Transcript Slide 1

Universitätsklinikum
Schleswig-Holstein
Kombination zielgerichteter
Therapien
Die Zukunft?
Walter Jonat
Univrersitätsfrauenklinik
UKSH Campus Kiel
TRASTUZUMAB
Source: Cell , Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013)
Copyright © 2011 Elsevier Inc. Terms and Conditions
Therapeutic Targeting of the Hallmarks of Cancer.
Drugs that interfere with each of the acquired capabilities
necessary for tumor growth and progression have been
developed and are in clinical trials or in some cases approved
for clinical use in treating certain forms of human cancer.
Additionally, the investigational drugs are being developed to
target each of the enabling characteristics and emerging
hallmarks depicted in Figure 3, which also hold promise as
cancer therapeutics. The drugs listed are but illustrative
examples; there is a deep pipeline of candidate drugs with
different molecular targets and modes of action in
development for most of these hallmarks.
Source: Cell , Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013)
Copyright © 2011 Elsevier Inc. Terms and Conditions
Adjuvant Trastuzumab Trials:
Summary of OS Data to Date
Median follow-up
HERA Trastuzumab 1 year arm
2 years
Combined analysis
2 years
BCIRG 006 ACDH
3 years
BCIRG 006 DCarboH
3 years
FinHer VH / DH
p=NS
0
Favours
Trastuzumab
1
HR
NS, not significant
Data from Joensuu et al 2006; Romond et al 2005; Slamon et al 2006; Smith et al 2007
3 years
Favours no
Trastuzumab
2
Trastuzumab improves survival
in combination with a taxane
Trastuzumab + docetaxel
Docetaxel alone
Probability, 1.0
OS
0.8
P<.05
Patients 30
surviving
≥3 years 25
30 (33%)
20
0.6
15
0.4
11 (21%)
10
0.2
22.7
0.0
0
4 (10%)
5
+37%
31.2
5 10 15 20 25 30 35 40 45 50
8.5 months
0
Trastuzumab Docetaxel
Docetaxel
+ docetaxel
then
alone
upfront
crossover
to Trastuzumab
Time (months)
OS, overall survival
1. Extra JM et al ASCO 2005 Abstr # 555; 2. Marty et al J Clin Oncol. 2005:4265-74.
The good news 2012
Herceptin
How long to treat
Ongoing Trials
Endpoint
Start
Enroll
Accrual
Nodes
HERA
DFS
12/2001
5043
5102
+/-
PHARE
TTR
5/2006
3400
3382
+/-
PERSEPHONE
DFS
10/2007
400
2334
+
3 yr DFS
10/2004
500
478
+/-
SOLD
DFS
1/2008
3000
1538
+/-
SHORT HER
DFS
OS
12/2007
2500
1250
1070
+/-
HELENIC
Goldhirsch et al. ESMO, SABCS 2012
HER2 - THE NEXT STEPS
dual/multiple targeting
small molecules
Landscape of Molecular Alterations
in Breast Cancer: HER Family
HER2: Amplification in
~20% of breast cancers1
HER2
EGFR: Amplification
in ~20% of TNBC2
HER1
(EGFR)
Tyrosine kinase
domains
Abbreviation: TNBC, triple-negative breast cancer.
1. Sircoulomb F, et al. BMC Cancer. 2010;10:539; 2. Toyama T, et al. BMC Cancer. 2008;8:309.
Key Message
• Several molecular entities are candidate
oncogenic drivers
• Some pathways (such as mTOR) can be
activated and could contribute to cancer
progression independently of genomic
alterations
• These pathways can be associated with
unrelated genomic alterations
Four Her2 Targeting
Agents Are Available
Trastuzumab, Pertuzumab, TDM1, and
Lapatinib
For Her2+ Aggressive MBC (?)
1st Line: Pertuzumab/Docetaxel/Trastuzumab
2nd Line: T-DM1
Questions still being working on.
How to best use them in combination and
sequenced with each other or with other
agents
PERTUZUMAB
(PLUS TRASTUZUMAB AND TAXANE)
San Antonio Breast Cancer Symposium – Cancer Therapyand Research Center at UT Health Science Center – December 4-8, 2012
Cleopatra: Phase III Trial of Pertuzumab In
Combination of Trastuzumab/Docetaxel
N= 808
1:1 Randomization
MBC, Her2 +
No prior chemotherapy or
biological therapy for MBC
Pertuzumab +
Trastuzumab/Docetaxel
Placebo +
Trastuzumab/Docetaxel
Trastuzumab (8 mg /kg LD then 6 mg/ kg Q3W and Docetaxel 75 mg/m2 Q3W
Pertuzumab 840 mg LD then 420 mg Q3W
Baselga; N Engl J Med 2012;366:109-119.
CLEOPATRA Overall Survival:
Predefined Interim Analysis
Median follow-up: 19.3 months; n = 165 OS events
100
HR = 0.64a
95% CI = 0.47, 0.88
P = .0053a
Overall Survival, %
90
80
70
60
50
40
30
Ptz + T + D: 69 events
20
Pla + T + D: 96 events
10
0
0
5
10
15
20
25
30
35
40
45
Time, mo
n at risk
Pertuzumab + T + D 402
387
367
251
161
87
31
4
0
0
Placebo + T + D
383
347
228
143
67
24
2
0
0
406
The interim OS analysis did not cross the prespecified O’Brien-Fleming stopping boundary (HR ≤ 0.603;
P ≤ .0012.). However, in an updated OS analysis the prespecified O’Brien-Fleming stopping boundary was crossed.
a
Abbreviations: D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab.
Baselga et al. SABCS 2011, Oral presentation S5-5; Baselga et al. N Engl J Med. 2012;366(2):109-119; Roche Press release, June 2012.
T-DM1
EMILIA Study Design1,2
HER2+ (central) LABC
or MBC (N = 991)
• Prior taxane and
trastuzumab
• Progression on
metastatic tx or
within 6 mo of
adjuvant tx
T-DM1
3.6 mg/kg q3w IV
PD
1:1
Capecitabine
1000 mg/m2 orally bid, days 1–14, q3w
+
Lapatinib
PD
1250 mg/day orally qd
• Stratification factors: World region, number of prior chemotherapy regimens
for MBC or unresectable LABC, presence of visceral disease
• Primary endpoints: PFS by independent review, OS, and safety
• Key secondary endpoints: PFS by investigator, ORR, duration of response,
time to symptom progression
LABC, locally advanced breast cancer; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS,
progression-free survival; T-DM1, trastuzumab emtansine.
1. Figure reprinted from Blackwell KL, et al. ASCO 2012, Abst LBA1 [presentation]; 2. Verma S, et al. New Engl J Med. 2012; DOI:10.1056/NEJMoa1209124.
Overall Survival: Interim Analysis
1.0
Proportion surviving
84.7%
Median, mo
No. events
Cap + Lap
23.3
129
T-DM1
NR
94
Stratified HR = 0.621; 95% CI, 0.48-0.81; P = .0005
Efficacy stopping boundary P = .0003 or HR = 0.617
0.8
77.0%
65.4%
0.6
47.5%
0.4
0.2
0.0
0
2
4
6
8
10 12 14 16 18
20 22 24 26 28 30 32 34 36
Time, mo
No. at risk:
Cap + Lap 496 469 438 364 296 242 195 155 129 97
T-DM1
495 484 461 390 331 277 220 182 149 123
Cap, capecitabine; Lap, lapatinib; NR, not reached; T-DM1, trastuzumab emtansine.
Unstratified HR = 0.63 (P = .0005).
Reprinted from Blackwell KL, et al. ASCO 2012, Abst LBA1 [presentation].
74
96
52
67
31
46
17
29
7
16
3
5
2
2
1
0
0
0
Overall Survival: Confirmatory
Analysis
Median, mo
No. events
Cap + Lap
25.1
182
T-DM1
30.9
149
Stratified HR = 0.682; 95% CI, 0.55-0.85; P = .0006
Efficacy stopping boundary P = .0037 or HR = 0.727
1.0
Proportion surviving
85.2%
0.8
78.4%
64.7%
0.6
51.8%
0.4
0.2
0.0
0
2
No. at risk:
Cap + Lap 496 471
T-DM1
495 485
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
110
136
86
111
63
86
45
62
27
38
17
28
7
13
4
5
Time, mo
453
474
435
457
403
439
368
418
297
349
240
293
204
242
159
197
133
164
Data cutoff July 31, 2012; unstratified HR = 0.70 (P = .0012).
Cap, capecitabine; Lap, lapatinib; T-DM1, trastuzumab emtansine.
Reprinted from Verma S, et al. ESMO 2012, Abst LBA12 [presentation], where it was adapted from Verma S, et al. New Engl J Med. 2012; DOI:10.1056/NEJMoa1209124.
Adverse Events
Grade ≥ 3 AEs With Incidence ≥ 2%
Cap + Lap ( n = 488)
Adverse Event
T-DM1 (n = 490)
All Grades, %
Grade ≥ 3, %
All Grades, %
Grade ≥ 3, %
Diarrhea
79.7
20.7
23.3
1.6
Hand-foot syndrome
58.0
16.4
1.2
0
Vomiting
29.3
4.5
19.0
0.8
Hypokalemia
8.6
4.1
8.6
2.2
Fatigue
27.9
3.5
35.1
2.4
Nausea
44.7
2.5
39.2
0.8
Mucosal inflammation
19.1
2.3
6.7
0.2
Increased AST
9.4
0.8
22.4
4.3
Increased ALT
8.8
1.4
16.9
2.9
Anemia
8.0
1.6
10.4
2.7
Thrombocytopenia
2.5
0.2
28
12.9
Cap, capecitabine; Lap, lapatinib; T-DM1, trastuzumab emtansine.
Verma S, et al. New Engl J Med. 2012; DOI:10.1056/NEJMoa1209124.
TRASTUZUMAB+
REFRACTORY HER2 ABC
Lapatinib in Trastuzumab
Refractory BC
• HER2+ BC progressing after an
anthracycline, taxane, and
trastuzumab
Patients Free of Disease Progression, %
100
P < .001
80
LAP + CAP
(49 events)
Median TTP = 8.4 mo
60
40
– Lapatinib  ORR vs
monotherapy (22% vs 14%;
P = .09)
CAP alone
(72 events)
Median TTP = 4.4 mo
20
0
0
10
20
No. of patients at risk
CAP
163
96
30
Time, wk
52
LAP +
161
CAP
33
78
• Randomized to capecitabine
alone (n = 161) or capecitabine
+ lapatinib (n = 163)
40
50
60
21
10
4
3
14
4
1
0
Abbreviations: CAP, capecitabine; LAP, lapatinib; TTP, time to progression.
Adapted from Geyer CE, et al. N Engl J Med. 2006;355(26):2733-2743.
– Lapatinib  TTP
(HR = 0.49; P < .001)
– No significant OS difference
– Most common grade 3/4 AEs
included diarrhea and HFS
LAPATINIB +
TRASTUZUMAB
CEREBEL:
A Randomized, Multicentre, Open-Label, Phase III Study of
Lapatinib plus Capecitabine versus Trastuzumab plus
Capecitabine in Pts with Anthracycline- or Taxane-Exposed
ErbB2-Positive MBC.
Progression free survival
Overall survival
Lapatinib
Trastuzumab
Lapatinib
Trastuzumab
+ Capecitabin + Capecitabin + Capecitabin + Capecitabin
N
Events, n (%)
Median, M. (95 % KI)
HR (95 % KI) a
271
269
271
269
160 (59)
134 (50)
70 (26)
58 (22)
6,60
8,05
22,7
27,3
(5,72 - 8,11)
(6,14 -8,9)
(19,5 - )
(22,7 - )
1,30 (1,04 -1,64)
1,34 (0,95 - 1,90)
Phase 3 Trial: Lapatinib ± Trastuzumab
in Heavily Pretreated MBC Following
Progression on Trastuzumab
Lapatinib (1500 mg/day PO)
(n = 148)
N = 296
• HER2+ (FISH+/IHC 3+)
• Progressed on most recent
trastuzumab regimen
• Prior anthracycline- and
taxane-based regimens
R
A
N
D
O
M
I
Z
E
Crossover if PD after 4 wk therapy (N=73)
Primary endpoint:
Progression-free survival: Investigator
Secondary endpoints include:
• Overall survival
• Overall response rate
• Clinical benefit rate
• Quality of life
• Safety
FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MBC, metastatic breast cancer.
Blackwell KL, et al. J Clin Oncol. 2010;28(7):1124-1130.
Lapatinib (1000 mg/day PO) +
Trastuzumab (4 mg/kg load → 2
mg/kg weekly)
(n = 148)
Overall Survival in ITT
Alive without progression,
cumulative %
Lapatinib +
Lapatinib trastuzumab
n = 146
n = 145
100
80
80
Died, n
Median, weeks
Hazard ratio (95% CI)
P
70
60
45
6-month OS
40
36
20
0
No. of patients at risk
L
148
L+T
148
12-month OS
L+T
L
20
40
60
Time from randomization, weeks
106
121
ITT, intent-to-treat population; L, lapatinib; OS, overall survival; T, trastuzumab.
Reprinted from Blackwell KL, et al. J Clin Oncol. 2010;28(7):1124-1130.
30
40
3
4
69
56
39.0
51.6
0.75 (0.53 to 1.07)
.106
TRASTUZUMAB +
PERTUZUMAB
Co-Targeting HER2 With Antibodies:
Phase 2 Trial of Pertuzumab Plus
Trastuzumab in Pts. With HER2+ MBC
Trastuzumab: 4 mg/kg load → 2 mg/kg qw or 8 mg/kg load → 6 mg/kg q3w
Pertuzumab: 840 mg load → 420 mg q3w
Response
Patients (N = 66)
Complete Response
7.6%
Partial Response
16.7%
Stable Disease ≥ 6 mo
25.8%
Objective Response Rate
24.2%
Clinical Benefit Rate
MBC, metastatic breast cancer; PFS, progression-free survival.
Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.
50%
Median PFS: 5.5 mo
EVEROLIMUS
32
TAMRAD
TAMRAD: Tamoxifen ± Everolimus
in HR+ Advanced Breast Cancer
Progressing During/After AI Therapy
Phase 2 study;
N = 111
Postmenopausal
women with ER+
HER2– advanced
breast cancer
Previously treated
with aromatase
inhibitor therapy in
adjuvant or
metastatic setting
Tamoxifen 20 mg/d +
Everolimus 10 mg/d
Tamoxifen 20 mg/d +
Placebo
Stratification:
Primary or secondary
hormone resistance
Primary endpoint:
CBR at 6 mo
Secondary
endpoints:
TTP, OS, ORR,
biomarkers, safety
Abbreviations: AE, adverse event; AI, aromatase inhibitor; CBR, clinical benefit rate; ER, estrogen receptor; EVE, everolimus; HER2, human epidermal growth factor
receptor-2; ORR, overall response rate; OS, overall survival; SERM, selective estrogen-receptor modulator; TAM, tamoxifen; TTP, time to progression.
Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724.
TAMRAD: Primary Endpoint,
Clinical Benefit Rate
Clinical Benefit Rate, % of Patients
70
P = .045 (exploratory analysis)
61
60
50
42
Everolimus increased CBR
45% over tamoxifen alone
(absolute difference 19%)
40
30
20
10
0
Tamoxifen
Abbreviation: CBR, clinical benefit rate.
Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724.
Tamoxifen + Everolimus
BOLERO-2
BOLERO-2: Everolimus +
Exemestane in HR+ Advanced
Breast Cancer
N = 724
• Postmenopausal ER+
• Unresectable locally
advanced or metastatic BC 2:1
• Recurrence or progression
after letrozole or anastrozole
R
Endpoints
EVE 10 mg daily
+
EXE 25 mg daily (n = 485)
Placebo
+
EXE 25 mg daily (n = 239)
Stratification
1. Sensitivity to prior hormonal therapy
2. Presence of visceral disease
• Primary: PFS (local assessment)
• Secondary: OS, ORR, QOL, safety, bone markers, PK
Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; NSAI, nonsteroidal aromatase inhibitor; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.
BOLERO-2: PFS at 18 Months’
Median Follow-up
80
HR = 0.45 (95% CI = 0.38, 0.54)
HR = 0.38 (95% CI = 0.31, 0.48)
100
Log-rank P value: < .0001
Everolimus + Exemestane: 7.8 mo
Placebo + Exemestane: 3.2 mo
Probability (%) of Event
Probability (%) of Event
100
60
40
20
Log-rank P value: < .0001
Everolimus + Exemestane: 11.0 mo
80
Placebo + Exemestane: 4.1 mo
60
40
20
0
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
Time, wk
Number of patients still at risk
485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10
EVE+EXE
PBO+EXE
239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1
Local Assessment
Time, wk
8
0
2
0
1
0
0
0
Number of patients still at risk
485 427 359 292 239 211 166 140 108 77
EVE+EXE
PBO+EXE
239 179 114 76 56 39 31 27 16 13
48
6
32
4
21
1
Central Assessment
Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival.
Piccart M, et al. ASCO 2012, abstract 559.
62
9
18
0
11
0
10
0
5
0
0
0
BOLERO-2: Overall Response
Rate and Clinical Benefit Rate
60
Everolimus + Exemestane
Patients, %
50
51.3%
Placebo + Exemestane
P < .0001
40
30
26.4%
20
P < .0001
12.6%
10
1.7%
0
ORR
Abbreviations: CBR, clinical benefit rate; ORR, overall response rate.
Piccart M, et al. ASCO 2012, abstract 559.
CBR
The END
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