Transcript Trastuzumab

Controversias y estrategias
terapéuticas prometedoras en el
cáncer de mama HER2 positivo
Francisco J. Esteva, MD, PhD
Professor of Medicine
Department of Breast Medical Oncology
MD Anderson Cancer Center
Houston, Texas
Signal Transduction by the HER Family Promotes
Proliferation, Survival, and Invasiveness
Receptor specific
ligands
HER2
HER2
HER4
HER1, HER2,
HER3*, or HER4
HER3
VEGF
HER1
(EGFR)
Plasma
membrane
P
PI3K
Tyrosine kinase
domains
Akt
Nucleus
SOS
P
RAS
MAP
K
Cytoplasm
P
P
RAF
MEK
Cell proliferation
Cell survival
Cell mobility and invasiveness
Transcription
Adapted from Hudis. N Engl J Med. 2007;357:39
HER2 Targeted Therapies
• Monoclonal Antibodies
– Trastuzumab*
– Pertuzumab
– Trastuzumab-DM1
• Small Molecule TKIs
– Lapatinib*
– Neratinib
• Vaccines
*FDA-approved for breast cancer
Adapted from Esteva FJ and Hortobagyi GN. Sci Am 2008
Trastuzumab Improves Outcomes in
Women with HER2+ Breast Cancer
• First-line therapy as a single agent
– Vogel et al. 2002
• Second-line therapy as a single
agent
– Cobleigh et al. 1999
• First-line therapy in combination
with chemotherapy
– Slamon et al. 2001, Marty et al.
2005
• Adjuvant therapy in combination or
following chemotherapy
– Romond et al. 2005, PiccartGebhart et al. 2005
Capecitabine + Lapatinib Locally
Advanced or Metastatic Disease
HER2 + stage IIIB or IIIC or
metastatic disease
Randomization
Capecitabine 2000 mg/m2 PO
BID days 1 - 14
Capecitabine 2000 mg/m2 PO
BID days 1 - 14
Lapatinib 1250mg PO q day
x 21 days
Results: Improved Time to Progression in patients
Treated with Cape/Lapatinib c/w Cape alone
Geyer et al. N Engl J Med. 2006;355(26):2733-2743.
Geyer et al. N Engl J Med. 2006;355:2733-2743.
An Evaluation of the Safety and Efficacy of
Lapatinib Plus Trastuzumab Plus Paclitaxel in
First-Line HER2+ Metastatic Breast Cancer
Key Inclusion Criteria
•
•
•
•
•
•
Stage IV invasive, measurable breast cancer
HER2+ by FISH or IHC (score, 3+)
No prior treatment for MBC
No prior HER2 inhibitor, other than adjuvant
trastuzumab
• >12 months since adjuvant trastuzumab
If neo/adjuvant taxane given, progression must have
occurred 12 mo after completion of this treatment
No CNS metastases or leptomeningeal involvement
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
An Evaluation of the Safety and Efficacy of
Lapatinib Plus Trastuzumab Plus Paclitaxel in
First-Line HER2+ Metastatic Breast Cancer
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Diarrhea Incidence by Maximum Severity
Grade
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Pharmacokinetics
• The pharmacokinetic interaction between lapatinib and paclitaxel
observed at higher doses also occurs at lower doses
• Additional data will be required to estimate the magnitude of this
interaction
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Efficacy Data: Response Rate
Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046)
Case Discussion
• 45 y/o female diagnosed with stage II left
breast cancer (IDC ER/PR+), s/p
mastectomy/reconstruction, FAC x 6,
adjuvant tamoxifen
• After taking tamoxifen for 5 years, a routine
chest x-ray showed pulmonary metastases.
Biopsy: MBC, ER+, HER2+
• Treatment: letrozole -> exemestane ->
trastuzumab (single agent)
Response to Trastuzumab
August 2001
December 2001
Progression on Trastuzumab
December 2001
January 2003
Treatment Beyond Trastuzumab
Progression in HER2+ MBC
Lapatinib 1,500 mg PO (n=148)
HER2+ MBC,
Previous
antrhacycline,
taxane,
Trastuzumab
(N=296)
R
Lapatinib 1,000 mg PO
+ Trastuzumab 4mg/kg IV load,
then 2 mg/kg IV weekly
(n=148)
Lapatinib
Lapatinib +
Trastuzumab
Odds Ratio
P Value
Response Rate
6.9
10.3
1.5
0.46
Clinical Benefit
Rate
12.4
24.7
2.2
0.01
O’Shaughnessy J, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015)
Patient Characteristics
ITT Population
Lapatinib
n = 148
Lapatinib + Trastuzumab
n = 148
Median Age (Years)
51
52
% ECOG 0/1/2
47/49/4
54/41/5
Median Prior Chemotherapy
Regimens
4
5
Median Prior Trastuzumab
Regimens for MBC
3
3
> 6 Prior Treatment
Regimens
28%
34%
HER2(+)
98.6%
99.3%
% HR(-)
51
51
O’Shaugnessy J, et al. J Clin Oncol. 2008;26(15S): Abstract 1015.
Progression-Free Survival
Cumulative % Alive without Progression
Lapatinib + trastuzumab vs. Lapatinib in HER2+ MBC progressing on or after trastuzumab
100
80
60
L
N = 145
L+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
40
0.008
28%
6 Mo PFS
20
13%
0
0
10
Subjects At Risk
L
L+T
148
148
53
73
20
30
40
21
42
13
27
5
8
Time from Randomization (wks)
50
60
0
2
O’Shaughnessy J, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015)
Trastuzumab and Lapatinib Resistance in
Breast Cancer: Clinical Considerations
• Less than a third of patients with HER2+ MBC
respond to single-agent trastuzumab or lapatinib
• Most responding patients develop progressive
disease within one year.
• Approximately 15% of patients with early-stage
breast cancer develop metastatic disease
regardless of trastuzumab adjuvant therapy
Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107
Potential Molecular Mechanisms of
Trastuzumab Resistance
Disrupted antibodyreceptor interaction
HER-2
MAPK
PI3K
Increased receptor
signaling: HER
members, IGF-IR
p27-cdk2
cyclin D1
Alterations in
downstream molecules:
PTEN downregulation,
increased Akt signaling,
reduced p27kip1
Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107
 
p
p
p

p
p
p
p
p
p

p
p
p
p
p

p
PI3-kinase
p
p
p
p
p85
p110
PKB(AKT)
mTOR/FRAP
p70S6K
Proliferation
Survival
Differentiation
Cell metabolism
Patients with PTEN deficient breast tumors have a poor
response rate to Trastuzumab-based therapy
80
CR+PR
SD+PD
n=30
100
*
n=17
60
40
20
0
Response rate (%)
Response rate (%)
100
80
*
CR+PR
SD+PD
*
n=9
n=38
60
40
20
0
12-9
6-0
PTEN IRS
12-4
3-0
PTEN IRS
Nagata Y et al. Cancer Cell 2004;6:117-127
Combined treatment with PI3K inhibitors and
Trastuzumab Significantly Inhibits the Growth of
PTEN AS- treated, BT 474 Xenografts
Agents tested in vivo: Perifosine, Edelfosine, Triciribine, KP-372-1, A838, RAD001
500
250
*
*
750
RAD+HCP
RAD
HCP
DMSO
(N=7)
3
tumor size (mm )
TCN+HCP
TCN
HCP
DMSO
(N=7)
3
tumor size (mm )
750
500
250
* p<0.05
0
0
0
1
2
3
4
5
6
weeks
Trastuzumab + Triciribine
0
1
2
3
4
weeks
Trastuzumab + RAD001
Lu CH, et al. Clin Cancer Res 2007
Simultaneous Targeting of Her2 signaling at two levels:
Rationale for combining Rad001 and Trastuzumab
Her2/neu
P
P
P
P
P
src
P
PI3K
Akt
PTEN
P
Rapamycin
TOR
P
Phase I / II: Everolimus + Trastuzumab in HER2+
Patients With Resistance to Trastuzumab
Everolimus 10 mg qday
and
Trastuzumab 6 mg/kg
q3wk
• Pts had ≤ 2 prior
trastuzumab regimens
and 1 prior lapatinibbased regimen for MBC
Best Response
N (%)
N = 47
Complete response (CR)
-
Partial response (PR)
7 (15%)
Stable disease ≥ 24 weeks
(SD)
9 (19%)
Overall response rate
7 (15%)
Clinical benefit rate
16 (34%)
Median time to progression
3.4 months
(Range 1-14)
Most frequent grade 3 / 4
adverse events (> 10%)
Lymphopenia,
hyperglycemia,
mucositis
Morrow PK, et al. J Clin Oncol 28:7s, 2010 (abstr 1014)
Trastuzumab/RAD001
Protocol 2005-0471 (Pt#10)
CT at Baseline (7/30/07)
Baseline PET scan (8/1/07)
SUV=9.1
CT after Cycle 2 (9/20/07)
PET scan after C2 (8/29/07)
SUV=5.5
CT after C12 (4/16/08)
PD after x 12 cycles
(best response: SD)
Molecular targets and therapeutic approaches to
overcome trastuzumab and lapatinib resistance
mTOR
Adapted from Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107
Pertuzumab: a HER dimerization inhibitor
Prevents
pairing with
other HER
family
members,
including
HER3, HER1,
and HER4
Combination of Trastuzumab and Pertuzumab:
Increased Apoptosis in vitro
% Annexin V + 7-AAD Cells
30
25
20
15
10
5
0
0
0.1
1
10
100
Trastuzumab + 2C4 (ug/mL)
Trastuzumab
0
0.1
1
10 0.1
2C4
1
Trastuzumab + 2C4
10
0.1 1
10
PARP
Full length 116kD
89 kD
24 kD
Nahta. Nahta R, Hung MC, Esteva FJ. Cancer Res 2004;64:2343-6
Antitumor activity of trastuzumab and/or pertuzumab in NSCLC (Calu-3) and breast cancer
(KPL-4) xenograft tumor models.
Scheuer W et al. Cancer Res 2009;69:9330-9336
©2009 by American Association for Cancer Research
HER2  A Good ADC Target
•
•
•
Tumor expression >>> Normal-tissue expression
Absolute Expression levels very high
Internalized without down regulation
Austin et al. (2004) Mol Biol Cell 15, 5268-82.
Trastuzumab-DM1
– Binds to HER2 with affinity similar to trastuzumab
– Provides intracellular delivery of anti-microtubule agent DM1
• Binds to tubulin competitively with vinca alkaloids, 20-100 times
more potently than vincristine2-4
– Combines trastuzumab mediated inhibition of HER2 signaling with
selective delivery of potent cytotoxic
Phase II study of trastuzumab-DM1 for the treatment of
HER2+ breast cancer after prior HER2-directed therapy
Burris H A et al. J Clin Oncol 2011;29:398-405
Phase II study of trastuzumab-DM1 for the
treatment of HER2-positive breast cancer
after prior HER2-directed therapy
Efficacy based on centrally
assessed HER2 status and
quantitative reverse transcriptase
polymerase chain reaction (qRTPCR) expression levels of HER2
Burris H A et al. J Clin Oncol 2011;29:398-405
Ongoing and Planned Randomized Trials of
Trastuzumab, Pertuzumab and T-DM1 in HER2+
Metastatic Breast Cancer
Combination
Trial
Trastuzumab/Docetaxel +/- Pertuzumab
CLEOPATRA (phase III)*
Trastuzumab/Docetaxel vs. T-DM1
Randomized phase II*
Trastuzumab/taxane vs.
T-DM1 vs.
T-DM1 + Pertuzumab
MARIANNE (phase III)*
T-DM1 vs. Capecitabine/Lapatinib
EMILIA (phase III)**
*first-line
**second-line after trastuzumab
Trastuzumab
& Erythropoietin
Liang, et al. Cancer Cell 18:423-435, 2010
Trastuzumab & Epo = Resistance
Liang, et al. Cancer Cell 18:423-435, 2010
Trastuzumab & Epo = Resistance
Liang, et al. Cancer Cell 18:423-435, 2010
SRC is a Key Modulator of Trastuzumab Response
Zhang S., et al. Nat Med 2011
SRC Trastuzumab treatment plus SRC inhibition
overcomes multiple resistance mechanisms in vitro
Zhang S., et al. Nat Med 2011
Trastuzumab plus SRC inhibition overcomes
trastuzumab resistance in vivo
Zhang S., et al. Nat Med 2011
Trastuzumab plus saracatinib combinatorial treatment
overcomes trastuzumab resistance in vivo
Zhang S., et al. Nat Med 2011
Zhang S., et al. Nat Med 2011
Future Directions
• Incorporate prospective tissue collection in clinical trials to
assess molecular changes in breast cancer tissue
– Characterize mechanisms of action and resistance
– Identify patients most likely to benefit
• Preclinical and clinical development of novel combination
targeting receptors and pathways
• Integrate non-invasive methods to monitor response to
treatment
• Characterize the potential toxicity of long-term pathway
blockade (especially important in adjuvant setting)
Thank you for your attention!