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3.3 beslija es obreast2011final
1. Targeted therapy:
Trastuzumab and beyond
Semir Beslija, MD, PhD
Institute of oncology
Clinical Center of Sarajevo
University
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
2. Prevalence and clinical relevance of
HER2 overexpression
• ~430,000 new cases of breast cancer per year in
Europe1
• In 2006, breast cancer represented 13.5% of all
cancers diagnosed, and 29% of all female
cancers, with 131,900 deaths due to breast cancer1
• HER2 is overexpressed in up to 30% of breast
tumours2, and recognised as independent marker for
poor prognosis3,4
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
1. Ferlay et al. Ann Oncol 2007;18:581–92; 2. Slamon et al. Science 1987;235:177–82; Dubrovnik, Croatia
2. 3. Goldhirsch et al. Ann Oncol 2005;16:1569–83; 4. Thuerlimann et al. Eur J Cancer 2007;43:46–52
3. The HER receptor tyrosine kinases as
targets in breast cancer therapy
• Family of four type HER
receptor tyrosine kinases
• Important in human growth
and development
• Similar structure, but:
– HER2 lacks ligand-
binding domain
– HER3 lacks functional HER1 (EGFR) HER2 (HER2) HER3 HER4
intracellular tyrosine
kinase domain
1. Holbro & Hynes. Annu Rev Pharmacol Toxicol 2004;44:195-217; ESO Balkan Masterclass in Clinical Oncology
2. Marmor et al. Int J Radiat Oncol Biol Phys 2004;58:903-13; 3. Rowinsky. Annu Rev Med 2004;55:433-57; 11.5.2011- 15.5.2011
4. Wiseman et al. Cancer 2005;103(9):1770-7; 5. Sundvall et al. J Mammary Gland Biol Neoplasia 2008;13:259-68 Dubrovnik, Croatia
4. Homodimers and Heterodimers
A+B B+B
• Ligand binding causes HER receptors to associate in pairs in a
process called dimerization.
• Dimerization and autophosphorylation must occur for downstream
signal transmission.
• Pairs can be formed between 2 identical receptors (homodimers) or
between 2 different family members (heterodimers).
• HER2 is the preferred dimerization partner with other HER
receptors.
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
5. HER2 receptors signal through two main
pathways: MAPK and PI3K
Ligands
Other HER HER2
MAPK pathway
(Ras/Raf/ PI3K/Akt pathway
MEK/ERK)
Proliferation Cell cycle, ESO Balkan15.5.2011 in Clinical Oncology
Survival
11.5.2011-
Masterclass
Dubrovnik, Croatia
1. Citri & Yarden. Nature Rev Molecular Cell Biol 2006;7:505-16; 2. Wiseman et al. Cancer 2005;103(9):1770-7
6. HER2 detection by IHC
HER2 status, either gene copy number
or the protein expression level , is the
best predictive marker available for
assessing response to HER2 targeted
therapy.
ESO Balkan Masterclass in Clinical Oncology
Histopathology. 2010 Apr 11.5.2011- 15.5.2011
Dubrovnik, Croatia
7. HER2 by FISH and CISH
Histopathology. 2010 Apr FISH+ and IHC 3+ testing correlated best with improved clinical
J Clin Oncol. 2009 Mar
benefit (response and/or survival) ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
A survival advantage with trastuzumab was seen in Dubrovnik, Croatia
patients with FISH+ or IHC 3+ tumors
8. Trastuzumab binds to the extracellular
domain of HER2 to induce anti-tumour effect
Trastuzumab
binds to ErbB2
on tumour cells
Immune cells bind to trastuzumab and
release substances that promote tumour
cell death
• Effect of trastuzumab on cell signalling not well understood
• Activity has been attributed to antibody-dependent cellular
cytotoxicity (ADCC)1–4
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
1. Nahta & Esteva. Breast Cancer Res 2006;8:215; 2. Clynes et al. Nat Med 2000;6:443–6; 3. Gennari et al. Clin Cancer Res 2004;10:5650–5; Dubrovnik, Croatia
2. 4. Arnould et al. Br J Cancer 2006;94:259–67
9. Pivotal Concurrent Trial of 1st-Line
Chemotherapy Trastuzumab in MBC:
Efficacy
Trastuzumab + chemotherapy (N=235)
Months (TTP, survival)
Chemotherapy (N=234)
ORR (%)
ORR Median Median
P<0.001 TTP Survival
P<0.001 P=0.046
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Slamon. N Engl J Med. 2001;344:783; Herceptin (trastuzumab) PI.
Dubrovnik, Croatia
10. Trastuzumab in MBC: Safety
• Most adverse events mild to moderate in
severity
– Infusion-associated symptoms, including fever and
chills, primarily with first dose
• Serious adverse events infrequent
• Increased incidence of cardiac
dysfunction, particularly when administered
with anthracycline-based therapy
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Slamon DJ, et al. N Engl J Med. 2001;344:783-792. Dubrovnik, Croatia
11. Trastuzumab provides proven OS benefit
in first-line HER2-positive MBC
P
H0648g p=0.046
(IHC 3+)1 P+H
T p=0.033
M770012
T+H
T+C+H
BCIRG 0073 p=0.65
T+H
US Oncology P + C + H
(IHC 3+)4
p=0.5
P+H
0 10 20 30 40 50
Median survival (months)
IHC, immunohistochemistry;
P, paclitaxel (Taxol); H, trastuzumab (Herceptin); ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
1. Slamon et al. NEJM 2001; 2. Marty et al. JCO 2005;
T, docetaxel (Taxotere); C, carboplatin 3. Pegram et al. JCO 2007; 4. Robert et al. JCO 2006 Dubrovnik, Croatia
12. Adjuvant Trastuzumab Trials
Disease-free Survival
Study FU, yrs Pts HR
1 3,387 0.54
HERA
2 3,401 0.64
NSABP B-31/ 2 3,351 0.48
NCCTG 9831 4 3,968 0.48
1.5 1,964 0.87
NCCTG 9831 seq
3 3,222 0.61
BCIRG 006
0.42
FinHer 3 231
PACS 04 4 528 0.86
0 1
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011 2
In favor of T In favor of Obs.
Dubrovnik, Croatia
13. Adjuvant Trastuzumab Should Be Added
for HER2+ Breast Cancer
Implications
• Reliable HER2 testing for all patients
– IHC or FISH
• Timing of starting trastuzumab to be further
investigated, but concurrent Rx with
chemotherapy appears better
• Several chemotherapy options
• D at i on of t r eat m
ur ent : 1 year
• Careful cardiac monitoring required
• Translational studies
• Platform for new HER2 + adjuvant studies
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
14. Pivotal trials of first-line trastuzumab–taxane combinations
showed that a proportion of patients do not respond
Trial N ORR
M77001 (Marty 2005)1 92 61%
H0648g (Slamon/Smith
68* 49%
2001)2,3
*ErbB2 IHC 3+ subgroup ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
1. Marty et al. J Clin Oncol 2005;23:4265–74; Dubrovnik, Croatia
2. 2. Slamon et al. N Engl J Med 2001;344:783–92; 3.Smith et al. Anticancer Drugs 2001;12(Suppl 4):S3–10
15. Majority of patients with HER2-positive MBC responding
to trastuzumab plus taxane or vinorelbine 1st-line progress
within 1 year
0 2 4 6 8 10 12 months
61
7.12,3*
Median TTP
7.84
9.95
11.16
11.77
12.48
*ErbB2 IHC 3+ subgroup
1. Burstein et al. Cancer 2007;110(5):965–72; 2. Slamon et al. N Engl J Med 2001;344:783–92; 3. Smith et al. Anticancer Drugs 2001;12(Suppl
4):S3–10; 4. Burstein et al. J Clin Oncol 2001;19:2722–30; 5. Gasparini et al. Breast Cancer Res Treat 2007;110(5):965–72; ESO Balkan Masterclass in Clinical Oncology
6. Pegram et al. J Clin Oncol ASCO Annual Meeting Proceedings 2007;25(18S): Abstract #LBA1008; 11.5.2011- 15.5.2011
7. Marty et al. J Clin Oncol 2005;23:4265–74; 8. Tedesco et al. J Clin Oncol 2004;22(6):1071–7 Dubrovnik, Croatia
16. Studies with trastuzumab in HER2-
positive EBC
100
Resistant
80
Sensitive
Disease-free survival (%)
60
HERA Trial
40 3-year
Events DFS HR 95% CI p value Already
20 218 80.6 0.63 0.53, 0.75 <0.0001 cured
316 74.0
0
0 6 12 18 24 30 36
• More than 17,000 patients, including four registration trials, nearly all
with central labs for ErbB2 testing. But…
• Not a single effort to identify mechanisms of resistance ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Smith et al. Lancet 2007; 369: 29–36
17. Trastuzumab resistance
• Possible mechanisms include:1,2
– Altered binding to ErbB2 receptor1,3,4–6
• Truncated ECD (p95 ErbB2)
• Receptor mutations
• Binding of other proteins (MUC 4)
– Loss of PTEN function leading to
constitutive activation of the PI3K /
AKT pathway1,7,8
– Switching to alternate growth
regulatory pathways e.g. IGFR
pathway1,9
ESO Balkan Masterclass in Clinical Oncology
1. Nahta R et al. Breast Cancer Res 2006; 2. Meric-Bernstam F, Hung M-C. Clin Cancer Res 2006; 11.5.2011- 15.5.2011
3. Scaltriti M et al. J Natl Cancer Inst 2007; 4. Moy B, Goss PE. Oncologist 2006; 5. Price-Schiavi SA et al. Int J Cancer 2002; Dubrovnik, Croatia
6. Nagy P et al. Cancer Res 2005; 7. Nagata Y et al. Cancer Cell 2004; 8. Fujita T et al. Br J Cancer 2006; 9. Lu Y et al. J Natl Cancer Inst 2001
18. Current anti-ErbB2 molecules
Ligands
• Trastuzumab binds to
Other HER HER2
extracellular domain of
ErbB2 – mAb
-Trastuzumab • Trastuzumab-DM1 is
Pertuzumab DM1 trastuzumab linked to a
antimicrotubule drug –
Investigational mAb
• Pertuzumab inhibits ErbB2-
HER3 dimerization –
Investigational
Lapatinib is directed toward
Lapatinib intracellular kinase domain –
TKI
Only lapatinib and trastuzumab are approved anti-ErbB2 therapies
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
19. What does this mean for clinical
practice in patients with
progressive disease on
trastuzumab?
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
20. GBG26; Trastuzumab beyond
progression
Patients with ErbB2-positive locally advanced or metastatic
breast cancer who progressed on one line of trastuzumab
(N=156)
RANDOMIZATION
Capecitabine 2500
mg/m2/day Capecitabine 2500
po Days 1–14 mg/m2/day
q3wk po Days 1–14
+ continuation of q3wk
trastuzumab 6 mg/kg
q3wk
Trial stopped early due to slow accrual and introduction
of lapatinib – analysed with 156 out
of planned 482 patients ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Von Minckwitz et al. J Clin Oncol 2009; 27: 1999–2006
21. GBG26; Kaplan-Meier estimates of time to
progression
1.0
Progression-free survival (probability)
Capecitabine (n=78) 5.6 (4.2–6.3) months
Trastuzumab 8.2 (7.3–11.2) months
0.8 + capecitabine (n=78)
p<0.0467
Censored
0.6 HR=0.69
(two-sided p=0.0338; one-sided p=0.017)
0.4
0.2
0
0 10 20 30 40
No. at risk Time (months)
Capecitabine 74 40 15 8 5 3 2 1 1
Trastuzumab + capecitabine 77 55 29 12 4 3 1 1 1 ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Von Minckwitz et al. J Clin Oncol 2009; 27: 1999–2006
22. Lapatinib — A Dual Receptor
Tyrosine Kinase Inhibitor
• Potent, oral,
reversible dual
tyrosine kinase
inhibitor
• Binds to ATP site of
erbB-1 and erbB-2
receptor kinases,
blocking kinase
activity and
downstream signaling ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
23. Lapatinib + capecitabine versus
capecitabine
EGF1001511,2
Patients with ErbB2-positive locally advanced or metastatic breast cancer who
progressed after prior anthracycline, taxane and trastuzumab
(N=399)
RANDOMIZATION
Lapatinib 1250 mg po Capecitabine 2500
qd continuously + mg/m2/day
capecitabine 2000 po Days 1–14
mg/m2/day q3wk
po Days 1–14 q3wk
Trial stopped early due to achievement of primary endpoint (TTP) at
planned interim analysis – analysed with 399 patients out of planned
528 patients
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
1. Cameron et al. Breast Cancer Res Treat 2008; 112: 533–43; 2. Geyer et al. N Engl J Med 2006; 355: 2733–43
24. EGF100151 patient population:
pre-treatment
• >75% patients were third line or later
– Patients enrolled had progressed after prior treatment
with an anthracycline, a taxane and trastuzumab in
metastatic setting1,2
• EGF100151 trial halted early due to achievement
of study endpoint (superior efficacy in lapatinib +
capecitabine arm)1
– 399 of planned 528 patients enrolled between March 2004
and April 2006
– Cross-over allowed in April 20062
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
1. Geyer et al. N Engl J Med 2006; 355: 2733–43; 2. Cameron et al. Breast Cancer Res Treat 2008; 112: 533–43
25. EGF100151:
Kaplan-Meier estimates of time to progression
100
Cumulative progression-free (%)
90
Lapatinib + capecitabine (n=198)
80 Capecitabine (n=201)
70 HR: 0.57 (95% CI: 0.43, 0.77)
60 Log-rank p=0.00013
50
40
30
20
18.6 weeks 27.1 weeks
10
(4.3 months) (6.2 months)
0
0 10 20 30 40 50 60 70 80 90
Time (weeks)
• These data led to the EMEA registration of lapatinib in
June 2008 ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Cameron et al. Breast Cancer Res Treat 2008; 112: 533–43
26. EGF100151: safety profile
• The safety profile of lapatinib + capecitabine was
generally predictable and manageable
70
1
Grade 1
60
13 Grade 2
50 Grade 3
12
Patients (%)
2 2 Grade 4
14
40
20 10 13 15
30 2
2 <1
14 29 25 2 7
20 6 3 3
29 27 7 9 10 1
10 31 20 4
16
13 12 18 13 12 11 9
0
L+C C L+C C L+C C L+C C L+C C L+C C
Diarrhoea PPE Nausea Vomiting Fatigue Balkan Masterclass in Clinical Oncology
ESO
Rash
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Cameron et al. Breast Cancer Res Treat 2008; 112: 533–43
27. Brain Metastases as
Site of First Progression
• Patients with ErbB2+ breast cancer are at increased risk of
developing brain metastases1
EGF100151: Post hoc analysis (April 2006 dataset)2
Lapatinib + Capecitabine Capecitabine
(n=198) (n=201)
Patients with CNS relapse
as site of first 4 (2%) 13 (6%)
progression*
*P-value (Fisher’s exact, 2-sided) = 0.045
1. Lin Clin Cancer Res 2007 ESO Balkan Masterclass in Clinical Oncology
2. EGF100151: Cameron et al. Breast Cancer Res Treat 2008 11.5.2011- 15.5.2011
Dubrovnik, Croatia
28. Rationale for combining
lapatinib with trastuzumab
• Combining lapatinib with trastuzumab may provide total
blockade of HER2 resulting in greater anti-tumour activity
versus either agent alone, and potential to overcome
trastuzumab resistance
MUC4
ErbB1–ErbB3 ErbB2–ErbB2
PTEN ErbB2–ErbB3
ErbB1–p95
ErbB1–ErbB1
SOS
PI3K
RAS
Akt RAF
MAPK MEK
Cell proliferation
Cell survival
Cell mobility and invasiveness
ESO Balkan Masterclass in Clinical Oncology
Transcription 11.5.2011- 15.5.2011
Dubrovnik, Croatia
29. EGF104900: study design
Lapatinib 1500 mg po od
Key inclusion criteria
n=148
•ErbB2-positive MBC
(FISH+/ IHC3+)
•Progression on
• Anthracycline Crossover if PD after
• Taxane 4 weeks of therapy
• Trastuzumab (n=77)
•Progression on
most recent
trastuzumab regimen Lapatinib 1000 mg po od
Trastuzumab 4 2 mg/kg IV
qw n=148
Primary endpoint: PFS
Secondary endpoints: OS, ORR and CBR Oncology
ESO Balkan Masterclass in Clinical
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Blackwell et al. J Clin Oncol 2010; DOI:1200/JCO.2008.21.4437
30. Lapatinib in combination with trastuzumab
provides an OS benefit in this heavily pre-
treated patient population
100
Lapatinib
Cumulative % alive without progression
Lapatinib +
80% n=145 trastuzumab
80 n=146
113 (78) 105 (72)
Median, months 9.5 14
60 70%
Hazard ratio (95% CI) 0.74 (0.57, 0.97)
56% Log-rank p value 0.026
40
6-month OS
41%
20
12-month OS
0
0 5 10 15 20 25 30 35
Patients at risk Time from randomization (months)
L 148 121 88 64 43 25 1
ESO Balkan Masterclass in Clinical Oncology
L+T 148 102 65 47 28 13 11.5.2011- 15.5.2011
Dubrovnik, Croatia
Blackwell et al. Cancer Res 2009; 69(Suppl): 9157, abstract 61 and oral presentation
31. Rationale for combined targeted
therapy
• Dual targeting of oestrogen and growth factor signalling
(EGFR/HER2) is one rational approach to overcome endocrine
resistance1–4
• Agents that target both EGFR and HER2 may be more
efficacious at overcoming endocrine resistance than those
that target HER2 alone1,5
1. Johnston. Breast Cancer Res 2008; 10(Suppl 4): S20; 2. Xia et al. Proc Natl Acad Sci U S A 2006; 103: 7795–800;Clinical Oncology
ESO Balkan Masterclass in 3. Chu et al.
11.5.2011- 15.5.2011
Cancer Res 2005; 65: 18–25: 4. Leary et al. Clin Cancer Res; 2010; 16(5): 1486–97; Dubrovnik, Croatia
5. Prat and Baselga. Nat Clin Pract Oncol 2008; 5: 531–42
32. Phase III, Randomized, Double-Blind
Controlled Trial: Study Design
Patient Population
• ER+ and/or PgR+ R
• Postmenopausal
• HER2+ , HER2-ve / Unknown A Letrozole 2.5 mg daily +
• Stage IIIb/IIIc/IV N Placebo
• No prior treatment for MBC D
O
Stratification
M
• Disease sites
I Letrozole 2.5 mg daily +
• Bone only / visceral or
soft tissue Z Lapatinib 1500 mg daily
• Interval since adjuvant E
tamoxifen therapy
• < 6 mo / ≥ 6 mo or none
N=1286 (including n=219 HER2+) ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
33. Progression free survival:
EGF30008 ErbB2+ population
100 (N=219) Letrozole Letrozole
+ +
% Alive without progression
80 placebo lapatinib
(N=108) (N=111)
Progressed or died 89 (82%) 88 (79%)
60 Median PFS, mo 3.0 8.2
Hazard ratio (95% CI) 0.71 (0.53, 0.96)
p value 0.019
40
20
0
3.0 8.2
0 5 10 15 20 25 30 35 40 45 50
Time from randomization (months)
Pts at risk:
Let + lap 111 69 33 20 12 8 4 1 1
Let + plac 108 43 26 18 12 7 5 2 2 Balkan Masterclass in Clinical Oncology
ESO
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Johnston et al. J Clin Oncol 2009; 27(33): 5538–46
34. Response rate:
EGF30008 ErbB2+ population (N=219)
60
50 p=0.003
% of patients
40 48%
p=0.021
30
28% 29%
20
10 15%
0
CR PR SD ≥ 6 mo ORR CBR
Letrozole + placebo Letrozole + lapatinib
Response rates were compared using stratified Fisher’s exact test
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Johnston et al. J Clin Oncol 2009; 27(33): 5538–46
36. EGF30008: summary
• In postmenopausal women with HR+, ErbB2+ MBC lapatinib
plus letrozole showed
– Significant reduction in risk of disease
progression (29%)
– Improvement in median PFS from 3.0 to 8.2 months
– Significant improvement in CBR
• The safety profile of lapatinib and letrozole was predictable
and manageable
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Johnston et al. J Clin Oncol 2009; 27(33): 5538–46
37. HER2:HER3 dimers may provide an
escape mechanism from trastuzumab
Homodimers Heterodimers
HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4
HER3:HER3 HER2:HER3
HER2:HER2 HER2:HER4
HER1:HER1 HER3:HER4
+ + + + + + + +
+ + + +
+ +
Inhibition of HER2:HER dimerization may
provide a more comprehensive blockade of
+
HER2-driven signaling
Signaling activity
Tzahar et al. Mol Cell Biol 1996; ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Sergina et al. Nature 2007 Tzahar, et al. Mol Cell Biol 1996
Dubrovnik, Croatia
38. Pertuzumab and trastuzumab bind to different
regions on HER2 and have synergistic activity
HER2 receptor
Pertuzumab
Trastuzumab
Dimerization domain
of HER2
Subdomain IV of HER2
● Preferentially inhibits ligand-independent ● Inhibits formation of HER2 dimer pairs
HER2 signaling ● Suppresses multiple HER signalling
● Prevents shedding of HER2 ECD pathways, leading to a more comprehensive
● Flags cells for destruction by the blockade of HER2-driven signalling
immune system ● Flags cells for destruction by the
immune system
ESO Balkan Masterclass in Clinical Oncology
Junttila et al. Cancer Cell 2009 11.5.2011- 15.5.2011
Dubrovnik, Croatia
39. BO17929: a Phase II trial of pertuzumab + trastuzumab in
HER2-positive MBC patients progressing during
trastuzumab-based therapy
HER2-positive MBC Pertuzumab +
Cohorts Progressed on trastuzumab +
1 and 21 trastuzumab
chemotherapy
(Cohorts 1 and 2, n=66) (n=66)
HER2-positive MBC Pertuzumab +
Pertuzumab
Cohort 32 Progressed on trastuzumab + trastuzumab
(n=29)
chemotherapy (n=29) (n=15)
Primary objectives
● Safety and efficacy
Population
● ≤3 prior lines cytotoxic therapy (including adjuvant treatment)
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
1. Baselga et al. JCO 2010; 2. Baselga et al. SABCS 2009 Dubrovnik, Croatia
40. Pertuzumab / trastuzumab combination therapy
more active than treatment with either agent alone
Cohorts 1 and 21,2 Cohort 33 Cohort 33
(P + H) (P) (P P + H)
(n=66) (n=27*) (n=11†)
CR, % 7.6 0.0 0.0
PR, % 16.7 3.4 21.4
ORR, % 24.2 3.4 21.4
SD 6 months, % 25.8 6.9 21.4
CBR, %
(CR + PR + SD 6 months) 50.0‡ 10.3 37.5
PD, % 50.0 82.8 57.1
*n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of assessment
during this phase); †n=11, as at data cut-off 4/15 patients had not reached overall best response endpoint
(8 cycles of assessment during this phase); ‡at data cut-off, 21 (31.8%) patients had not experienced PD
1. Gelmon et al. ASCO 2008;
2. Baselga et al. JCO 2010; ESO Balkan Masterclass in Clinical Oncology
3. Baselga et al. SABCS 2009 11.5.2011- 15.5.2011
CR, complete response; PR, partial response; SD, stable disease Dubrovnik, Croatia
41. T-DM1: the first-in-class HER2-targeted
antibody-drug conjugate
Target expression: HER2
Monoclonal antibody: trastuzumab
Cytotoxic agent: DM1
Highly potent chemotherapy
(maytansine derivative)
T-DM1
Linker
Systemically stable
Breaks down in target cancer cell
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
42. T-DM1 selectively delivers a highly toxic
payload to HER2-positive tumor cells
• Trastuzumab-like activity by binding to HER2 to the HER2 protein
T-DM1 binds
on cancer cells
• Targeted intracellular delivery of a potent antimicrotubule
agent, DM1
Receptor-T-DM1 complex is
Potent antimicrotubule
internalized into HER2-positive
agent is released once inside
cancer cell
the HER2-positive
tumor cell
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
43. Single-agent T-DM1 shows promising efficacy in
pretreated HER2-positive MBC patients
Phase I • Dose escalation, q1w and q3w
TDM3569g1, 2 • DLT: grade 4 thrombocytopenia
(n=52) • T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended
1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; ESO Balkan Masterclass in Clinical Oncology
DLT, dose-limiting toxicity 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 11.5.2011- 15.5.2011
q3w, every 3 weeks Dubrovnik, Croatia
44. Single-agent T-DM1 shows promising efficacy in
pretreated HER2-positive MBC patients
Phase I • Dose escalation, q1w and q3w
TDM3569g1, 2 • DLT: grade 4 thrombocytopenia
(n=52) • T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended
• Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab
Phase II pretreated (60% lapatinib) and ≥1 line of chemotherapy for MBC
TDM4258g2–5 • ORR: 34% (centrally confirmed HER2-positive patients)5
(n=112) • No new safety signals identified
1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; ESO Balkan Masterclass in Clinical Oncology
DLT, dose-limiting toxicity 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 11.5.2011- 15.5.2011
q3w, every 3 weeks Dubrovnik, Croatia
45. Single-agent T-DM1 shows promising efficacy in
pretreated HER2-positive MBC patients
Phase I • Dose escalation, q1w and q3w
TDM3569g1, 2 • DLT: grade 4 thrombocytopenia
(n=52) • T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended
• Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab
Phase II pretreated (60% lapatinib) and ≥1 line of chemotherapy for MBC
TDM4258g2–5 • ORR: 34% (centrally confirmed HER2-positive patients)5
(n=112) • No new safety signals identified
• Pivotal study of T-DM1 (3.6 mg/kg i.v. q3w) in patients pretreated with
Phase II anthracyclines, taxanes, capecitabine, trastuzumab and lapatinib
TDM4374g2–5
(n=112) • ORR: 41% (centrally confirmed HER2-positive patients)5
• No new safety signals identified
1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; ESO Balkan Masterclass in Clinical Oncology
DLT, dose-limiting toxicity 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 11.5.2011- 15.5.2011
q3w, every 3 weeks Dubrovnik, Croatia
46. TDM4450g: Study Design
T-DM1
3.6 mg/kg Q3W until PD
1:1
HER2-positive
Trastuzumab
MBC (n=137)
8 mg/kg dose; 6 mg/kg
Q3W
PD Crossover
+ Docetaxel
T-DM1
75 or 100 mg/m2 Q3W
• Randomized, phase II, international, open-label study
• Stratification: region, prior adjuvant trastuzumab, disease-free interval
• Primary endpoints: PFS by INV, safety
• Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Perez EA, et al. Abstr LBA3. ESMO 2010
47. TDM4450g: Overall Response (ITT)
Trastuzumab +
T-DM1 Docetaxel
(n=67) (n=70)
Patients with an Objective Response,* n (%) 32 (47.8) 29 (41.4)
95% CI (35.4, 60.3) (30.2, 53.8)
Patients with Clinical Benefit,† n (%) 37 (55.2) 40 (57.1)
95% CI (43.1, 67.2) (44.8, 68.9)
Objective Responses, n (%)
Complete Response 3 (4.5) 1 (1.4)
Partial Response 29 (43.3) 28 (40.0)
Stable Disease‡ 22 (32.8) 29 (41.4)
Progressive Disease 8 (11.9) 4 (5.7)
Unable to Evaluate 4 (6.0) 4 (5.7)
‡ Stabledisease includes 11 patients with unconfirmed partial response
(5 in T-DM1 arm and 6 in the trastuzumab + docetaxel arm)
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Perez EA, et al. Abstr LBA3. ESMO 2010
48. TDM4450g: Adverse Event
Summary
Trastuzumab +
T-DM1
Docetaxel
(n=67)
(n=68)
Any AE, n (%) 63 (94.0) 68 (100.0)
Grade ≥3 AE 25 (37.3) 51 (75.0)
Serious AE* 13 (19.4) 15 (22.1)
Three most common AEs (any grade) in T-DM1 arm
Nausea 32 (47.8) 27 (39.7)
Fatigue 31 (46.3) 29 (46.2)
Pyrexia 24 (35.8) 14 (20.6)
Three most common AEs (any grade) in trastuzumab +
docetaxel arm
1 (1.5) 45 (66.2)
Alopecia
5 (7.5) 39 (57.4)
Neutropenia
7 (10.4) 31 (45.6)
Diarrhea
* AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing
hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth
defects
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
Perez EA, et al. Abstr LBA3. ESMO 2010
49. The PI3K/AKT/mTOR Pathway
Growth factors including
IGF-1, VEGF, ErbB
• mTOR (mammalian
target of rapamycin)
signaling plays a key
PI3K
Oxygen, ener
gy, and
PTEN
role in
– Cell growth
Estrogen
nutrients AKT receptor
TSC2 TSC1 – Cell proliferation
Ras/Raf
– Regulation of
pathway
kinases
mTOR • Apoptosis
• Angiogenesis
• Lymphocytes
S6K1 4E-BP1
Protein production elF-4E
S6
• Homeostasis
Angiogenesis
Cell growth
and proliferation
Nutrient uptake
and metabolism • Metabolism
ESO Balkan Masterclass in Clinical Oncology
1. Bjornsti MA, et al. Nat Rev Cancer. 2004;34(5):335-348; 2. Crespo JL, et al. Microbiol Mol Biol Rev. 2002;66(4):579-591; 11.5.2011- 15.5.2011
3. Huang S, et al. Cancer Biol Ther. 2003;2(3):222-232; 4. Mita MM, et al. Clin Breast Cancer. 2003;4(2):126-137; Dubrovnik, Croatia
5. Wullschleger S, et al. Cell. 2006;124(3):471-484; 6. Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.
50. Everolimus Overcomes Trastuzumab
Resistance Mechanisms
Nutrients
IGF-1R EGFR/HER2 Increased signaling through
IGF-1R
PI3K Truncated HER-2
PTEN
LKB1 Constitutive PI3K/AKT activation
AKT
Absent or low PTEN
AMPK
TSC1 TSC2
Elevated AKT or pAKT
RHEB
Downstream inhibition with
mTOR
Everolimus everolimus counters
Cell growth and
proliferation resistance mechanisms
Receptor Constitutive activation of
Angiogenesis Cell metabolism signaling downstream pathways
ESO Balkan Masterclass in Clinical Oncology
1. Widakowich C, et al. Anticancer Agents Med Chem. 2008,8(5):488-496; 2. Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S. 11.5.2011- 15.5.2011
Dubrovnik, Croatia
51. Everolimus + Trastuzumab:
Phase Ib/II Data
Study/Patient population Treatments N Outcome
NCT00426556 Everolimus, trastuzumab, 55 Clinical benefit
paclitaxel (≥ SD for ≥ 24 wk) in
•HER-2+ mBC 40% of patients1
•Refractory to trastuzumab AND
taxanes
•Previous chemotherapy for mBC
≤ 6 lines
NCT00317720 Everolimus, trastuzumab 47 Clinical benefit
(without chemotherapy) (≥ SD for ≥ 24 wk) in
•HER-2+ mBC 34% of patients2
•Disease progression on/after
trastuzumab
•Prior lapatinib OK
ESO Balkan Masterclass in Clinical Oncology
Abbreviations: mBC, metastatic breast cancer; SD, stable disease. 11.5.2011- 15.5.2011
Dubrovnik, Croatia
1. Dalenc F, et al. J Clin Oncol. 2010.; 2. Morrow PH, et al. Presented at: ASCO 2010. Abstract 1014.
53. Conclusions
•There is efficacy data of trastuzumab in combination with
paclitaxel, docetaxel, and vinorelbine in the first-line metastatic
setting, suggesting that trastuzumab is a therapeutic equalizer
that renders the choice of partnering chemotherapy secondary,
allowing for the selection of a treatment regimen that will be
best tolerated.
•Five adjuvant trials with trastuzumab in HER2 over-expressing
EBC have shown its strengths and weaknesses Major DFS and
OS gain were obtained when:
Trastuzumab was given concomitantly with taxanes
Anthracyclines were included in the schema
•The risk of myocardial damage formally contraindicate
concurrent administration of anthracyclines and trastuzumab1
•Little knowledge in the mechanism of HER2 resistance in EBC
orv MBC ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
54. Conclusions
• Lapatinib trials are on the go to provide
– Comprehensive understanding of the HER2 machinery
– Explore the potential synergism with anthracyclines
– Confirm the effectiveness of the dual blockage of HER2 by the
trastuzumab and lapatinib combination
• The most promising systemic therapies for HER2- positive central
nervous system (CNS) metastases following cranial irradiation are
lapatinib and capecitabine, after progression during treatment
with trastuzumab.
• There is an urgent need to increase therapeutic options in this
subgroup of patients with novel agents and multimodality
treatment through trials with specific CNS end points.
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
55. Conclusions
•Discordances in HER2 assessment can influence clinical
decision making with anti-HER2 therapies.
•Reassessment of tumor phenotype at relapse is
rec-ommended, particularly after a substantial interval
period has passed since the last pathologic assessment.
•Pertuzumab, TDM-1 and everolimus new exciting
molecules
•Total HER2 blockade by combining molecules without CT
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia
56. Targeted treatments of HER2
positive breast cancers: 2010 news
• In combination • In combination
with Trastuzumab with Trastuzumab
Lapatinib Pertuzumab
RAD001 TDM-1
• In combination • Active as
with monotherapy
Trastuzumab • Maybe better In
combination with
Pertuzumab
ESO Balkan Masterclass in Clinical Oncology
11.5.2011- 15.5.2011
Dubrovnik, Croatia