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I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia.

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Presentation on theme: "I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Cattedra di Oncologia Medica e Laboratori di Terapia Molecolare Dipartimento di Endocrinologia e Oncologia."— Presentation transcript:

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

2 Farmaci che bloccano più recettori della stessa famiglia, per aumentare lefficienza 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

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

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

5 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). Co-expression of EGFR and ErbB-2

6 Phase I study of Erlotinib plus Trastuzumab and Taxol Escalating doses of Erlotinib (25 to 150 mg); Taxol 80 or 90 mg/m 2 ; 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/m 2, 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 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

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

10 EGF20009: A Phase II, Randomized trial using Lapatinib as a first-line treatment in patients with FISH Positive Advanced or Metastatic Breast Cancer ResponseInvestigator Review N=40 Independent Review N=40 CR00 PR12 (30%)14 (35%) Unconfirmed PR*3 (7.5%)2 (5%) SD13 (32.5%)14 (35%) PD10 (25%)5 (12.5%) Unknown2 (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 EGF Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m 2 /d po days 1-14 q 3 wk Capecitabine 2500 mg/m 2 /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 RANDOMIZERANDOMIZE *Trastuzumab must have been administered for metastatic disease N=528

12 Prior Therapy Lapatinib + Capecitabine (n=160) Capecitabine (n=161) Anthracyclines156 (98%)156 (97%) Taxanes157 (98%)159 (99%) Trastuzumab156 (97%) Metastatic149 (93%)146 (91%) Adjuvant 7 (4%) 10 (6%)

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

14 Time (weeks) Cumulative Progression-Free Survival, % Progression-Free Survival - ITT Population P-value (log-rank, 1-sided) 73 (45%)45 (28%)Progressed or died 0.48 (0.33, 0.70)Hazard ratio (95% CI) Median PFS, wk No. of pts Capecitabine Lapatinib + capecitabine

15 Overall Survival - ITT Population P value (log-rank, 2-sided) 29 (18%) Deaths 0.93 (0.55, 1.59)Hazard ratio (95% CI) NR Median OS No. of pts Time (weeks) Cumulative Survival % Capecitabine Lapatinib + Capecitabine 6080

16 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*411 Patients with CNS as only site of relapse 310 *P-value (Fishers exact, 2-sided) = 0.110

17 Mean LVEF at Scheduled Assessments Week 12Week 18 Week 24 Week 36Week 48Week 6Screening Assessment Lapatinib + Capecitabine Capecitabine Mean LVEF (%) n=160 n=108 n=92 n=84 n=67 n=63 n=37 n=26 n=15 n=9 n=7 n=1

18 EGF 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 0% 50% 100% Cohort A ErbB2+ 24 patients 5 enrolled patients were not evaluable (did not express target or died prior to Day 28) Cohort B ErbB1+/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%

20 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


22 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 P EGFR/ERbB 2 HER3/erbB3 EGFR HER2/HER3 Tortora et al., 2007

23 IGF-1R and resistance Lu, JNCI, 24: , 2001 a-IR3 (Ab anti-IGF-1R) Control IGFBP-3 MCF-7 + HER2 IGF-1 and activation of IGF-1R are also involved in resistance to EGFR inhibitors

24 mTOR Pathway is linked to EGFR and VEGF Akt/PKB PI3-K PTEN Oxygen, energy, and nutrients TSC2TSC1 Growth factors IGF-1, VEGF, ErbB, etc Protein production 4E-BP1 S6 S6K1 elF-4E mTOR Ras/Raf pathway kinases Ras/Raf, Abl, ER Cell growth Angiogenesis Cell division X XX HIF- 1 VEGF -CCI-779 (temsirolimus) - RAD-001 (everolimus) - AP23573

25 109 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: Randomized Phase II Trial with Temsirolimus/CCI-779 in advanced breast cancer

26 Progression of pro-Angiogenic activity in Breast cancer VEGF bFGF VEGF bFGF TGF VEGF bFGF TGF PLGF VEGF bFGF TGF PLGF PD-ECGF VEGF bFGF TGF PLGF PD-ECGF Etc…. Modified by Tortora, 2003 from Relf et al., Cancer Res. 1997

27 PKAI PI3K PLC GRB2 SOS p21 ras Raf MAPK Cyclin D1 CDK Rb Cell Proliferation E2F mdm2 p53 PKC Cross-talk tra diverse vie di segnale : base Per l acquisizione di resistenza a terapie selettive AKT Bcl-2 mTOR Angiogenesis Invasion metastasis VEGF MEK P P PP c-KITR PDGFR, HER/erbB Apoptosis PTEN IGF-R1 Endothelial cells VEGFR1VEGFR2 Tortora et al., 2006

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


30 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 Multitargeted agents affecting VEGF-Rs and EGFR, PDGF-Rs, Kit etc.

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

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 Miller KD, Clin Cancer Res 2005;11(9)May 1, mg/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.

33 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


35 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 Average Tumor Volume, mm 3 Days After Dosing Began Docetaxel ,000 1, Abrams et al. Mol Cancer Ther. 2003;2: , with permission. Vehicle control 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

36 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

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 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

38 Ongoing studies with Sunitinib Phase 1-2 study of Sunitinib in combination with Exemestane in 1 st 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 (Sorafenib) Bisaryl urea, multiple targeted inhibitor. Inhibits B-Raf-1 kinase (including the mutated form) with IC 50 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 F 3 CNHNH O O N NH CH 3 O

40 Sorafenib 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

41 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 (Vatalanib) A phase I/II study of vatalanib in combination with trastuzumab in HER-2-overexpressing MBC

42 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/II trial with AG plus docetaxel vs. docetaxel plus placebo in first-line MBC.

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 GW (Pazopanib) in combination with Lapatinib in breast cancer xenografts

46 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* PD Lapatinib 1500 mg/day + Pazopanib 800 mg/day Phase III Randomized double blind study with Pazopanib in combination with Lapatinib in MBC

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.

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