i farmaci multitargeted nel cancro della mammella cattedra di oncologia medica e laboratori di...
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I FARMACI MULTITARGETED
NEL CANCRO DELLA MAMMELLA
Cattedra di Oncologia Medica eLaboratori di Terapia Molecolare
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica Università di Napoli “Federico II”
Giampaolo Tortora
Farmaci che bloccano più recettori della stessa famiglia, per aumentare l’efficienza del “targeting” selettivo.
Farmaci che bloccano recettori e proteine di segnale di classi e funzioni diverse, per bloccare a più livelli la trasmisione di segnali.
Farmaci con bersagli multipli
PKAIPI3K
PLC
GRB2 SOS p21ras Raf
MAPK
Cyclin D1
CDK
RbCell ProliferationCell Proliferation
E2Fmdm2
p53
PKC
SIGNALLING PATHWAYS IN CANCER CELLS
AKT
Bcl-2
mTOR
Angiogenesis
Invasionmetastasis
VEGFMEK
P
PP P
c-KITR
PDGFR,
HER/erbB
Apoptosis
PTEN
P
EGFR/ErbB2 EGFR/ErbB3EGFR
Tortora et al., 2007
I recettori della famiglia ErbB/HER funzionano in coppia, formando omo- o eterodimeri
Co-expression of EGFR and ErbB-2 has been observed in 10-30% primary human breast carcinomas.
Overexpression of both ErbB-2 and EGFR is associated with a poorer prognosis than overexpression of either receptor alone in breast cancer patients.
A recent study has demonstrated an adverse prognostic independent role of ErbB-2 and EGFR coexpression in a subset of radically resected early breast cancers. (Di Giovanna et
al., JCO, 23: 1152-1160, 2005).
Co-expression of EGFR and ErbB-2
Phase I study of Erlotinib plus Trastuzumab and Taxol
Escalating doses of Erlotinib (25 to 150 mg); Taxol 80 or 90 mg/m2; Trastuzumab 2 mg/kg. Weekly administration with different schedules.
Selected the 1, 8, 15, 28 schedule and the recommended doses of Erlotinib 150 mg, Taxol 90 mg/m2, Trastuzumab 2 mg/kg.
14/16 patients had MBC, HER2+ (8 pre-treated with Tastuzumab).
Mild toxicity and PKA interaction.
1 CR and 2 PR in patients HER2+, taxane-resistant. In 2 cases also Trastuzumab-resistant.
Important the role of Taxanes ? Major activity of Erlotinib ?
A. Patnaik, ASCO 2005
Doppi inibitori di EGFR e HER-2
Pertuzumab e Lapatinib
Omnitarg Riconosce Epitopi diversi da Trastuzumab su HER2 e impedisce la etero-dimerizzazione EGFR-HER2
HER2
Ligand-binding domain(inactive)
Cell membrane
Tyrosine kinase domain
Omnitarg
Trastuzumab
N
N
O O
NH
O O NH
S
O
N
N
NH
Cl
OO
O
F
N
O
N
N
O O
NH
Cl F
Erlotinib Gefitinib GW572016 Lapatinib
Small head group quinazolines Large head group quinazoline
Lapatinib inhibits EGFR and HER-2
EGF20009: A Phase II, Randomized trial using Lapatinib as a first-line treatment in patients with FISH Positive Advanced or
Metastatic Breast Cancer
Response Investigator ReviewN=40
Independent ReviewN=40
CR 0 0
PR 12 (30%) 14 (35%)
Unconfirmed PR* 3 (7.5%) 2 (5%)
SD 13 (32.5%) 14 (35%)
PD 10 (25%) 5 (12.5%)
Unknown 2 (5%)** † 5 (12.5%) ** †
*Two subjects considered to have a PR by investigator had <28 day confirmation scans.** One subject not evaluated due to death from multiple injuries prior to tumor assessment.† 1 subject by the investigator review and 4 subjects by independent review had only one timepoint and that timepoint did not meet the criteria for SD per the protocol (8 weeks). Sledge group updated from ASCO 2005 and SABCS
Randomized Phase III Study EGF100151
• Progressive, HER2+ MBC or LABC
• Previously treated with anthracycline, taxane and trastuzumab*
• No prior capecitabine
Lapatinib 1250 mg po qd continuously +
Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk
Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk
Patients on treatment until progression or unacceptable toxicity, then followed for survival
Stratification:• Disease sites• Stage of disease
RANDOMIZE
*Trastuzumab must have been administered for metastatic disease
N=528
Prior Therapy
Lapatinib + Capecitabine(n=160)
Capecitabine(n=161)
Anthracyclines 156 (98%) 156 (97%)
Taxanes 157 (98%) 159 (99%)
Trastuzumab 156 (97%) 156 (97%)
Metastatic 149 (93%) 146 (91%)
Adjuvant 7 (4%) 10 (6%)
Time to Progession – ITT Population
70
10
20
30
40
50
60
70
80
90
0
100
* Censors 4 patients who died due to causes other than breast cancer
10 20 30 40 50 600Time (weeks)
CapecitabineLapatinib +
Capecitabine
0.00016P-value (log-rank, 1-sided)
69 (43%)45 (28%)Progressed or died*
19.736.9Median TTP, wk
161160No. of pts
0.51 (0.35, 0.74)Hazard ratio (95% CI)
% o
f p
atie
nts
fre
e fr
om
pro
gre
ssio
n*
Time (weeks)0 10 20 30 40 50 60 70
Cu
mu
lati
ve P
rog
ress
ion
-Fre
e S
urv
ival
, %
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival - ITT Population
0.000045P-value (log-rank, 1-sided)
73 (45%)45 (28%)Progressed or died
0.48 (0.33, 0.70)Hazard ratio (95% CI)
17.936.9Median PFS, wk
161160No. of pts
CapecitabineLapatinib +
capecitabine
Overall Survival - ITT Population
0.800P value (log-rank, 2-sided)
29 (18%)29 (18%)Deaths
0.93 (0.55, 1.59)Hazard ratio (95% CI)
NRNRMedian OS
161160No. of pts
Time (weeks)0 10 20 30 40 50 70 90
Cu
mu
lati
ve S
urv
ival
%
0
10
20
30
40
50
60
70
80
90
100
CapecitabineLapatinib +
Capecitabine
60 80
Brain Metastases as Site of Progression
Lapatinib + Capecitabine(n=160)
Capecitabine(n=161)
Patients with CNS metastases at baseline
2 2
Patients with CNS relapse* 4 11
Patients with CNS as only site of relapse
3 10
*P-value (Fisher’s exact, 2-sided) = 0.110
Mean LVEF at Scheduled Assessments
Week 12 Week 18 Week 24 Week 36 Week 48Week 6Screening
Assessment
Lapatinib + Capecitabine
Capecitabine
Mea
n L
VE
F (
%)
80
75
70
65
60
55
50
n=160 n=160
n=108
n=92
n=84 n=67
n=63n=37
n=37 n=26
n=15n=9
n=7n=1
EGF103009A Phase II Trial of Lapatinib (Tykerb) Monotherapy
in Patients With Relapsed/Refractory Inflammatory Breast Cancer (IBC):
Clinical Activity and Biologic Predictors of Response
Spector N, K Blackwell, J Hurley, J Harris, D Lombardi, S Bacus, SB Ahmed, H Boussen, M Frikha, FB Ayed
Cohort AErbB2+
Cohort BErbB1+/ErbB2-
0%
50%
100%
Cohort AErbB2+
24 patients
5 enrolled patients were not evaluable (did not express target or died prior to Day 28)
Cohort BErbB1+/ErbB2-
12 patients
8.3%
17%SD
58%PD
17%pending
Preliminary Results: Treatment Response
62%PR
21%SD
17%PD
62% clinical responders
ErbB2 (IHC 3+/FISH+)p-ErbB2 positive
100%
PTEN deficient
69%
The proposed phase II and III dose for this combination is 1000 mg/day lapatinib and standard weekly trastuzumab
The most frequent AEs with this combination were diarrhea, fatigue, nausea, and anorexia
The combination of lapatinib and trastuzumab was very active (6/27 CR+PR and 2/27 PR in the PK groups = 8% total) in this heavily pretreated population, all of whom had progressed on prior trastuzumab
Additional randomized studies are planned with lapatinib and trastuzumab
Storniolo et al., ASCO 2005 and SABCS
EGF10023:
Phase I, open-label study of the Safety, Tolerability and Pharmacokinetics of
Lapatinib in combination with Trastuzumab
STUDI IN CORSO : ADIUVANTE, METASTATICO
E NEOADIUVANTE
• The prevalence of certain ErbB heterodimers may cause an
alternative driving force for the growth of cancer cells
bypassing the blackade by specific inhibitors.
• For instance the heterodimer HER2-HER3 is an “odd couple”
with a powerful kinase activity.
Heterodimers formation
PEGFR/ERbB2
HER3/erbB3EGFR HER2/HER3
Tortora et al., 2007
mTOR Pathway islinked to EGFR
and VEGF
Akt/PKB
PI3-K
PTENOxygen, energy, and nutrients
TSC2 TSC1
Growth factorsIGF-1, VEGF, ErbB, etc
Protein production
4E-BP1
S6
S6K1
elF-4E
mTORRas/Raf pathway kinases
Ras/Raf,
Abl, ER
Cell growth AngiogenesisCell division
XX XX XX
HIF-1
VEGF
-CCI-779 (temsirolimus)- RAD-001 (everolimus)- AP23573
109 patients randomized to receive 75 mg or 250 mg i.v weekly.
Toxicity profile favored 75mg dose: Anaemia, hyperglycemia, hypophostatemia & hypertrigliceridemia as grade 3/4 events
Overall response: 9% (10 PRs), 26% MR
mTTP: 3 m, mOS: 15m
Phase III development ongoing in combination with letrozole
Chan, S. et al. J Clin Oncol; 23:5314-5322 2005
Randomized Phase II Trial with Temsirolimus/CCI-779 Randomized Phase II Trial with Temsirolimus/CCI-779 in advanced breast cancerin advanced breast cancer
Progression of pro-Angiogenic activity in Breast cancer
VEGF VEGFbFGF
VEGFbFGFTGF
VEGFbFGFTGFPLGF
VEGFbFGFTGFPLGF
PD-ECGF
VEGFbFGFTGFPLGF
PD-ECGFEtc….
Modified by Tortora, 2003 from Relf et al., Cancer Res. 1997
PKAIPI3K
PLC
GRB2 SOS p21ras Raf
MAPK
Cyclin D1
CDK
RbCell ProliferationCell Proliferation
E2Fmdm2
p53
PKC
Cross-talk tra diverse vie di segnale : base Per l’ acquisizione di resistenza a terapie selettive
AKT
Bcl-2
mTOR
Angiogenesis
Invasionmetastasis
VEGFMEK
P
PP P
c-KITR
PDGFR,HER/erbB
Apoptosis
PTEN
IGF-R1
Endothelial cells
VEGFR1 VEGFR2
Tortora et al., 2006
Novel Paradigm :“Multi-targeted therapy”
• Multiple targeted cells– Cancer cells– Endothelial cells– Pericytes– Fibroblasts
• Multiple molecular targets– HER– VEGF/VEGFR– PDGF/PDGFR– KIT/MET/RET– Others kinases
Angiogenesis
Receptor tyrosine kinases
Faivre et al. Sem Oncol, 2006
Serine/threonine kinases
I recettori del VEGFI recettori del VEGF
VEGFR-1/Flt-1 VEGFR-2/KDR
VEGFR-3/Flt-4
LYMPHANGIOGENESIS
ANGIOGENESIS
ZD6474/Vandetanib (VEGFR2 + EGFR + RET)
AE778 (VEGF-R2 + EGFR)
Sunitinib (VEGFRs + PDGFRs+ c-Kit)
Sorafenib (VEGFRs + PDGFRs + raf1 + MAPK + Erk + c-Kit)
PTK787/Vatalanib (VEGFRs + PDGF-Rs)
GW786024 (Pazopanib) (VEGFRs + PDGF-Rs+ c-Kit)
AG013736 (VEGFRs + PDGF-Rs
Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs, Kit etc.
EGFR
VEGF
Endothelial cells
Cancer cells
TGF
KDR
Angiogenesis
Cell Proliferation
ZD6474ZD6474
Tortora & Ciardiello 2003Carlomagno et al, Cancer Res. 2002Ciardiello et al., Clin Cancer Res. 2003Ciardiello et al., Clin Cancer Res. 2005Damiano et al., Clin Cancer Res 2005
ZD6474 inhibits KDR and EGFR
RET
A Multicenter Phase II Trial of ZD6474, a VEGFR-2 and EGFR TKI, in Patients with Previously Treated Metastatic Breast Cancer
Kathy D.Miller, JoseManuelTrigo, Catherine Wheeler, Alan Barge, Jacqui Rowbottom, George Sledge, and Jose Baselga
Miller KD, Clin Cancer Res 2005;11(9)May 1, 2005
100mg/d n=22
300mg/d n=24
There were no responses (only 1patient, in 300 mg/d group, had a SD for >24 weeks)
The median time to progression was similar in both groups: 45 days in the 300mg group; 44 days in the 100mg/d group.
The endothelial cell-pericyte network of signals
Nature Review Cancer
• Pericytes protects endothelial cells from apoptosis and overexpress PDGF-R• PDGF-R is overexpressed in many tumors• PDGF-R and VEGF cooperate
SU11248 is an Oral, Multi-targeted, RTK Inhibitor With Selective Activity against PDGFR, VEGFR, KIT, and FLT3
Split Kinase Domain RTKs
FLT1FLK1/KDRFLT4
FGFR1FGFR2FGFR3FGFR4
PDGFR
CSF1RKITFLT3/FLK2
PDGFR
Potent Activity vs. Class III, Class V RTKs:Biochemical Ki values <10nMCellular IC50 values 5-50nM
Weak Activity vs. Class IV RTKs:Biochemical Ki values 1000 nMCellular IC50 values 6000 nM
Highly selective for Class III, Class V RTKs, versus other tyrosine kinases and serine/threonine kinases evaluated
Class III Class V Class IV
• Direct anti-tumor activity via inhibition of target RTKs
- VEGFR in Melanoma, PDGFR in Glioma, KIT in GIST, FLT3 in AML
• Indirect inhibition of tumor growth via inhibition of angiogenesis
- VEGFR and PDGFR
SU11248 increased activity in combination with Docetaxel in a breast cancer model
Complete regression in 33% of mice, with no regrowth 3 months after dosing stopped on day 72
SU11248
Ave
rag
e T
um
or
Vo
lum
e, m
m3
Days After Dosing BeganDocetaxel
0
500
1,000
1,500
0 10 20 30 40 50 60 70
Abrams et al. Mol Cancer Ther. 2003;2:1011-1021, with permission.
Vehicle controlSU11248 40 mg/kg per day PO
Docetaxel 15 mg/kg IV once per week x 3SU11248 40 mg/kg per day + docetaxel 15 mg/kg once per week x 3
Phase II study of Sunitinib in MBC
Miller et al., ASCO 2005 e SABC
6 weeks cycle (50 mg/day for 28 d. and 2 weeks rest).
64 pts enrolled (84% HER-2 negative/unknown; 56% ER pos).
82% with (multiple) visceral sites. Heavily pretreated (several previous CT regimens in adjuvant setting and in metastatic setting).
Asthenia and diarrhea major grade 2 toxicities. 40% grade 3 neutropenia.
51 evaluable for responses. PR: 7 (14%); SD > 6 mo: 1 (2%).
No clear correlation between response and ER or HER-2 status.
KD Miller, HJ Burstein, AD Elias, HS Rugo, MA Cobleigh, AC Wolff, PD Eisenberg, MD Pegram, M Collier, BJ Adams, CM Baum
Ongoing studies with Sunitinib
Phase III randomized study of Sunitinib + capecitabine vs capecitabine in pretreated advanced breast cancer patients
430 pts. Primary endpoint: PFS
Phase 2 randomized, double blind study of Sunitinib in combination with Trastuzumab in 1st line for MBC. Primary endpoint: Response Rate
2 Phase I studies of Sunitinib in combination with Paclitaxel (or with Docetaxel) in 1st line for MBC.
20 pts. each Primary endpoint: Safety
Phase III randomized study of Sunitinib vs capecitabine in advanced breast cancer patients who failed both taxane and anthracycline (or failed a taxane and anthracycline therapy is not indicated).
700 pts. Primary endpoint: PFS
Ongoing studies with Sunitinib
Phase 1-2 study of Sunitinib in combination with Exemestane in 1st line for MBC.
70 pts. Primary endpoint: PFS, Safety
Phase 2 randomized study of Sunitinib vs Standard of care in previously treated Triple receptor negative (ER, PR, HER2) BC.
200 pts. Primary endpoint: PFS
BAY 43-9006 (Sorafenib)
• Bisaryl urea, multiple targeted inhibitor.
• Inhibits B-Raf-1 kinase (including the mutated form) with IC50 of 6 nM, MAPK, ERK.
• Inhibits also endothelial cells and VEGFR2, VEGFR-3, FLT-3, PDGFR, c-Kit.
• Raf is probably important in endothelial cells and double targeting (Raf and VEGFR-2) may be critical.
Cl
F3C NH NH
OO
N
NHCH3
O
SorafenibPhase II trial in metastatic breast cancer patients failing
anthracycline and/or taxane
Limited single-agent activity. Only 1/23 patients responding to therapy. Moreno-Aspitia A et al., JCO 24:18S, 2006 (abstract #577)
A phase I trial combining sorafenib with bevacizumab
Dose escalation trial in 34 patients with multiple tumor types. Both toxicity and efficacy are increased compared with single-agent therapy. Azad N et al., ASCO 2006, abstract # 3004
• Complete inhibitor of the VEGF receptor tyrosine kinases VEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R.
• Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo)
PTK787/ZK 222584 PTK787/ZK 222584 (Vatalanib)(Vatalanib)PTK787/ZK 222584 PTK787/ZK 222584 (Vatalanib)(Vatalanib)
A phase I/II study of vatalanib in combination with trastuzumab in HER-2-overexpressing MBC
Analysis of the phase I study showed good tolerability and activity.
The Phase II is ongoing and has currently enrolled over 60 patients. (Rugo et l., 2006).
International Phase I/IItrial with AG-013736 plus docetaxel vs.
docetaxel plus placebo in first-line MBC.
Anti-VEGFRs, c-Kit and PDGFRs GW786034 (Pazopanib)
Horizontal and Vertical blockadeHorizontal and Vertical blockade
Combinations of targeted agents to block signaling with:
• an horizontal blockade : EGFR, VEGF and PDGFR.
• a vertical blockade : at two levels of the same pathways: HIF + VEGF or VEGF+VEGFR
GW786034 (Pazopanib) in combination with Lapatinib in breast cancer xenografts
relapsed or refractory inflammatory breast cancer
overexpressing ErbB2(n=320)
Lapatinib 1500 mg/day +placebo
Primary endpoint: PFS
Secondary endpoint: overall Response Rate, time-to-response, response duration, quality of life, overall survival (OS), safety and tolerability, biomarkers, pharmacokinetics and pharmacogenomics
Patients in the bevacizumab plus CP arm may receive single-agent bevacizumab until disease progression
PD*
PDLapatinib 1500 mg/day +Pazopanib 800 mg/day
Phase III Randomized double blind study with Pazopanib in combination with Lapatinib in MBC
CONCLUSIONI
I farmaci multitargeted sono agli esordi nella terapia dei tumori della mammella.
Molti studi sono in corso e prevedono analisi genomiche e farmacodinamiche che ptrebbero aiutare a interpretare I risultati e a selezionare I pazienti.