(.pdf) dr.ssa Antonella Ferro - Progettoeventi
(.pdf) dr.ssa Antonella Ferro - Progettoeventi
(.pdf) dr.ssa Antonella Ferro - Progettoeventi
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Utilizzo dei farmaci nei diversi<br />
contesti clinici<br />
<strong>Antonella</strong> <strong>Ferro</strong><br />
UO Oncologia Medica<br />
Trento
There are four receptors in the Human<br />
Epidermal Receptor network<br />
HER1/EGFR HER2 HER3 HER4<br />
Yarden, Sliwkowsky. Nat Rev Mol Cell Biol 2001;2:127–137
HER2 positive breast cancer<br />
“Targeted Targeted therapies” therapies<br />
TRASTUZUMAB<br />
Early disease<br />
LAPATINIB<br />
Advanced disease<br />
Pertuzumab<br />
T-DM1
TRASTUZUMAB nel carcinoma<br />
mammario<br />
•anticorpo monoclonale<br />
“umanizzato”<br />
•diretto contro HER2/neu<br />
•<br />
•approvato dall’FDA nel<br />
1998
Trastuzumab (Herceptin)<br />
• Il Trastuzumab ha cambiato la storia naturale del<br />
tumore della mammella HER-2 positivo<br />
• In fase metastatica<br />
– In Monoterapia<br />
– In associazione ad agenti chemioterapici o ormonoterapici<br />
• In fase neo e adiuvante
MBC<br />
I linea II linea<br />
HO648<br />
M77001<br />
US Oncology<br />
BCIRG 007<br />
CHAT<br />
Tandem<br />
Rhea<br />
Studi clinici con Trastuzumab<br />
GBG-26<br />
Studi Fase II<br />
Neo<br />
NOAH<br />
MDACC<br />
GeparQuattro<br />
Studi Fase II<br />
EBC<br />
HERA<br />
Adj<br />
NSABP-B31<br />
NCCTG N9831<br />
BCIRG 006<br />
FinHER<br />
PACS-04
Trastuzumab<br />
binds to ErbB2<br />
on tumour cells<br />
Trastuzumab binds to the extracellular domain of<br />
ErbB2 to induce anti-tumour effect<br />
Immune cells bind to trastuzumab and release<br />
substances that promote tumour cell death<br />
• Effect of trastuzumab on cell signalling not well understood<br />
• Activity has been attributed to antibody-dependent cellular<br />
cytotoxicity (ADCC) 1–4<br />
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<br />
2004;10:5650–5; 4. Arnould et al. Br J Cancer 2006;94:259–67
Aumento dell’endocitosi e<br />
distruzione del recettore
Antibody-Dependent Cellular<br />
Cytotoxicity (ADCC)
Potenziale meccanismo d’azione di<br />
trastuzumab<br />
Cytotoxic Cytotoxic Cytostatic<br />
ADCC DNA repair inhibition Cell growth inhibition<br />
NK<br />
DNA<br />
repair<br />
Drug<br />
DNA<br />
damage<br />
Signaling<br />
pathway<br />
RECIST RECIST OS/DFS<br />
Citotossico Citotossico Citostatico<br />
Recist Recist Survival<br />
Molecular Targeting Unit
Potenziale meccanismo di trastuzumab in<br />
base a clinical setting<br />
Clinical setting Inhibition of ADCC Inhibition of<br />
proliferation DNA repair<br />
Survival Recist Recist<br />
Neoadjuvant<br />
-trastuzumab alone + ++ -<br />
-trastuzumab plus<br />
chemotherapy + +/- ++<br />
Adjuvant<br />
-concomitant + +/- ++<br />
-sequential ++ +/- -<br />
Molecular Targeting Unit
Potenziale meccanismo di trastuzumab in<br />
base a clinical setting<br />
• Il trastuzumab (> da solo) esplica la sua attività tramite<br />
ADCC nella fase precoce della malattia e quando il<br />
sistema immunitario è integro (NO precedente CT)<br />
Gennari R CCR 2004<br />
• Molti studi hanno dimostrato un effetto sinergico di<br />
trastuzumab con la chemioterapia<br />
• CT + T concomitanti: blocco della riparazione del danno<br />
di DNA (indotto da CT)<br />
• CT→T: blocco della proliferazione (effetto citostatico)<br />
Dowsett M JCO 2009
Malattia<br />
adiuvante
Entrambe le opzioni<br />
(sequenziale/concomitante) appaiono valide<br />
Study FU, yrs Pts<br />
HERA<br />
NSABP B-31/<br />
NCCTG 9831<br />
NCCTG 9831 seq<br />
BCIRG 006<br />
1 3,387<br />
2 3,401<br />
2 3,351<br />
4 3,968<br />
1.5<br />
3<br />
1,964<br />
3,222<br />
FinHer 3 231<br />
PACS 04 4 528<br />
HR<br />
0.54<br />
0.64<br />
0.48<br />
0.48<br />
0.87<br />
0.61<br />
0.42<br />
0.86<br />
0 1 2<br />
In favor of T In favor of Obs.
DFS: Sequential (Arm B: AC → T → H ) vs<br />
Concurrent (Arm C: AC → T + H → H )<br />
Alive and Disease Free (%)<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
949<br />
954<br />
Log rank P = .0190<br />
837<br />
830<br />
788<br />
766<br />
AC → T + H → H<br />
(138 events)<br />
89.1 %<br />
84.2 %<br />
85.7 %<br />
79.8 %<br />
AC → T → H<br />
(174 events)<br />
740<br />
705<br />
676<br />
641<br />
0 1 2 3 4 5<br />
Perez EA, et al. SABCS 2009. Abstract 80.<br />
Yrs From Randomization<br />
456<br />
418<br />
No. at risk
Presente e futuro<br />
Presente e futuro<br />
• Trattamento standard<br />
– 1 anno, 52 settimane, 18 infusioni<br />
– In concomitanza o in sequenza rispetto a CT<br />
• Studi in corso: da 9 settimane a 2 anni<br />
• Risultati attesi,<br />
studio HERA : 1 anno verso 2 anni
Malattia<br />
Neo-<br />
adiuvante
Neoadjuvant Trastuzumab significantly<br />
pCR<br />
(%)<br />
improves pCR rates in the NOAH trial<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
Without Trastuzumab<br />
With Trastuzumab<br />
p=0.002<br />
HER2 positive<br />
(n=228)<br />
p=0.004<br />
23 43 17 19 55 29<br />
HER2<br />
negative<br />
(n=99)<br />
HER2 positive<br />
(n=62)<br />
Total population IBC population<br />
pCR, pathological complete response in the breast<br />
IBC, inflammatory breast cancer<br />
HER2<br />
negative<br />
(n=14)<br />
Baselga et al 2007; Gianni et al 2007
Studio NOAH: Event Free Survival nella<br />
popolazione HER2-positiva<br />
Probabilità di EFS<br />
1.00<br />
0.75<br />
0.50<br />
0.25<br />
0.00<br />
H+CT<br />
CT<br />
Pazienti<br />
115<br />
112<br />
Eventi<br />
0 6 12 18 24 30 36 42<br />
Mesi<br />
Follow-up mediano 3 anni<br />
*non aggiustato per le variabili della stratificazione: HR aggiustata=0.55, p= 0.0<br />
HR, hazard ratio; IC, intervallo di confidenza<br />
36<br />
52<br />
HR a<br />
0.56<br />
IC 95%<br />
0.36 – 0.85<br />
Gianni L et al, 31th San Antonio Breast Cancer Symposium 2008<br />
p a<br />
0.006
Malattia<br />
Metastatica
Trastuzumab has transformed the<br />
prognosis of HER2+ breast cancer<br />
Overall survival probability<br />
1.0<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0<br />
0 12 24 36 48 60<br />
Months from diagnosis<br />
HER2+/trastuzumab<br />
HER2 –<br />
HER2+/no trastuzumab<br />
Dawood, et al. ASCO 2008 (abstract 1018)
Trastuzumab has transformed the<br />
prognosis of HER2+ breast cancer<br />
• Secondo le stime presentate all’ASC0 e SABCS 2008, si prevede che in<br />
Europa, nei prossimi 10 anni, saranno circa 28.000 le pazienti che avranno<br />
tratto beneficio dalla somministrazione di trastuzumab.<br />
• E’ stato calcolato che nei prossimi 25 anni 50.000 donne non svilupperanno<br />
recidive grazie all’utilizzo di trastuzumab
Definition of resistance<br />
In most tumors a multiplicity of<br />
genetic alterations contributes to<br />
tumor growth and progression<br />
intrinsic resistance acquired resistance
Potenziali meccanismi di resistenza al<br />
trastuzumab<br />
• Prevenzione del legame di trastuzumab a HER2<br />
• Inibizione dei meccanismi immuno-mediati<br />
• Up-regulation dei signaling pathways downstream di<br />
HER2<br />
• Up-regulation di growth factor receptor-signaling<br />
pathways alternativi<br />
• Recettore p95 troncato
Truncated HER2 (p95 HER2 ): clinical<br />
significance<br />
Extracellular domain<br />
(ECD) released • A constitutively active, truncate form of<br />
HER2, p95HER2, has kinase activity but<br />
lacks the extracellular domain and the<br />
binding site of trastuzumab<br />
Truncated HER2<br />
receptor<br />
(p95 HER2 )<br />
• Truncated p95HER2 is expressed at<br />
high frequency (up to 60%) in HER2overexpressing<br />
breast cancer<br />
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<br />
trastuzumab in breast cancer<br />
HER2-positive MBC patients receiving trastuzumab (N=46)<br />
p185 HER2 (n=37)<br />
ORR: 51.4%<br />
p=0.029<br />
p95 HER2 (n=9)<br />
ORR: 11.1%<br />
Scaltriti et al. J Natl Cancer Inst 2007;99:628–38
Trastuzumab<br />
Capecitabine<br />
von Minckwitz, JCO<br />
2009<br />
How to best treat patients beyond<br />
progression ?<br />
Progression after<br />
anthracycline/taxane/trastuzumab<br />
Lapatinib<br />
Capecitabine<br />
Randomized clinical trials<br />
Geyer, NEJM 2006<br />
Trastuzumab<br />
Lapatinib<br />
Blackwell, SABCS 2009
GBG-26 is the 1st randomised Phase III study to<br />
investigate continuation of Trastuzumab beyond<br />
progression<br />
Progression under Trastuzumab-based 1st-line therapy + taxane<br />
(n=114)<br />
or<br />
Progression under Herceptin monotherapy or non-taxane (n=42)<br />
Capecitabine 1,250 mg/m 2<br />
bid d1-14 q21d<br />
+<br />
continuation of<br />
Trastuzumab 6 mg/kg q3w<br />
(n=78)<br />
Primary endpoint: Time to Progression<br />
R<br />
Capecitabine 1,250<br />
mg/m 2 bid d1-14 q21d<br />
(n=78)<br />
von Minckwitz et al, J Clin Oncol 2009
GBG 26/BIG 03-05: main results<br />
Capecitabine<br />
Capecitabine<br />
Plus<br />
Trastuzumab<br />
Overall RR 27% 48.1%<br />
HR<br />
2.50<br />
(odds ratio)<br />
P<br />
Value<br />
.011<br />
Median TTP 5.6 mo 8.2 mo 0.69 .034<br />
Median OS 20.4 mo 25.5 0.76 .25<br />
von Minckwitz et al, J Clin Oncol 2009
Probability<br />
1.0<br />
0.8<br />
0.6<br />
0.4<br />
0.2<br />
0.0<br />
0<br />
74<br />
77<br />
+<br />
Continuation of Trastuzumab prolongs<br />
median TTP in the GBG-26 study<br />
++<br />
+<br />
+<br />
+<br />
+<br />
5.6 a<br />
a Median TTP in months<br />
HR, hazard ratio<br />
40<br />
55<br />
+<br />
+<br />
+<br />
+<br />
8.2 a<br />
+<br />
+<br />
+<br />
+ +<br />
10 20 30<br />
15<br />
29<br />
Time from 1st progression (months)<br />
8<br />
12<br />
5<br />
4<br />
Trastuzumab + Capecitabine (n=78)<br />
Capecitabine (n=78)<br />
HR=0.69 (95% CI, 0.48-0.97, p=0.034)<br />
3<br />
3<br />
2<br />
1<br />
+<br />
1<br />
1<br />
40<br />
1<br />
1<br />
von Minckwitz et al, J Clin Oncol 2009<br />
+<br />
+
Phase III, randomised, controlled study of Lapatinib plus<br />
capecitabine versus capecitabine alone (study<br />
EGF100151)<br />
Patients with ErbB2-positive locally advanced or metastatic<br />
breast cancer that progressed after prior anthracycline, taxane<br />
and trastuzumab<br />
(N=399*)<br />
Lapatinib 1250 mg po<br />
qd continuously +<br />
capecitabine 2000 mg/m 2 /day<br />
po, Days 1–14 q3wk<br />
RANDOMISATION<br />
Treatment continued until progression<br />
Capecitabine 2500 mg/m 2 /day<br />
po, Days 1–14 q3wk<br />
*Planned 528; stopped at interim analysis, following achievement of primary endpoint<br />
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*<br />
Time to Progession – ITT Population<br />
100<br />
90<br />
80<br />
70<br />
60<br />
50<br />
40<br />
30<br />
20<br />
10<br />
0<br />
0<br />
1<br />
0<br />
Lapatinib +<br />
Capecitabine Capecitabine<br />
No. of pts<br />
160 161<br />
Progressed or died* 45 (28%) 69 (43%)<br />
Median TTP, wk 36.9 19.7<br />
Hazard ratio (95% CI) 0.51 (0.35, 0.74)<br />
P-value (log-rank, 1-sided) 0.00016<br />
20 30 40 50 60<br />
Time (weeks)<br />
* Censors 4 patients who died due to causes other than breast cancer<br />
70
Lapatinib<br />
• Binds to intracellular ATP binding site of<br />
EGFR (ErbB-1) and HER2 (ErbB-2)<br />
preventing phosphorylation and activation<br />
• Blocks downstream signaling through<br />
homodimers and heterodimers of EGFR<br />
(ErbB-1) and HER2 (ErbB-2)<br />
• Dual blockade of signaling may be more<br />
effective than the single-target inhibition<br />
provided by agents such as trastuzumab<br />
Lapatinib<br />
1+1 2+2 1+2<br />
Downstream signaling<br />
cascade<br />
Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;<br />
Konecny et al. Cancer Res. 2006;66:1630-1639
Lapatinib: indicazioni cliniche<br />
• Tyverb cp (1250 mg tot) tutti i gg +<br />
Capecitabina 2000 mg/mq dal 1-14 gg<br />
• Indicazione: in malattia metastatica dopo<br />
trastuzumab (almeno una linea<br />
metastatica)
Lapatinib may sensitise HER2 positive cells to<br />
subsequent trastuzumab (in vitro findings)<br />
• Lapatinib counteracts the phosphorylation, ubiquitination and<br />
degradation of ErbB2<br />
• Lapatinib-induced cell surface accumulation of inactive HER2<br />
significantly enhances trastuzumab-mediated ADCC<br />
HER2<br />
Lapatinib<br />
K K K K<br />
HER2<br />
homodimer heterodimer<br />
K K K K K K K K K K<br />
ATP<br />
Dimerization, reduced phosphorylation<br />
and signaling inhibition<br />
Scaltriti M et al. Oncogene 2009; 28: 803-814.<br />
trastuzumab<br />
K = kinase domain<br />
ADCC = antibody-dependent cell cytotoxicity<br />
NK cell<br />
FcR<br />
K K<br />
Stabilization of HER2 dimers and<br />
receptor accumulation leads to ADCC
EGF104900: Updated Overall Survival in ITT<br />
80%<br />
70%<br />
6 Month OS<br />
56%<br />
41%<br />
12 Month OS<br />
L<br />
N =145<br />
L+T<br />
N =146<br />
Died, N (%) 113 (78) 105 (72)<br />
Median, months 9.5 14<br />
Hazard ratio (95% CI) 0.74 (0.57, 0.97)<br />
Log-rank P value .026<br />
SABCS 2009
Pertuzumab<br />
• Pertuzumab, inibitore della dimerizzazione di HER2<br />
• Pertuzumab in combinazione con trastuzumab<br />
– un più completo blocco dei signaling pathways di HER<br />
– efficacia antitumorale sinergica, come nei modelli preclinici<br />
• Questa combinazione ha il potenziale di fornire efficacia<br />
al di là di quella di correnti terapie per malattia<br />
metastatica HER2-positiva, con incoraggiante<br />
tollerabilità
HER1:HER1<br />
HER2:HER3 dimers have the strongest<br />
mitogenic signaling<br />
Homodimers Heterodimers<br />
HER2:HER2<br />
Tzahar et al. Mol Cell Biol 1996;16:5276–5287<br />
HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4<br />
HER2:HER3<br />
HER2:HER4<br />
Signaling activity<br />
HER3:HER4
HER2 dimerization is key to signaling activity<br />
HER2 HER3<br />
Ligand-activatedHER2:HER3 dimer<br />
P<br />
P<br />
P<br />
P<br />
Phosphorylation of the tyrosine<br />
kinase domain by HER2 initiates intracellular signaling<br />
Ferguson et al. Mol Cell 2003;11:507–517. Olayioye et al. EMBO J 2000;19:3159–3167. Hynes et al. Nat Rev Cancer<br />
2005;5:341–354. Rowinsky. Annu Rev Med 2004;55:433–457
Trastuzumab +<br />
Pertuzumab
Trastuzumab binds to subdomain IV of HER2, continually<br />
suppresses HER2 activity and flags cells for destruction by the<br />
immune system<br />
angiogenesis<br />
RAS Sos Grb2 Shc<br />
Raf<br />
MEK<br />
MAPK<br />
HER2<br />
mTOR<br />
PI3K<br />
Cyclin D1<br />
cell cycle<br />
control<br />
proliferation<br />
HER2<br />
p27<br />
PDK1<br />
BAD<br />
AKT<br />
NFκB<br />
↓ apoptosis<br />
GSK3β<br />
↑ survival
Pertuzumab binds to the dimerisation domain of HER2, prevents<br />
HER2 forming dimer pairs and may flag cells for destruction by the<br />
immune system<br />
angiogenesis<br />
RAS<br />
Raf<br />
MEK<br />
MAPK<br />
HER2<br />
mTOR<br />
Cyclin D1<br />
cell cycle<br />
control<br />
proliferation<br />
p27<br />
BAD<br />
NFκB<br />
↓ apoptosis<br />
HER3<br />
GSK3β<br />
↑ survival
Trastuzumab and pertuzumab may have synergistic<br />
activity<br />
Trastuzumab<br />
Subdomain IV of HER2<br />
Trastuzumab continually suppresses HER2<br />
activity<br />
Flags cells for destruction by the immune<br />
system<br />
Does not inhibit HER2 dimerisation<br />
HER2 receptor<br />
Pertuzumab<br />
Dimerisation domain of<br />
HER2<br />
Pertuzumab inhibits HER2 forming dimer<br />
pairs<br />
Suppresses multiple HER signalling pathways<br />
Flags cells for destruction by the immune<br />
system
T-DM1: the first-in-class HER2-targeted<br />
antibody-<strong>dr</strong>ug conjugate<br />
Target expression: HER2<br />
Monoclonal antibody: trastuzumab<br />
Cytotoxic agent: DM1<br />
Highly potent chemotherapy<br />
(maytansine derivative)<br />
Linker<br />
Systemically stable<br />
Breaks down in target cancer cell<br />
T-DM1
Receptor-T-DM1 complex is<br />
internalized into cancer cell<br />
T-DM1: meccanismo d’azione<br />
• Trastuzumab-like activity by binding to HER2<br />
• Targeted intracellular delivery of DM1<br />
T-DM1 binds to the HER2 protein<br />
on cancer cells<br />
Potent antimicrotubule<br />
agent is released once inside<br />
the tumor cell
Conclusioni<br />
• La malattia HER2 rappresenta un sottotipo<br />
prognosticamente sfavorevole<br />
• La terapia anti-HER2, in particolare Trastuzumab, ha<br />
modificato significativamente l’evoluzione di tale malattia<br />
• Altre terapie anti-HER (lapatinib, pertuzumab e T-DM1)<br />
hanno contribuito a modificare il processo di cura<br />
migliorando la prognosi di tale malattia