(.pdf) dr.ssa Antonella Ferro - Progettoeventi

Utilizzo dei farmaci nei diversi
contesti clinici
Antonella Ferro
UO Oncologia Medica
Trento

There are four receptors in the Human
Epidermal Receptor network
HER1/EGFR HER2 HER3 HER4
Yarden, Sliwkowsky. Nat Rev Mol Cell Biol 2001;2:127–137

HER2 positive breast cancer
“Targeted Targeted therapies” therapies
TRASTUZUMAB
Early disease
LAPATINIB
Advanced disease
Pertuzumab
T-DM1

TRASTUZUMAB nel carcinoma
mammario
•anticorpo monoclonale
“umanizzato”
•diretto contro HER2/neu
•
•approvato dall’FDA nel
1998

Trastuzumab (Herceptin)
• Il Trastuzumab ha cambiato la storia naturale del
tumore della mammella HER-2 positivo
• In fase metastatica
– In Monoterapia
– In associazione ad agenti chemioterapici o ormonoterapici
• In fase neo e adiuvante

MBC
I linea II linea
HO648
M77001
US Oncology
BCIRG 007
CHAT
Tandem
Rhea
Studi clinici con Trastuzumab
GBG-26
Studi Fase II
Neo
NOAH
MDACC
GeparQuattro
Studi Fase II
EBC
HERA
Adj
NSABP-B31
NCCTG N9831
BCIRG 006
FinHER
PACS-04

Trastuzumab
binds to ErbB2
on tumour cells
Trastuzumab binds to the extracellular domain of
ErbB2 to induce anti-tumour effect
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
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; 4. Arnould et al. Br J Cancer 2006;94:259–67

Aumento dell’endocitosi e
distruzione del recettore

Antibody-Dependent Cellular
Cytotoxicity (ADCC)

Potenziale meccanismo d’azione di
trastuzumab
Cytotoxic Cytotoxic Cytostatic
ADCC DNA repair inhibition Cell growth inhibition
NK
DNA
repair
Drug
DNA
damage
Signaling
pathway
RECIST RECIST OS/DFS
Citotossico Citotossico Citostatico
Recist Recist Survival
Molecular Targeting Unit

Potenziale meccanismo di trastuzumab in
base a clinical setting
Clinical setting Inhibition of ADCC Inhibition of
proliferation DNA repair
Survival Recist Recist
Neoadjuvant
-trastuzumab alone + ++ -
-trastuzumab plus
chemotherapy + +/- ++
Adjuvant
-concomitant + +/- ++
-sequential ++ +/- -
Molecular Targeting Unit

Potenziale meccanismo di trastuzumab in
base a clinical setting
• Il trastuzumab (> da solo) esplica la sua attività tramite
ADCC nella fase precoce della malattia e quando il
sistema immunitario è integro (NO precedente CT)
Gennari R CCR 2004
• Molti studi hanno dimostrato un effetto sinergico di
trastuzumab con la chemioterapia
• CT + T concomitanti: blocco della riparazione del danno
di DNA (indotto da CT)
• CT→T: blocco della proliferazione (effetto citostatico)
Dowsett M JCO 2009

Malattia
adiuvante

Entrambe le opzioni
(sequenziale/concomitante) appaiono valide
Study FU, yrs Pts
HERA
NSABP B-31/
NCCTG 9831
NCCTG 9831 seq
BCIRG 006
1 3,387
2 3,401
2 3,351
4 3,968
1.5
3
1,964
3,222
FinHer 3 231
PACS 04 4 528
HR
0.54
0.64
0.48
0.48
0.87
0.61
0.42
0.86
0 1 2
In favor of T In favor of Obs.

DFS: Sequential (Arm B: AC → T → H ) vs
Concurrent (Arm C: AC → T + H → H )
Alive and Disease Free (%)
100
90
80
70
60
50
40
949
954
Log rank P = .0190
837
830
788
766
AC → T + H → H
(138 events)
89.1 %
84.2 %
85.7 %
79.8 %
AC → T → H
(174 events)
740
705
676
641
0 1 2 3 4 5
Perez EA, et al. SABCS 2009. Abstract 80.
Yrs From Randomization
456
418
No. at risk

Presente e futuro
Presente e futuro
• Trattamento standard
– 1 anno, 52 settimane, 18 infusioni
– In concomitanza o in sequenza rispetto a CT
• Studi in corso: da 9 settimane a 2 anni
• Risultati attesi,
studio HERA : 1 anno verso 2 anni

Malattia
Neo-
adiuvante

Neoadjuvant Trastuzumab significantly
pCR
(%)
improves pCR rates in the NOAH trial
90
80
70
60
50
40
30
20
10
0
Without Trastuzumab
With Trastuzumab
p=0.002
HER2 positive
(n=228)
p=0.004
23 43 17 19 55 29
HER2
negative
(n=99)
HER2 positive
(n=62)
Total population IBC population
pCR, pathological complete response in the breast
IBC, inflammatory breast cancer
HER2
negative
(n=14)
Baselga et al 2007; Gianni et al 2007

Studio NOAH: Event Free Survival nella
popolazione HER2-positiva
Probabilità di EFS
1.00
0.75
0.50
0.25
0.00
H+CT
CT
Pazienti
115
112
Eventi
0 6 12 18 24 30 36 42
Mesi
Follow-up mediano 3 anni
*non aggiustato per le variabili della stratificazione: HR aggiustata=0.55, p= 0.0
HR, hazard ratio; IC, intervallo di confidenza
36
52
HR a
0.56
IC 95%
0.36 – 0.85
Gianni L et al, 31th San Antonio Breast Cancer Symposium 2008
p a
0.006

Malattia
Metastatica

Trastuzumab has transformed the
prognosis of HER2+ breast cancer
Overall survival probability
1.0
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60
Months from diagnosis
HER2+/trastuzumab
HER2 –
HER2+/no trastuzumab
Dawood, et al. ASCO 2008 (abstract 1018)

Trastuzumab has transformed the
prognosis of HER2+ breast cancer
• Secondo le stime presentate all’ASC0 e SABCS 2008, si prevede che in
Europa, nei prossimi 10 anni, saranno circa 28.000 le pazienti che avranno
tratto beneficio dalla somministrazione di trastuzumab.
• E’ stato calcolato che nei prossimi 25 anni 50.000 donne non svilupperanno
recidive grazie all’utilizzo di trastuzumab

Definition of resistance
In most tumors a multiplicity of
genetic alterations contributes to
tumor growth and progression
intrinsic resistance acquired resistance

Potenziali meccanismi di resistenza al
trastuzumab
• Prevenzione del legame di trastuzumab a HER2
• Inibizione dei meccanismi immuno-mediati
• Up-regulation dei signaling pathways downstream di
HER2
• Up-regulation di growth factor receptor-signaling
pathways alternativi
• Recettore p95 troncato

Truncated HER2 (p95 HER2 ): clinical
significance
Extracellular domain
(ECD) released • A constitutively active, truncate form of
HER2, p95HER2, has kinase activity but
lacks the extracellular domain and the
binding site of trastuzumab
Truncated HER2
receptor
(p95 HER2 )
• Truncated p95HER2 is expressed at
high frequency (up to 60%) in HER2overexpressing
breast cancer
Molina et al. Clin Cancer Res 2002;8:347-53; Saez et al. Clin Cancer Res 2006;12:424-31; 3.

Expression of p95 HER2 and response to
trastuzumab in breast cancer
HER2-positive MBC patients receiving trastuzumab (N=46)
p185 HER2 (n=37)
ORR: 51.4%
p=0.029
p95 HER2 (n=9)
ORR: 11.1%
Scaltriti et al. J Natl Cancer Inst 2007;99:628–38

Trastuzumab
Capecitabine
von Minckwitz, JCO
2009
How to best treat patients beyond
progression ?
Progression after
anthracycline/taxane/trastuzumab
Lapatinib
Capecitabine
Randomized clinical trials
Geyer, NEJM 2006
Trastuzumab
Lapatinib
Blackwell, SABCS 2009

GBG-26 is the 1st randomised Phase III study to
investigate continuation of Trastuzumab beyond
progression
Progression under Trastuzumab-based 1st-line therapy + taxane
(n=114)
or
Progression under Herceptin monotherapy or non-taxane (n=42)
Capecitabine 1,250 mg/m 2
bid d1-14 q21d
+
continuation of
Trastuzumab 6 mg/kg q3w
(n=78)
Primary endpoint: Time to Progression
R
Capecitabine 1,250
mg/m 2 bid d1-14 q21d
(n=78)
von Minckwitz et al, J Clin Oncol 2009

GBG 26/BIG 03-05: main results
Capecitabine
Capecitabine
Plus
Trastuzumab
Overall RR 27% 48.1%
HR
2.50
(odds ratio)
P
Value
.011
Median TTP 5.6 mo 8.2 mo 0.69 .034
Median OS 20.4 mo 25.5 0.76 .25
von Minckwitz et al, J Clin Oncol 2009

Probability
1.0
0.8
0.6
0.4
0.2
0.0
0
74
77
+
Continuation of Trastuzumab prolongs
median TTP in the GBG-26 study
++
+
+
+
+
5.6 a
a Median TTP in months
HR, hazard ratio
40
55
+
+
+
+
8.2 a
+
+
+
+ +
10 20 30
15
29
Time from 1st progression (months)
8
12
5
4
Trastuzumab + Capecitabine (n=78)
Capecitabine (n=78)
HR=0.69 (95% CI, 0.48-0.97, p=0.034)
3
3
2
1
+
1
1
40
1
1
von Minckwitz et al, J Clin Oncol 2009
+
+

Phase III, randomised, controlled study of Lapatinib plus
capecitabine versus capecitabine alone (study
EGF100151)
Patients with ErbB2-positive locally advanced or metastatic
breast cancer that progressed after prior anthracycline, taxane
and trastuzumab
(N=399*)
Lapatinib 1250 mg po
qd continuously +
capecitabine 2000 mg/m 2 /day
po, Days 1–14 q3wk
RANDOMISATION
Treatment continued until progression
Capecitabine 2500 mg/m 2 /day
po, Days 1–14 q3wk
*Planned 528; stopped at interim analysis, following achievement of primary endpoint
1. Cameron et al. Breast Cancer Res Treat 2008; 2. Geyer et al. N Engl J Med 2006;355:2733–43

% of patients free from progression*
Time to Progession – ITT Population
100
90
80
70
60
50
40
30
20
10
0
0
1
0
Lapatinib +
Capecitabine Capecitabine
No. of pts
160 161
Progressed or died* 45 (28%) 69 (43%)
Median TTP, wk 36.9 19.7
Hazard ratio (95% CI) 0.51 (0.35, 0.74)
P-value (log-rank, 1-sided) 0.00016
20 30 40 50 60
Time (weeks)
* Censors 4 patients who died due to causes other than breast cancer
70

Lapatinib
• Binds to intracellular ATP binding site of
EGFR (ErbB-1) and HER2 (ErbB-2)
preventing phosphorylation and activation
• Blocks downstream signaling through
homodimers and heterodimers of EGFR
(ErbB-1) and HER2 (ErbB-2)
• Dual blockade of signaling may be more
effective than the single-target inhibition
provided by agents such as trastuzumab
Lapatinib
1+1 2+2 1+2
Downstream signaling
cascade
Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;
Konecny et al. Cancer Res. 2006;66:1630-1639

Lapatinib: indicazioni cliniche
• Tyverb cp (1250 mg tot) tutti i gg +
Capecitabina 2000 mg/mq dal 1-14 gg
• Indicazione: in malattia metastatica dopo
trastuzumab (almeno una linea
metastatica)

Lapatinib may sensitise HER2 positive cells to
subsequent trastuzumab (in vitro findings)
• Lapatinib counteracts the phosphorylation, ubiquitination and
degradation of ErbB2
• Lapatinib-induced cell surface accumulation of inactive HER2
significantly enhances trastuzumab-mediated ADCC
HER2
Lapatinib
K K K K
HER2
homodimer heterodimer
K K K K K K K K K K
ATP
Dimerization, reduced phosphorylation
and signaling inhibition
Scaltriti M et al. Oncogene 2009; 28: 803-814.
trastuzumab
K = kinase domain
ADCC = antibody-dependent cell cytotoxicity
NK cell
FcR
K K
Stabilization of HER2 dimers and
receptor accumulation leads to ADCC

EGF104900: Updated Overall Survival in ITT
80%
70%
6 Month OS
56%
41%
12 Month OS
L
N =145
L+T
N =146
Died, N (%) 113 (78) 105 (72)
Median, months 9.5 14
Hazard ratio (95% CI) 0.74 (0.57, 0.97)
Log-rank P value .026
SABCS 2009

Pertuzumab
• Pertuzumab, inibitore della dimerizzazione di HER2
• Pertuzumab in combinazione con trastuzumab
– un più completo blocco dei signaling pathways di HER
– efficacia antitumorale sinergica, come nei modelli preclinici
• Questa combinazione ha il potenziale di fornire efficacia
al di là di quella di correnti terapie per malattia
metastatica HER2-positiva, con incoraggiante
tollerabilità

HER1:HER1
HER2:HER3 dimers have the strongest
mitogenic signaling
Homodimers Heterodimers
HER2:HER2
Tzahar et al. Mol Cell Biol 1996;16:5276–5287
HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4
HER2:HER3
HER2:HER4
Signaling activity
HER3:HER4

HER2 dimerization is key to signaling activity
HER2 HER3
Ligand-activatedHER2:HER3 dimer
P
P
P
P
Phosphorylation of the tyrosine
kinase domain by HER2 initiates intracellular signaling
Ferguson et al. Mol Cell 2003;11:507–517. Olayioye et al. EMBO J 2000;19:3159–3167. Hynes et al. Nat Rev Cancer
2005;5:341–354. Rowinsky. Annu Rev Med 2004;55:433–457

Trastuzumab +
Pertuzumab

Trastuzumab binds to subdomain IV of HER2, continually
suppresses HER2 activity and flags cells for destruction by the
immune system
angiogenesis
RAS Sos Grb2 Shc
Raf
MEK
MAPK
HER2
mTOR
PI3K
Cyclin D1
cell cycle
control
proliferation
HER2
p27
PDK1
BAD
AKT
NFκB
↓ apoptosis
GSK3β
↑ survival

Pertuzumab binds to the dimerisation domain of HER2, prevents
HER2 forming dimer pairs and may flag cells for destruction by the
immune system
angiogenesis
RAS
Raf
MEK
MAPK
HER2
mTOR
Cyclin D1
cell cycle
control
proliferation
p27
BAD
NFκB
↓ apoptosis
HER3
GSK3β
↑ survival

Trastuzumab and pertuzumab may have synergistic
activity
Trastuzumab
Subdomain IV of HER2
Trastuzumab continually suppresses HER2
activity
Flags cells for destruction by the immune
system
Does not inhibit HER2 dimerisation
HER2 receptor
Pertuzumab
Dimerisation domain of
HER2
Pertuzumab inhibits HER2 forming dimer
pairs
Suppresses multiple HER signalling pathways
Flags cells for destruction by the immune
system

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)
Linker
Systemically stable
Breaks down in target cancer cell
T-DM1

Receptor-T-DM1 complex is
internalized into cancer cell
T-DM1: meccanismo d’azione
• Trastuzumab-like activity by binding to HER2
• Targeted intracellular delivery of DM1
T-DM1 binds to the HER2 protein
on cancer cells
Potent antimicrotubule
agent is released once inside
the tumor cell

Conclusioni
• La malattia HER2 rappresenta un sottotipo
prognosticamente sfavorevole
• La terapia anti-HER2, in particolare Trastuzumab, ha
modificato significativamente l’evoluzione di tale malattia
• Altre terapie anti-HER (lapatinib, pertuzumab e T-DM1)
hanno contribuito a modificare il processo di cura
migliorando la prognosi di tale malattia