1. I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA
Giampaolo Tortora
Cattedra di Oncologia Medica e
Laboratori di Terapia Molecolare
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica
Università di Napoli “Federico II”

2. Farmaci con bersagli multipli
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.

3. SIGNALLING PATHWAYS IN CANCER CELLS
PDGFR,
c-KITR
HER/erbB P P
GRB2
SOS
p21
ras
Raf P
PKAI P
PI3K
PLCg
VEGF
MEK
MAPK
PKC
PTEN
AKT
Angiogenesis
Bcl-2
Cyclin D1
mdm2
E2F
Invasion
metastasis
mTOR
CDK
p53
Cell Proliferation Rb
Apoptosis

4. I recettori della famiglia ErbB/HER funzionano in coppia, formando omo- o eterodimeri
EGFR
EGFR/ErbB2
EGFR/ErbB3
Tortora et al., 2007

5. Co-expression of EGFR and ErbB-2
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: , 2005).

6. 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

7. Doppi inibitori di EGFR e HER-2 Pertuzumab e Lapatinib

8. Ligand-binding domain
Omnitarg Riconosce Epitopi diversi da Trastuzumab su HER2 e impedisce la etero-dimerizzazione EGFR-HER2
HER2
Ligand-binding domain
(inactive)
Omnitarg
Trastuzumab
Cell membrane
Tyrosine kinase domain

9. Lapatinib inhibits EGFR and HER-2
Erlotinib Gefitinib GW Lapatinib
Small head group quinazolines Large head group quinazoline

10. Investigator Review N=40
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 Review N=40
Independent Review N=40 CR PR
12 (30%)
14 (35%)
Unconfirmed PR*
3 (7.5%)
2 (5%) SD
13 (32.5%) 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

11. Randomized Phase III Study EGF100151
Progressive, HER2+ MBC or LABC
Previously treated with anthracycline, taxane and trastuzumab*
No prior capecitabine R A N D O M I Z E
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
Stratification:
Disease sites
Stage of disease
Patients on treatment until progression or unacceptable toxicity, then followed for survival
N=528
*Trastuzumab must have been administered for metastatic disease

12. Lapatinib + Capecitabine (n=160)
Prior Therapy
Lapatinib + Capecitabine (n=160)
Capecitabine (n=161)
Anthracyclines
156 (98%)
156 (97%)
Taxanes
157 (98%)
159 (99%)
Trastuzumab
Metastatic
149 (93%)
146 (91%)
Adjuvant
7 (4%)
10 (6%)

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

14. Progression-Free Survival - ITT Population
Lapatinib + capecitabine
100
Cumulative Progression-Free Survival, %
Capecitabine 90
No. of pts
160
161
Progressed or died
45 (28%)
73 (45%) 80
Median PFS, wk
36.9
17.9 70
Hazard ratio (95% CI)
0.48 (0.33, 0.70)
P-value (log-rank, 1-sided) 60 50 40 30 20 10 10 20 30 40 50 60 70
Time (weeks)

15. Overall Survival - ITT Population
100
Cumulative Survival % 90 80 70 60 50
Lapatinib + Capecitabine
Capecitabine 40
No. of pts
160
161 30
Deaths
29 (18%)
29 (18%)
Median OS NR NR 20
Hazard ratio (95% CI)
0.93 (0.55, 1.59) 10
P value (log-rank, 2-sided)
0.800 10 20 30 40 50 60 70 80 90
Time (weeks)

16. Brain Metastases as Site of Progression
Lapatinib + Capecitabine (n=160)
Capecitabine (n=161)
Patients with CNS metastases at baseline 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

17. Mean LVEF at Scheduled Assessments80
Lapatinib + Capecitabine
Capecitabine 75 70 65
Mean LVEF (%) 60 55
n=160 n=160
n= n=92
n=84
n=67
n=63
n=37
n=37
n=26
n=15
n=9
n=7
n=1 50
Screening
Week 6
Week 12
Week 18
Week 24
Week 36
Week 48
Assessment

18. EGF103009
A 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 A
ErbB2+
Cohort B
ErbB1+/ErbB2-

19. Preliminary Results: Treatment Response
100%
17% PD
8.3%
17% SD
58% PD
pending
PTEN
deficient
21% SD
100%
50%
62% clinical
responders
69%
62% PR
100% of responders in Cohort A are ErbB2 3+ and FISH +
Change to 100% of responders are p-ErbB2 positive 0%
Cohort A
ErbB2+
24 patients
Cohort B
ErbB1+/ErbB2-
12 patients
ErbB2 (IHC 3+/FISH+)
p-ErbB2 positive
5 enrolled patients were not evaluable (did not express target or died prior to Day 28)

20. EGF10023: Phase I, open-label study of the Safety, Tolerability and Pharmacokinetics of Lapatinib in combination with Trastuzumab
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

21. STUDI IN CORSO : ADIUVANTE, METASTATICO E NEOADIUVANTE

22. Heterodimers formation
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. P
EGFR/ERbB2
HER3/erbB3
EGFR
HER2/HER3
Tortora et al., 2007

23. IGF-1R and resistance MCF-7 + HER2 IGF-1 and activation of IGF-1R
Lu, JNCI, 24: , 2001
a-IR3
(Ab anti-IGF-1R)
Control
IGFBP-3
MCF-7 + HER2
There are data showing that the insulin-like growth factor-1 (IGF-1) receptor pathway can also negate the effect of trastuzumab. I say this because there are a number of small molecules of antibodies in the industry that are being developed, and the plan is to eventually combine them with trastuzumab to abrogate this putative resistance.
This is an experiment published recently in which Pollak had transfected HER2 into MCF-7 cells that have low levels of HER2. These cells are not that sensitive to trastuzumab, as shown here, but because they have high levels of the IGF-1 receptor, they make a lot of IGF-1 and IGF-2. So they are not very sensitive to trastuzumab, but they are sensitive to IGF-1 receptor inhibitors. This shows an IGF-1 receptor antibody and an insulin-like growth factor binding protein (IGFBP)-3 that binds IGF-1. If one uses them in combination there is very nice synergistic activity, implying that these 2 receptors are operative in this cell, and its combined inhibition leads to synergist contact tumor activity. We're testing this in mice right now.
IGF-1 and activation of IGF-1R
are also involved in resistance to EGFR inhibitors

24. mTOR Pathway is linked to EGFR and VEGF
Growth factors
IGF-1, VEGF, ErbB, etc
PI3-K
Ras/Raf,
Abl, ER
PTEN
Oxygen, energy, and nutrients
Akt/PKB
VEGF
TSC2
TSC1
HIF-1
CCI-779 (temsirolimus)
RAD-001 (everolimus)
AP23573
Ras/Raf pathway kinases
mTOR
In cancer cells one or more of the proteins which positively (→) or negatively (—|) regulate mTOR may be deregulated, and this loss of regulation contributes to, and in some cases drives, the malignancy. These include overproduction of hormones, cytokines, and growth factors and aberrant expression of growth factor receptors and signaling molecules, such as PI3-K, PTEN, Akt, and TSC1/2 (and LKB1, which is not shown). Aberrant signaling in parallel signaling pathways also affects signaling through mTOR because these pathways are connected to the mTOR pathway. These connections are referred to as “cross-talk” and involve the Ras/Raf/MAPK pathway and Abl signaling1-5. Thus aberrant signaling in cancer cells upstream of mTOR converges on mTOR and is translated into the signals that regulate cell growth, cell division, production of angiogenic growth factors and contribute to other cellular processes.
RAD001 inhibits only mTOR activity but, because mTOR is downstream of the signaling defects that characterize many cancer cells, RAD001 counters the effects of these defects on cell growth, proliferation, and angioigenesis. Unlike other agents that directly affect signaling through the upstream kinases such as the several growth factor receptor kinase inhibitors (e.g., PTK/ZK, gefitinib, erlotinib, sorafenib, sunitinib), RAD001 acts downstream of these kinases and may be used in combination to enhance inhibition of signaling through the PI3-k/Akt pathways.
References
Bjornsti and Houghton. Nat Rev Cancer. 2004;
Crespo and Hall. Microbiol Mol Biol Rev. 2002;66:
Huang et al. Cancer Biol Ther. 2003;2:
Mita et al. Clin Breast Cancer 2003;4:
Wullschleger et al. Cell 2006;124:
S6K1
4E-BP1
elF-4E S6
Protein production X
Cell growth
Angiogenesis
Cell division

25. Randomized Phase II Trial with Temsirolimus/CCI-779
in advanced breast cancer
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:

26. Progression of pro-Angiogenic activity in Breast cancer
VEGF
VEGF
bFGF
VEGF
bFGF
TGFb
PLGF
PD-ECGF
Etc….
VEGF
bFGF
TGFb
VEGF
bFGF
TGFb
PLGF
VEGF
bFGF
TGFb
PLGF
PD-ECGF
Modified by Tortora, from Relf et al., Cancer Res. 1997

27. Cross-talk tra diverse vie di segnale : base
Per l’ acquisizione di resistenza a terapie selettive
Tortora et al., 2006
IGF-R1
PDGFR,
HER/erbB
c-KITR P P
GRB2
SOS
p21
ras
Raf P
PKAI P
PI3K
VEGF
PLCg
MEK
MAPK
PKC
PTEN
AKT
VEGFR1
VEGFR2
Endothelial cells
Bcl-2
Cyclin D1
mdm2
E2F
mTOR
CDK
Angiogenesis
p53
Cell Proliferation Rb
Apoptosis
Invasion
metastasis

28. 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
Serine/threonine kinases
Faivre et al. Sem Oncol, 2006

29. I recettori del VEGF ANGIOGENESIS LYMPHANGIOGENESIS VEGFR-3/Flt-4
VEGFR-2/KDR
LYMPHANGIOGENESIS
ANGIOGENESIS

30. Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs, Kit etc.
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)
GW (Pazopanib) (VEGFRs + PDGF-Rs+ c-Kit)
AG (VEGFRs + PDGF-Rs

31. ZD6474 inhibits KDR and EGFR
TGF
EGFR
ZD6474
KDR
RET
Endothelial cells
Cancer cells
VEGF
Angiogenesis
Tortora & Ciardiello 2003
Carlomagno et al, Cancer Res. 2002
Ciardiello et al., Clin Cancer Res. 2003
Ciardiello et al., Clin Cancer Res. 2005
Damiano et al., Clin Cancer Res 2005
Cell Proliferation

32. 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
100mg/d n=22
300mg/d n=24
The median time to progression was similar in both groups: 45 days in the 300mg group; 44 days in the 100mg/d group.
There were no responses (only 1patient, in 300 mg/d group, had a SD for >24 weeks)
Miller KD, Clin Cancer Res 2005;11(9)May 1, 2005

33. The endothelial cell-pericyte network of signals
Pericytes protects endothelial cells from apoptosis
and overexpress PDGF-R
PDGF-R is overexpressed in many tumors
PDGF-R and VEGF cooperate
Nature Review Cancer

35. Days After Dosing Began
SU11248 increased activity in combination with Docetaxel in a breast cancer model
Vehicle control
1,500
SU mg/kg per day PO
Docetaxel 15 mg/kg IV once per week x 3
SU mg/kg per day + docetaxel 15 mg/kg
once per week x 3
1,000
Average Tumor Volume, mm3
500
Complete regression in 33% of mice, with no regrowth 3 months after dosing stopped on day 72
SU11248 enhanced the antitumor activity of docetaxel (15 mg/kg) in a breast cancer model.
Athymic mice were implanted subcutaneously with MX-1 estrogen-independent human breast cancer tumor xenografts.
The tumors were allowed to grow until they reached a volume of 100 mm3. At this point, the mice were dosed orally with
SU11248 at 40 mg/kg per day
Docetaxel 15 mg/kg IV once weekly for 3 weeks
Both SU11248 and docetaxel at the same concentrations and on the same daily or weekly schedule
There were 10 mice per treatment group.
The above data represent the average tumor volume ± SEM.
By day 58:
SU docetaxel inhibited tumor growth by 82% compared with docetaxel alone (P = 0.008)
Three months after stopping SU11248 on day 72, one third of the mice treated with SU docetaxel were tumor-free. 10 20 30 40 50 60 70
Docetaxel
Days After Dosing Began
SU11248
Abrams et al. Mol Cancer Ther. 2003;2: , with permission.

36. Phase II study of Sunitinib in MBC
KD Miller, HJ Burstein, AD Elias, HS Rugo, MA Cobleigh, AC Wolff, PD Eisenberg, MD Pegram, M Collier, BJ Adams, CM Baum
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.
Miller et al., ASCO 2005 e SABC

37. 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 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
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

38. 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

39. BAY 43-9006 (Sorafenib) Bisaryl urea, multiple targeted inhibitor.Cl F 3 C N H O
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.
BAY has clear activity in several tumor types and is going on to phase II studies.

40. A phase I trial combining sorafenib with bevacizumab
Phase 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
BAY has clear activity in several tumor types and is going on to phase II studies.

41. PTK787/ZK (Vatalanib)
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)
A phase I/II study of vatalanib in combination with trastuzumab in HER-2-overexpressing MBC
The purpose of this slide is to introduce PTK/ZK as a multi-VEGF receptor inhibitor
PTK/ZK is multi-VEGF receptor inhibitor that completely inhibits the activation of VEGF receptors: VEGFR-1, VEGFR-2, and VEGFR-31,2
PTK/ZK also inhibits the PDGF receptor which plays a role in blood vessel stabilization
PTK/ZK is being codeveloped by Novartis Pharmaceuticals Corporation AG and Schering AG Berlin, Germany
1. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK , a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60:
2. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem. 2000;43(12):

42. International Phase I/II trial with AG-013736 plus docetaxel vs.
docetaxel plus placebo in first-line 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).
The purpose of this slide is to introduce PTK/ZK as a multi-VEGF receptor inhibitor
PTK/ZK is multi-VEGF receptor inhibitor that completely inhibits the activation of VEGF receptors: VEGFR-1, VEGFR-2, and VEGFR-31,2
PTK/ZK also inhibits the PDGF receptor which plays a role in blood vessel stabilization
PTK/ZK is being codeveloped by Novartis Pharmaceuticals Corporation AG and Schering AG Berlin, Germany
1. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK , a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60:
2. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem. 2000;43(12):

43. Anti-VEGFRs, c-Kit and PDGFRs
GW (Pazopanib)

44. Horizontal 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

45. GW786034 (Pazopanib) in combination with Lapatinib
in breast cancer xenografts

46. Phase III Randomized double blind study with
Pazopanib in combination with Lapatinib in MBC
Lapatinib 1500 mg/day +
placebo
PD*
relapsed or refractory inflammatory breast cancer overexpressing ErbB2
(n=320)
Lapatinib 1500 mg/day +
Pazopanib 800 mg/day PD
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
E4599 was a randomised, phase III trial of CP with or without Avastin in previously untreated patients with advanced (stage IIIb/IV) NSCLC.1 In this trial, 878 patients were randomised to one of two arms: CP alone or CP plus Avastin 15mg/kg every 3 weeks. Patients receive paclitaxel 200mg/m2 i.v. every 3 weeks with carboplatin i.v. to AUC 6mg/mL every 3 weeks for a total of six cycles.
In contrast to the phase II study, patients were not allowed to cross over in this phase III study. Patients in the CP plus Avastin arm could continue to receive single-agent Avastin after disease progression.
The primary endpoint was survival and the secondary endpoints included overall response rate.
Based on bleeding events seen in phase II trials, patients with squamous cell histology, in addition to central nervous system (CNS) metastases and active cardiovascular disease, were excluded from this trial.
Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # ) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) trial – E4599. J Clin Oncol 2005;23(June 1 Suppl.):2s (Abstract LBA4).

47. 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.