CI)0.72 0.72
(0.54(0.54‒‒0.94)0.94)
Est
imate
d p
robability
Est
imate
d p
robability
Time (months)Time (months)00 66 1212 1818 2424 3030 3636 4242 4848 5454
0.40.4
0.20.2
0.0 0.0
No. at risk:No. at risk:208208 149149 7575 3939 2424 1414 77 22 11 00216216 173173 101101 5858 3232 1515 1010 77 22 00
13.913.9 16.816.8
LogLog--rank rank pp--valuevalue 0.01620.0162
Gianni L et al. SABCS 2011
1.01.0
0.80.8
AVEREL AVEREL PFS according to baseline PFS according to baseline plasma plasma VEGFVEGF--AA
PlasmaPlasmaVEGFVEGF--AA HRHR (95% CI)(95% CI)
≤ median≤ median 0.830.83 (0.50(0.50‒‒1.36)1.36)
> median> median 0.700.70 (0.43(0.43‒‒1.14)1.14)
H + DOC + H + DOC + BEV betterBEV better
H + DOC H + DOC betterbetter
Est
imate
d p
robability
Est
imate
d p
robability
H + DOC low VEGFH + DOC low VEGF--A (A (nn=45)=45)
H + DOC high VEGFH + DOC high VEGF--A (n=37)A (n=37)
H + DOC + BEV low VEGFH + DOC + BEV low VEGF--A (A (nn=36)=36)
H + DOC + BEV high VEGFH + DOC + BEV high VEGF--A (A (nn=43)=43)
0.60.6
0.40.4
0.20.2
0.00.000 66 1212 1818 2424 3030 3636 4242 4848 5454
0.20.2 0.50.5 11 22 55HRHR
Est
imate
d p
robability
Est
imate
d p
robability
Time (months)Time (months)
13.613.68.58.5 16.516.516.616.6
Gianni L et al. SABCS 2011
pCRpCR and clinical response rates by and clinical response rates by neoadjuvantneoadjuvant systemic therapy typesystemic therapy type
PHPH--FECH FECH
(N=235)(N=235)
TCH TCH
(N=65)(N=65)
NN PercentPercent NN PercentPercent PP
pCRpCR
No pCRNo pCR 8989 39.439.4 3434 56.756.7 0.0160.0167070 P=0.016P=0.016
No pCRNo pCR 8989 39.439.4 3434 56.756.7 0.0160.016
pCRpCR 137137 60.660.6 2626 43.343.3
ClinClin ResponseResponse
CRCR 172172 80.880.8 3333 58.958.9 0.0060.006
PRPR 1515 7.07.0 1111 19.619.6
SDSD 1616 7.57.5 1111 19.619.6
PDPD 1010 4.74.7 11 1.81.8
RadRad ResponseResponse
CRCR 9696 41.241.2 1515 28.828.8 0.210.21
PRPR 130130 55.855.8 3636 69.269.2
SDSD 77 3.03.0 11 1.91.9
00
1010
2020
3030
4040
5050
6060
PHPH--FECH FECH TCHTCH
60.6%60.6% 43.3%43.3%
Bayraktar S et al. Cancer 2011
Multivariate logistic regression Multivariate logistic regression model for model for pCRpCR
pCRpCR
OROR 95% CI 95% CI PP
PHPH--FECH FECH vs.vs. TCHTCH 1.451.45 1.06 1.06 -- 1.981.98 0.020.02
Age: >50 Age: >50 vs.vs. ≤50≤50 1.141.14 0.68 0.68 -- 1.911.91 0.610.61
Race: Black Race: Black vs.vs. NonNon--BlackBlack 0.690.69 0.34 0.34 -- 1.41.4 0.300.30Race: Black Race: Black vs.vs. NonNon--BlackBlack 0.690.69 0.34 0.34 -- 1.41.4 0.300.30
BMIBMI: Overweight/obese : Overweight/obese vsvs. . Normal/underweightNormal/underweight
1.221.22 0.69 0.69 -- 2.142.14 0.490.49
ER Status: positive ER Status: positive vs.vs. Negative/weakNegative/weak 0.320.32 0.19 0.19 -- 0.550.55 <0.001<0.001
Grade: III Grade: III vs.vs. I/III/II 1.811.81 1.00 1.00 -- 3.273.27 0.050.05
Clinical T: T4 Clinical T: T4 vs.vs. T1T1--33 0.520.52 0.27 0.27 -- 0.980.98 0.0430.043
ClinicalClinical N: N1N: N1--3 3 vs.vs. N0N0 1.111.11 0.62 0.62 -- 1.991.99 0.730.73
Bayraktar S et al. Cancer 2011
RFS by NST type RFS by NST type
All PatientsAll Patients No IBC PatientsNo IBC Patients
Bayraktar S et al. Cancer 2011
PromisesPromises
•• TT--DM1 and its developmentDM1 and its development
•• subsub--groups of HER2groups of HER2--positive cancerspositive cancers
•• Targeting mechanisms of resistanceTargeting mechanisms of resistance
•• AntiAnti--HER2 vaccinesHER2 vaccines•• AntiAnti--HER2 vaccinesHER2 vaccines
Numerous treatments for HER2Numerous treatments for HER2--positive breast cancer in developmentpositive breast cancer in development
•• HER2 HER2 dimerizationdimerization inhibitorinhibitor
•• HER2 ADCHER2 ADC
•• PI3K pathway inhibitorsPI3K pathway inhibitors
•• EGFR/HER2 Tyrosine EGFR/HER2 Tyrosine kinasekinase inhibitorsinhibitors
•• HSP 90 inhibitorsHSP 90 inhibitors•• HSP 90 inhibitorsHSP 90 inhibitors
•• VEGF receptor inhibitorsVEGF receptor inhibitors
•• HER3 Monoclonal antibodiesHER3 Monoclonal antibodies
•• IGF1R Monoclonal antibodies and IGF1R Monoclonal antibodies and TKIsTKIs
•• IGF1R/IR Tyrosine IGF1R/IR Tyrosine kinasekinase inhibitorsinhibitors
•• cMET Monoclonal antibodies and cMET Monoclonal antibodies and TKIsTKIs
•• Anti HER2 vaccinesAnti HER2 vaccines
Monoclonal antibody: trastuzumabMonoclonal antibody: trastuzumab
Target expression: HER2Target expression: HER2
Cytotoxic agent: DM1Cytotoxic agent: DM1
TT--DM1: 1stDM1: 1st--inin--class HER2 antibodyclass HER2 antibody--drug drug conjugate (ADC)conjugate (ADC)
Highly potent chemotherapyHighly potent chemotherapy(maytansine derivative)(maytansine derivative)
Cytotoxic agent: DM1Cytotoxic agent: DM1
Systemically stableSystemically stableBreaks down in target cancer cellBreaks down in target cancer cell
LinkerLinkerTT--DM1DM1
TT--DM1 selectively delivers DM1 to DM1 selectively delivers DM1 to HER2HER2--positive tumor cellspositive tumor cells
TT--DM1 binds to the HER2 DM1 binds to the HER2 protein on cancer cellsprotein on cancer cells
•• Targeted intracellular delivery of a potent Targeted intracellular delivery of a potent antimicrotubule agent, DM1antimicrotubule agent, DM1
•• Spares normal tissue from toxicity of free DM1Spares normal tissue from toxicity of free DM1
•• TrastuzumabTrastuzumab--like activity by binding to HER2like activity by binding to HER2HER2HER2
ReceptorReceptor--TT--DM1 complex is DM1 complex is internalized into HER2internalized into HER2--positive cancer cellpositive cancer cell
Potent antimicrotubule Potent antimicrotubule agent is released once agent is released once inside the HER2inside the HER2--positivepositivetumor celltumor cell
Phase II trial of TPhase II trial of T--DM1 in HER2DM1 in HER2--positive MBC positive MBC patients progressing during HER2patients progressing during HER2--targeted therapytargeted therapy
TT--DM1DM13.6 mg/kg q3w3.6 mg/kg q3w
Patients with HER2Patients with HER2--positive MBC (n=110)positive MBC (n=110)Prior exposure to Prior exposure to anthracyclineanthracycline, , taxanetaxane, , capecitabinecapecitabine, ,
lapatiniblapatinib and and trastuzumabtrastuzumabPD on last regimen receivedPD on last regimen received
Tumour responseTumour response
Independent Independent reviewreview(n=110)(n=110)
Investigator Investigator assessedassessed(n=110)(n=110)
ORR, %ORR, %(95% CI)(95% CI)
32.732.7(24.1, 42.1)(24.1, 42.1)
30.030.0(22.0, 39.4)(22.0, 39.4)
Krop et al. SABCS 2009IRF, independent review facility
(95% CI)(95% CI) (24.1, 42.1)(24.1, 42.1) (22.0, 39.4)(22.0, 39.4)
CRCR 00 1.81.8
PRPR 32.732.7 28.228.2
SDSDaa 46.446.4 52.752.7
PDPD 18.218.2 13.613.6
UnevaluableUnevaluable 1.81.8 0.90.9
MissingMissing 0.90.9 2.72.7
CBR, %CBR, %(95% CI)(95% CI)
44.544.5(35.1, 54.3)(35.1, 54.3)
40.040.0(31.1, 49.3)(31.1, 49.3)
Median PFS, months (range)Median PFS, months (range) 7.3 (07.3 (0--11.7)11.7) n/an/a
Phase II Study Phase II Study DesignDesign
1:1 1:1 HER2HER2--positive, positive, recurrent locally recurrent locally advanced breast advanced breast cancer or MBC cancer or MBC
(N=137)(N=137)
TT--DM1DM13.6 mg/kg q3w IV3.6 mg/kg q3w IV
(n=67)(n=67)
TrastuzumabTrastuzumab8 8 mg/kg loading dose; mg/kg loading dose;
6 mg/kg q3w IV6 mg/kg q3w IV+ + DocetaxelDocetaxel
Crossover toCrossover toTT--DM1 DM1 (optional)(optional)
PDPD
PDPD
•• Randomized, phase II, international, openRandomized, phase II, international, open--label studylabel study
•• Stratification factors: World region, prior adjuvant trastuzumab therapy, diseaseStratification factors: World region, prior adjuvant trastuzumab therapy, disease--free interval free interval
•• Primary end points: PFS by investigator assessment, and safetyPrimary end points: PFS by investigator assessment, and safety
•• Data analyses were based on clinical data cut of Nov 15, 2010 prior to TData analyses were based on clinical data cut of Nov 15, 2010 prior to T--DM1 DM1 crossovercrossover
•• Key secondary end points: OS, ORR, DOR, CBR, and QOLKey secondary end points: OS, ORR, DOR, CBR, and QOL
+ + DocetaxelDocetaxel7575 or 100or 100 mg/mmg/m22 q3wq3w
(n=70)(n=70)
(optional)(optional)
Hurvitz et al, SABCS 2011
Objective Response by Investigator Objective Response by Investigator
Patients Patients With Measurable Disease at BaselineWith Measurable Disease at Baseline
TrastuzumabTrastuzumab + + docetaxeldocetaxel(n=69)(n=69)
TT--DM1 DM1 (n=67)(n=67)
Patients with an objective response, n (%)Patients with an objective response, n (%) 40 (58.0)40 (58.0) 43 (64.2)43 (64.2)
95% CI 95% CI 45.545.5––69.269.2 51.851.8––74.874.8
Patients with clinical benefit,Patients with clinical benefit, n (%)n (%) 56 (81.2)56 (81.2) 50 (74.6)50 (74.6)
95% CI95% CI 70.770.7––89.189.1 63.263.2––84.2 84.2 95% CI95% CI 70.770.7––89.189.1 63.263.2––84.2 84.2
Objective responses, n (%)Objective responses, n (%)
Complete responseComplete response 3 (4.3)3 (4.3) 7 (10.4)7 (10.4)
Partial responsePartial response 37 (53.6)37 (53.6) 36 (53.7)36 (53.7)
Stable diseaseStable disease 23 (33.3)23 (33.3) 13 (19.4)13 (19.4)
Progressive diseaseProgressive disease 4 (5.8)4 (5.8) 8 (11.9)8 (11.9)
Unable to evaluate or missingUnable to evaluate or missing 2 (2.9)2 (2.9) 3 (4.5)3 (4.5)
Median duration of response, Median duration of response, mosmos 9.59.5 NRNR
95% CI95% CI 6.66.6––10.610.6 ——
Hurvitz et al, SABCS 2011
ProgressionProgression--Free Survival Free Survival by by InvestigatorInvestigator
Randomized PatientsRandomized Patients
Prop
ortion
pro
gress
ion
Prop
ortion
pro
gress
ion--
free
free
1.01.0
0.80.8
0.60.6
MedianMedianPFS, PFS, mosmos
Hazard Hazard ratioratio 95% CI95% CI
LogLog--rank rank PPvaluevalue
9.29.2
14.214.2 0.5940.594 0.3640.364––0.9680.968 0.03530.0353
TrastuzumabTrastuzumab+ + docetaxeldocetaxel (n=70)(n=70)
TT--DM1 DM1 (n=67)(n=67)
Time (months)Time (months)
Prop
ortion
pro
gress
ion
Prop
ortion
pro
gress
ion
0.40.4
0.20.2
0.00.000 22 44 66 88 1010 1212 1414 1616 1818 2020
Hurvitz et al, SABCS 2011
Hurvitz et al, SABCS 2011
HER2HER2--positive incurable locally advanced positive incurable locally advanced breast cancer or MBC breast cancer or MBC
Prior trastuzumab and / or taxanePrior trastuzumab and / or taxane(n=580)(n=580)
EMILIA: ongoing Phase III study of TEMILIA: ongoing Phase III study of T--DM1 DM1 vsvs capecitabinecapecitabine + + lapatiniblapatinib in the in the
2nd2nd--line settingline settingPrimary end pointsPrimary end points•• PFS (independent PFS (independent
assessment)assessment)
•• SafetySafety
Secondary end Secondary end pointspoints
(n=580)(n=580)pointspoints
•• OSOS
•• PFS (investigator PFS (investigator assessment)assessment)
•• ORRORR
•• CBR CBR
•• DoRDoR
•• Quality of lifeQuality of life
•• TTFTTF
TT--DM1 DM1 3.6 mg/kg q3w3.6 mg/kg q3w
Capecitabine Capecitabine + lapatinib+ lapatinib
1:1 1:1
www.clinicaltrials.gov
PI3K pathway: markers vs. targetsPI3K pathway: markers vs. targets
INPP4BLKB1
Modified from McAuliffe P et al. Clin Breast Cancer 2010
LKB1
Phase I Study of Phase I Study of EverolimusEverolimus Plus Weekly Plus Weekly PaclitaxelPaclitaxel and and TrastuzumabTrastuzumab in Patients With in Patients With Metastatic Breast Cancer Pretreated With Metastatic Breast Cancer Pretreated With
TrastuzumabTrastuzumab
Andre F et al, J Clin Oncol 2010
Phase I/II Study of Phase I/II Study of TrastuzumabTrastuzumab in Combinationin CombinationWith With EverolimusEverolimus (RAD001) in Patients With(RAD001) in Patients With
HER2HER2--Overexpressing Metastatic Breast Cancer WhoOverexpressing Metastatic Breast Cancer WhoProgressed on Progressed on TrastuzumabTrastuzumab--Based TherapyBased Therapy
Morrow PK et al, J Clin Oncol 2011
EverolimusEverolimus in HER2in HER2--positive positive MBCMBC
BOLERO 1BOLERO 1
www.clinicaltrials.gov
BOLERO 3BOLERO 3
HER2HER2--Derived Peptide VaccineDerived Peptide Vaccine
•• E75E75–– 9 9 aaaa peptide from extracellular domainpeptide from extracellular domain
–– ImmunodominantImmunodominant epitopeepitope of HER2/of HER2/neuneu
–– MHC class I peptide MHC class I peptide →→ stimulated CD8stimulated CD8++–– MHC class I peptide MHC class I peptide →→ stimulated CD8stimulated CD8++
T cellsT cells
–– High affinity for HLAHigh affinity for HLA--A2 /A3A2 /A3
E75E75GMGM--CSFCSF
HER2/HER2/neuneu
Clinical Benefit to Clinical Benefit to VaccinationVaccination
0.040.0414.2%14.2%5.6%5.6%Recurrence Recurrence
PP--valuevalueControlControlVaccinatedVaccinated
DFSDFS
Primary analysis at 18 months median followPrimary analysis at 18 months median follow--upup
0.100.1095.1%95.1%99.0%99.0%Overall Overall SurvivalSurvival
0.040.0477.0%77.0%92.5%92.5%Disease Disease Free Free SurvivalSurvival
0.040.0414.2%14.2%5.6%5.6%Recurrence Recurrence RateRate
p=0.04p=0.04
Peoples et al. Clin Cancer Res 2008
AE37/GP2 Phase II TrialAE37/GP2 Phase II Trial
SSTTRRAATTIIFFYY
RRAANNDDOOMMIIZZEE
AE37+GMAE37+GM
GM onlyGM only
Specific AimsSpecific Aims
1.1. RecurrenceRecurrence2.2. Time to Time to
RecurrenceRecurrence3.3. Immunologic Immunologic
A2A2--•• NP or highNP or high--risk NNrisk NN
•• HER2 IHC HER2 IHC 1+, 2+ or 3+1+, 2+ or 3+ GM onlyGM only 3.3. Immunologic Immunologic
response response correlationcorrelation
SSTTRRAATTIIFFYY
RRAANNDDOOMMIIZZEE
GM onlyGM only
GP2+GMGP2+GM
A2+A2+
1+, 2+ or 3+1+, 2+ or 3+•• NED after NED after
SOC therapySOC therapy
www.clinicaltrials.gov
ConclusionsConclusions
•• Much progress and many promisesMuch progress and many promises
•• HER2 is still a therapeutic target even in HER2 is still a therapeutic target even in trastuzumabtrastuzumab resistanceresistance
•• Don’t automatically abandon Don’t automatically abandon trastuzumabtrastuzumab after the onset of after the onset of resistanceresistance
•• Combined receptor inhibitors or receptor inhibitors combined with Combined receptor inhibitors or receptor inhibitors combined with downstream/alternative signaling inhibitors show better results downstream/alternative signaling inhibitors show better results and will become standardand will become standard
•• De Novo and acquired resistance occur and there are many De Novo and acquired resistance occur and there are many potential mechanisms. potential mechanisms.
•• Predicting the mechanism of resistance in the primary tumor will Predicting the mechanism of resistance in the primary tumor will be critical for appropriate patient selection and saving costsbe critical for appropriate patient selection and saving costs
Thank you !!!!Thank you !!!!
[email protected]@mdanderson.org
Thanks to Luca Gianni for providing all slide materialsThanks to Luca Gianni for providing all slide materials