targeting the her2 network: what’s new? p pronzato, genova
TRANSCRIPT
Targeting the HER2 network:what’s new?
P Pronzato, Genova
2
HER2 Overexpression Leads to Increased Signaling
• Increased cell proliferation• Increased cell migration• Resistance to apoptosis
Yarden et al. Nat Rev Mol Cell Biol 2001
HER2 testing
• In a randomized trial, benefit confined to HER2/neu amplified/overexpressors (Seidman, CALGB 9840)
• Subset analysis of CALGB 9840 suggests benefit in FISH-negative patients with Chr 17 2.2 (polysomy) (Kaufman, ASCO 2007)
Trastuzumab and HER2 Status in Advanced Breast Cancer:
Prior Observations
R Livingston, ASCO 2008
Kaplan-Meier Estimates of PFS: HER2-Negative Subjects
Time, weeks
Cu
mu
lati
ve p
rog
ress
ion
-fre
e su
rviv
al
0 20 40 60 80 100 120
0
0.2
0.4
0.6
0.8
1.0Polysomy 17 ≤ 2.2, L+P (n = 178)
Polysomy 17 > 2.2, L+P (n = 23)
Polysomy 17 ≤ 2.2, P (n = 183)
Polysomy 17 > 2.2, P (n = 21)
Discordance
Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH
positive tumors
Paik et. Al, ASCO 2007, abstr. 511
Central HER2
FISH neg.
Central IHCneg. (0-2+)
Both Negative
Before
amendment (any lab)103/529 (19.5%) 122/528 (23.1%) 87/529 (16.4%)
After amendment
(qualified lab for IHC)104/1266 (8.2%) 177/1259 (14.1%) 87/1266 (6.8%)
Total 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)
Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH
positive tumors
Paik et. Al, ASCO 2007, abstr. 511
Central HER2
FISH neg.
Central IHCneg. (0-2+)
Both Negative
Before
amendment (any lab)103/529 (19.5%) 122/528 (23.1%) 87/529 (16.4%)
After amendment
(qualified lab for IHC)104/1266 (8.2%) 177/1259 (14.1%) 87/1266 (6.8%)
Total 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)
Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH
positive tumors
Paik et. Al, ASCO 2007, abstr. 511
Central HER2
FISH neg.
Central IHCneg. (0-2+)
Both Negative
Before
amendment (any lab)103/529 (19.5%) 122/528 (23.1%) 87/529 (16.4%)
After amendment
(qualified lab for IHC)104/1266 (8.2%) 177/1259 (14.1%) 87/1266 (6.8%)
Total 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)
Discordance primary/relapse
ECD
JC Thery
RANDOMIZATION
Paclitaxel 175 mg/m2 q3wLapatinib 1,500 mg PO QD
(N = 291)
Paclitaxel 175 mg/m2 q3w Placebo PO QD
(N = 288)
Stratification
• Disease sites
• Stage of disease
Key Inclusion
• Incurable stage III/IV
• No prior treatment for M+
• HER2-negative or untested
EGF30001 Study Design
Endpoints• Primary: TTP• Secondary: PFS, OS, safety
N = 579
Serum ECD measured by ELISA (Oncogene Science) pretreatment, week 9, and q12 weeks.
Di Leo et al. J Clin Oncol. 2008. In press.
Baseline ECD
HE
R2
IHC
5 10 50 100 5000.
00.
51.
01.
52.
02.
53.
0
Poor Correlation of Baseline ECD With HER2 Status by FISH or IHC
Correlation with IHC3+ 47/64 = 73% *FISH+: R = 0.34 (P = 0.003; n = 75) FISH–: R = 0.03 (P = 0.596; n = 327)
Baseline ECD
FIS
H R
atio
5 10 50 100 500
15
10
R = 0.28 overall (P < 0.001;n = 402)*
R = 0.34 (P< 0.001; n = 461)
Conversion From ECD-negative to -positive Is Associated With Worse PFS in HER2-negative Patients
Converting
Non-converting
(remain negative)
P + Lapatinib
Converting(n = 20)
Non-Converting
(n = 92)
Median, weeks 22.4 32.1
HR (95% CI) 2.40 (1.34 , 4.31)
P-value 0.003
Converting(n = 7)
Non-Converting
(n = 111)
Median, weeks 13.4 30.6
HR (95% CI) 2.78 (1.27 , 6.10)
P-value 0.011
Converting
Non-converting
(remain negative)
P + Placebo
HR = Hazard of converting.
Time, weeks
PF
S
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
Time, weeks
PF
S
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
30 patients seroconvertered: 17 PR, 12 SD, 1 PD
Conversion From ECD-positive to -negative Is Associated With Improved PFS
Converting(n = 11)
Non-Converting
(n = 20)
Median, weeks 46.3 16.5
HR (95% CI) 0.20 (0.07, 0.55)
P-value 0.002
ConvertingNon-converting
(remain positive)
P + Lapatinib
Converting(n = 19)
Non-Converting
(n = 23)
Median, weeks 33.6 23.0
HR (95% CI) 0.50 (0.26 , 0.97)
P-value 0.040
ConvertingNon-converting
(remain positive)
P + Placebo
HR = Hazard of converting.
Time, weeks
PF
S
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
Time, weeks
PF
S
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
Trastuzumab for metastatic breast cancer
Study Design
arm A: trastuzumab (T) + docetaxel (D) (100mg/m2, q3wks),
with continuation of T after D until PD
R
arm B: trastuzumab docetaxel (100mg/m2, q3wks)
at PD
• loading dose trastuzumab 4 mg/kg, thereafter weekly 2 mg/kg
• docetaxel: at least 6 cycles
• no routine use of haematological growth factor support
Best Overall Response during treatment (RECIST criteria)
CR 7 13.5% 1 2.2 %
PR 31 59.6% 21 47.7 %
SD 6 11.5 % 15 34.1 %
PD 4 7.7 % 5 11.4 %
NE 4 7.7 % 2 4.6 %
p = 0.03
Combination Sequential
T + D T H
Median time to first progression0.
000.
250.
500.
751.
00
0 6 12 18 24 30 36analysis time
treat = A=H+T treat = B=H->T
months
time to progression 1
Monotherapy T : 3.9 mo
Combination therapyT + D: 9.4 mo
p=0.0001
Progression Free SurvivalCombination versus Sequential therapy
0.00
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36analysis time
treat = A=H+T treat = B=H->T
months
time to progression
Combination T + D:9.4 mo
Sequential T D: 10.8 mo
p=0.42
Overall Survival0.
000.
250.
500.
751.
00
0 6 12 18 24 30 36analysis time
treat = A=H+T treat = B=H->T
months
Hertaxsurvival
Combination T + D:30.5 mo
Sequential T D: 20.2 mo
p=0.15
Herceptin prolongs survival in women with 1st-line MBC
0 10 20 30 40 50
PH
PCarboH
DH
DCarboH
DH
D alone
PH
P alone
Median survival (months)
IHC, immunohistochemistry; P, paclitaxel
H, Herceptin; D, docetaxel; Carbo, carboplatin
H0648g(IHC 3+)
M77001
BCIRG 007
US Oncology(IHC 3+)
Smith et al 2001; Marty et al 2005 Robert et al 2006; Pegram et al 2007
CHAT: a large randomised phase II trial
No prior Herceptin, docetaxel or
Xeloda
Stratification: - prior paclitaxel
- prior anthracycline- liver metastases
- KPS
KPS = Karnofsky performance status
Wardley A et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S33(Abst 309)
HTHerceptin 8mg/kg (loading dose), d1 followed by 6mg/kg, d1, q21dDocetaxel 100mg/m2, d1
HTXHerceptin 8mg/kg (loading dose), d1followed by 6mg/kg, d1, q21dDocetaxel 75mg/m2, d1Xeloda 950mg/m2 bid, d1–14
RANDOMISATION
HTX significantly increases progression-free survival
1.0
0.8
0.6
0.4
0.2
0
Esti
mate
d p
rob
ab
ilit
y
0 5 10 15 20 25 30 35 40 45 50
Months
Events HR 95% CI p-value
HTX 75 0.725 0.529, 0.99 0.0402HT 85
Wardley A et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S33(Abst 309)
12.8 17.9
38
Phase III Study to Test if Total HER2 Blockade Improves Clinical Outcome
RANDOMIZATION
Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV qw N=148
Lapatinib 1500 mg/day PO N=148
Stratification Factors
• Visceral Disease
• Hormone Receptor
Key Inclusion
• HER2+(FISH+/ IHC3+) MBC
• Progression on• Anthracycline
• Taxane
• Trastuzumab
• Progression on most recent trastuzumab regimen
Crossover if PD after 4wk therapy (N=73)
Study conducted and funded by GlaxoSmithKline
J O Shaughnessy, ASCO 2008
39
Treatment Efficacy
*Confirmed CR+PR †CR+PR+SD ≥ 6 mo
L
N=145L + T
N=146
Response Rate, %*
(95% CI)
6.9
(3.4, 12.3)
10.3
(5.9, 16.4)
Odds Ratio (95% CI) 1.5 (0.6, 3.9)
p=0.46
Clinical Benefit Rate, %†
(95% CI)
12.4
(7.5, 18.9)
24.7
(17.9, 32.5)
Odds Ratio (95% CI) 2.2 (1.2, 4.5)
p=0.01
40
Progression-Free SurvivalL
N = 145L+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 0.008
6 Mo PFS
Cu
mu
lati
ve %
Ali
ve w
ith
ou
t P
rog
ress
ion
Subjects At Risk148148
LL+T
5373
2142
1327
58
02
13%
28%
0
20
40
60
80
100
0 10 20 30 40 50 60Time from Randomization (wks)
Adjuvant Trastuzumab
Adjuvant Herceptin has an extensive evidence base with >13,000 patients treated in 4 major trials
Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006
NCCTG N9831 (USA)
HERA (ex-USA) BCIRG 006 (global)
NSABP B-31 (USA)
IHC / FISH
(n=5,090)
Observation1 year
2 years
IHC / FISH
(n=3,505)
1 year
1 year
FISH(n=3,222)
1 year
1 year
IHC / FISH
(n=2,030)
1 year
Docetaxel
Docetaxel + carboplatin
Doxorubicin + cyclophosphamide
Herceptin
Standard CTx
PaclitaxelIHC, immunohistochemistry
FISH, fluorescence in situ hybridisation CTx, chemotherapy
HERA
HERA updateLancet 2007
Trastuzumab sequenziale
Trastuzumab Adjuvant Trials
0 2In favor of T
HR
0.64
0.87
0.48
0.61
0.42
0.86
Study FU yrs Pts
HERA 2 3401
N9831 (arm B) 1.5 1965
Joint analysis 4 3968
BCIRG 006 3 3222
FinHER 3 231
PACS 04 4 528
1In favor of Obs.
Adjuvant Herceptin has an extensive evidence base with >13,000 patients treated in 4 major trials
Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006
NCCTG N9831 (USA)
HERA (ex-USA) BCIRG 006 (global)
NSABP B-31 (USA)
IHC / FISH
(n=5,090)
Observation1 year
2 years
IHC / FISH
(n=3,505)
1 year
1 year
FISH(n=3,222)
1 year
1 year
IHC / FISH
(n=2,030)
1 year
Docetaxel
Docetaxel + carboplatin
Doxorubicin + cyclophosphamide
Herceptin
Standard CTx
PaclitaxelIHC, immunohistochemistry
FISH, fluorescence in situ hybridisation CTx, chemotherapy
Adjuvant Herceptin has an extensive evidence base with >13,000 patients treated in 4 major trials
Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006
NCCTG N9831 (USA)
HERA (ex-USA) BCIRG 006 (global)
NSABP B-31 (USA)
IHC / FISH
(n=5,090)
Observation1 year
2 years
IHC / FISH
(n=3,505)
1 year
1 year
FISH(n=3,222)
1 year
1 year
IHC / FISH
(n=2,030)
1 year
Docetaxel
Docetaxel + carboplatin
Doxorubicin + cyclophosphamide
Herceptin
Standard CTx
PaclitaxelIHC, immunohistochemistry
FISH, fluorescence in situ hybridisation CTx, chemotherapy
Trastuzumab Adjuvant Trials
0 2In favor of T
HR
0.64
0.87
0.48
0.61
0.42
0.86
Study FU yrs Pts
HERA 2 3401
N9831 (arm B) 1.5 1965
Joint analysis 4 3968
BCIRG 006 3 3222
FinHER 3 231
PACS 04 4 528
1In favor of Obs.
Neoadjuvant Trastuzumab
Trastuzumab resistance
Lapatinib and newer drugs
72
EGF 100151 - Design
Open-label Phase III studyTyverb + Capecitabine versus Capecitabine
RANDOMIZE
N = 528 (planned total)
Tyverb 1250 mg po/day continuous + Capecitabine (2000mg/m2/day, po days 1-14 every 21 days)
Capecitabine (2500mg/m2/day, po days 1-14 every 21 days)
Adv/Met Breast Ca Prior taxanes,
anthracyclines, trastuzumab
HER2 (ErbB2)Overexpression(IHC 3+, or 2+ and FISH+)
Endpoints• Primary = Time to
Progression (TTP) by blinded independent review
• Secondary = Survival (80% power on OS), PFS, ORR
GLOBAL
EGF 100151: TTP and OS
73
D Cameron, ASCO 2007
Effect on TTP of interval between last Trastuzumab dose and random
74
Interval between last Trastuzumab dose and random
Lapatinib + Capecitabine
Capecitabine
Median TTP (weeks)
Median TTP (weeks)
< 8 weeks 27.1 18.6
> 8 weeks 26.1 14.6
p=0.004
p=0.012
Response
Lapatinib + Capecitabine (n = 198)
Capecitabine(n = 201)
Complete Response 1 (<1%) 0 (0%)
Partial Response 46 (23%) 28 (14%)
Overall Response Rate (95% CL) 23.7% (18.0-30.3) 13.9 (9.5-19.5)
75D Cameron, ASCO 2007
p = 0.017
Study DesignStudy Design
RANDOMIZATION
Paclitaxel 175 mg/m2 q3wLapatinib 1500 mg po QD
Paclitaxel 175 mg/m2 q3w Placebo po QD
Stratification
• Disease site• Disease stage
Key Inclusion
• Incurable Stage III/IV • No prior treatment for M+• HER2 negative (0, 1+, 2+
FISH-, or FISH-) or untested
39Non-MBC events, n
235213Progression, n
5.36.7Median, months
0.87 (0.72, 1.05)Hazard ratio (95% CI)
0.142P value
P + Placebo(n=288)
P + L(n=291)
Time to Progression: ITT Analysis – Time to Progression: ITT Analysis – Investigator ReviewInvestigator Review
0
10
20
30
40
50
60
70
80
90
100
0
Cu
mu
lati
ve p
rog
ress
ion
-fre
e,
%
Time, months
P + LapatinibP + Placebo
3 2118151296 24 27 30
0128192953102192288P0269233462108196291P + L
Patients at risk
Response Rate & Duration by HER2 Status Response Rate & Duration by HER2 Status
Odds ratio = 2.9 (1.1, 7.9) p = 0.027
Resp
on
se r
ate
,%
P + L P
P + L P n = 202
n = 199 n = 52 n = 39
Median duration of response*
36 (21-53)
60 (45-73)
HER2-positive HER2-negative
31 (24-38)24 (18-30)
Odds ratio = 1.5 (0.9, 2.3) p = 0.118
Median duration of response* R
esp
on
se r
ate
,%
* Based on the number of responders.
n Median, months
P + L 31 7.4
P 14 5.5
n Median, months
P + L 61 6.2
P 48 8.5
Interaction test p = 0.208 (Zelen’s homogeneity test)
P + L(n = 52)
P(n = 39)
Median, mos 8.1 5.8
HR (95% CI) 0.57 (0.34, 0.93)
P value 0.011
Time to Progression by HER2 StatusTime to Progression by HER2 Status
HER2-positive HER2-negative
Interaction test p = 0.032 (Cox’s proportional hazards model)
P + L(n = 199)
P(n = 202)
Median, mos 5.8 5.3
HR (95% CI) 1.04 (0.83, 1.30)
P value 0.747
Total 75 events (83%)
Total 299 events (75%)
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30Time, months
Cu
mu
lati
ve p
rog
ress
ion
-fre
e,
%
P + Lapatinib
P + placebo
0
10
20
30
40
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24 27 30Time, months
P + Lapatinib
P + placebo
EGF105084: Study DesignEGF105084: Study Design
Stratification: PS and number of prior trastuzumab-containing regimens
Stratification: PS and number of prior trastuzumab-containing regimens
Lapatinib Monotherapy750 mg BID
Lapatinib Monotherapy750 mg BID
PDPD
Extension arms
Extension arms
CNS Composite Response
Best response Patients, n (%)
Complete response 0 (0)
Partial response 15 (6)
Stable disease* 102 (42)
EGF105084
* ≥ 8 weeks on study
EGF105084: Extension ArmsEGF105084: Extension Arms
Stratification: PS and number of prior trastuzumab-containing regimens
Stratification: PS and number of prior trastuzumab-containing regimens
Lapatinib Monotherapy750 mg BID
Lapatinib Monotherapy750 mg BID
PDPD
Extension arms
Extension arms
EGF105084 L + C Extension:Volumetric Reduction in Brain Metastases
n (%)
Median (range) cm3
≥ 50% Volumetric CNS tumor reductionAbsolute tumor volumetric reduction
8/40 (20)6.2 (3.2 - 12.9)
≥ 20% Volumetric CNS tumor reductionAbsolute tumor volumetric reduction
16/40 (40)3.9 (0.6 - 12.9)
EGF 100151 : Brain metastases
Lapatinib + Capecitabine(n = 198)
Capecitabine (n = 201)
Pts with symptomatic CNS progression as part of their first progression event *
4 (2%) 13 (6%)
* As assessed by independ review committee D Cameron, ASCO 2007
p = 0.045
DiarrhoeaPaclitaxel + Lapatinib (n=293)
Paclitaxel + Placebo (n=286)
Capecitabine + Lapatinib
Capecitabine
All grades 58% 26% 60% 39%
Grades 3-4 15-<1% 1-0% 12-1% 11-0%(a) (b)
(a) 3 deaths due to septic shock and diarhoea(b) management of side effects improved with
introduction of guideleines
Trastuzumab & Pertuzumab
KA Gelmon….PF Conte
Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain
Activates antibody-dependent cellular cytotoxicity
Inhibits HER2-mediated signalling
Inhibits shedding and, thus, formation of new p95
Inhibits HER2-related angiogenesis
Hubbard 2005
Herceptin
Pertuzumab
Activates antibody-dependent cellular cytotoxicity
Prevents receptor dimerisation
Potent inhibitor of HER2/HER2- and HER2/HER3-mediated signalling pathways
Tanespamycin + Trastuzumab
S Modi, MSKCC
Trastuzumab DM1
Scott Holden
Trastuzumab and RAD001
99
RAD001 (Everolimus) Inhibits Tumor Cell Growth and Angiogenesis
Cancer Cell Endothelial Cell
mTOR
PI3K
AKT/PKB
Reduced cell growth
and proliferation
Protein Production
Reduced gene
transcription
Reduced VEGFproduction
Reduced
cell growth
Reduced
proliferation
Nutrientsamino acids
Integrins
ILK
4E-BP1
eIF-4E P 70 S6k
Energy
PTEN
TSC1/2
mTOR
PI3K
AKT/PKB
FKBP12
RAD001
Growth factors
FKBP12
RAD001RAD001
VEGF
VEGFR
100
Efficacy
Three of the four Partial Responses assessable for biomarker expression were PTEN+ and four were pAKT473+
Best Overall Response
Overall(N=13)
5 mg Daily (N=5)
10 mg Daily (N=1)
30 mg Weekly (N=7)
Partial Response 6 /13 (46%)
4 0 2
Stable Disease 6 1 1 (7+) 4
Disease Control
(PR / SD>16 Weeks)
10/11
(91%)
5 NA 5
Progressive Disease 1 0 0 1
103
Acetylated -tubulin
-tubulin
ERER
HER2HER2
HSP90
DAC Inhibition Decreases Cell Proliferation and Prevents Invasiveness of Breast Cancer cells
DAC Inhibition in Breast Cancer Cells
DAC DAC InhibitorInhibitorDAC DAC InhibitorInhibitor
HDAC6HDAC6
Microtubule depolymerization
Acetylated HSP90– binding to HER2/ER prevented
Stabilization
Motility and Invasion
Microtubules stabilized
Proliferationand Survival
HER2/ER degraded
• Efficacy at weeks 6 and 12 using RECIST• Continuing patients assessed q 12 weeks • Study treatment discontinued when disease progression or
other
ENROLLME NT
Patient Population
• Stage IIIb/IIIc/IV
• HER2+
• Pretreated or untreated with trastuzumab
Safety Analysis After 10 Pts • If ≤ 3 tox. events at w6
•Recruit up to 50 pts• If 4+ tox. events at w6
•Reduce lapatinib to 1000 mg QD
•Evaluate 10 more pts •If acceptable, recruit to 50 pts
•If not, terminate study
Study Design
Lapatinib
1500 mg QD
+
Bevacizumab 10 mg/kg
q2w
N = 10 50
H Rugo, ASCO 2008
Efficacy: 12-week PFS and Best Response
• Crude 12-week PFS rate was 62.5% (95% CI: 43.7, 78.9)• Clinical benefit rate was 34.4% (95% CI: 18.6, 53.2)
Patients, n (%)
Lap + bevn = 32
Complete response (CR) 0
Partial response (PR) 4 (13)
Stable disease (SD) at 12 weeks 14 (44)
Stable disease 24 weeks 7 (22)
Clinical benefit (CR + PR + SD 24 weeks) 11 (34)
Progressive disease 9 (28)
Unevaluable* 5 (16)
* 5 patients withdrew prior to radiologic assessment at week 6.
H Rugo, ASCO 2008
D Slamon ASCO 2008
Conclusions
Risk Ratio for DFS of ACTH vs ACT
FISH+ (1588)
FISH- (207)
IHC 3+ (1488)
IHC <3+ (299)
FISH-&IHC <3+ (174)
0.00 0.25 0.50 0.75 1.00 1.25 1.50
0.4 p<0.0001
0.40 p=0.026
0.48 p<0.0001
0.32 p=0.0017
0.34 p=0.014
RR P Value
Paik et. Al, ASCO 2007, abstr. 511
Effects of lapatinib on BTCs. Modified from J Chang, Miami Breast Cancer Conference