Presentation on theme: "I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA"— Presentation transcript:
1I FARMACI MULTITARGETED NEL CANCRO DELLA MAMMELLA Giampaolo TortoraCattedra di Oncologia Medica eLaboratori di Terapia MolecolareDipartimento di Endocrinologia e Oncologia Molecolare e ClinicaUniversità di Napoli “Federico II”
2Farmaci 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.
3SIGNALLING PATHWAYS IN CANCER CELLS PDGFR,c-KITRHER/erbBPPGRB2SOSp21rasRafPPKAIPPI3KPLCgVEGFMEKMAPKPKCPTENAKTAngiogenesisBcl-2CyclinD1mdm2E2FInvasionmetastasismTORCDKp53Cell ProliferationRbApoptosis
4I recettori della famiglia ErbB/HER funzionano in coppia, formando omo- o eterodimeri EGFREGFR/ErbB2EGFR/ErbB3Tortora et al., 2007
5Co-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).
6Phase 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
7Doppi inibitori di EGFR e HER-2 Pertuzumab e Lapatinib
8Ligand-binding domain Omnitarg Riconosce Epitopi diversi da Trastuzumab su HER2 e impedisce la etero-dimerizzazione EGFR-HER2HER2Ligand-binding domain(inactive)OmnitargTrastuzumabCell membraneTyrosine kinase domain
9Lapatinib inhibits EGFR and HER-2 Erlotinib Gefitinib GW LapatinibSmall head group quinazolines Large head group quinazoline
10Investigator 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 CancerResponseInvestigator Review N=40Independent Review N=40CRPR12 (30%)14 (35%)Unconfirmed PR*3 (7.5%)2 (5%)SD13 (32.5%)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
11Randomized Phase III Study EGF100151 Progressive, HER2+ MBC or LABCPreviously treated with anthracycline, taxane and trastuzumab*No prior capecitabineRANDOMIZELapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wkCapecitabine 2500 mg/m2/d po days 1-14 q 3 wkStratification:Disease sitesStage of diseasePatients on treatment until progression or unacceptable toxicity, then followed for survivalN=528*Trastuzumab must have been administered for metastatic disease
13Time to Progession – ITT Population % of patients free from progression*CapecitabineLapatinib + CapecitabineP-value (log-rank, 1-sided)69 (43%)45 (28%)Progressed or died*19.736.9Median TTP, wk161160No. of pts0.51 (0.35, 0.74)Hazard ratio (95% CI)100102030405060Time (weeks)10203040506070809070* Censors 4 patients who died due to causes other than breast cancer
14Progression-Free Survival - ITT Population Lapatinib + capecitabine100Cumulative Progression-Free Survival, %Capecitabine90No. of pts160161Progressed or died45 (28%)73 (45%)80Median PFS, wk36.917.970Hazard ratio (95% CI)0.48 (0.33, 0.70)P-value (log-rank, 1-sided)60504030201010203040506070Time (weeks)
15Overall Survival - ITT Population 100Cumulative Survival %9080706050Lapatinib + CapecitabineCapecitabine40No. of pts16016130Deaths29 (18%)29 (18%)Median OSNRNR20Hazard ratio (95% CI)0.93 (0.55, 1.59)10P value (log-rank, 2-sided)0.800102030405060708090Time (weeks)
16Brain Metastases as Site of Progression Lapatinib + Capecitabine (n=160)Capecitabine (n=161)Patients with CNS metastases at baseline2Patients with CNS relapse*411Patients with CNS as only site of relapse310*P-value (Fisher’s exact, 2-sided) = 0.110
18EGF103009A Phase II Trial of Lapatinib (Tykerb) Monotherapy in Patients With Relapsed/Refractory Inflammatory Breast Cancer (IBC): Clinical Activity and Biologic Predictors of ResponseSpector N, K Blackwell, J Hurley, J Harris, D Lombardi, S Bacus, SB Ahmed, H Boussen, M Frikha, FB AyedCohort AErbB2+Cohort BErbB1+/ErbB2-
19Preliminary Results: Treatment Response 100%17%PD8.3%17%SD58%PDpendingPTENdeficient21%SD100%50%62% clinicalresponders69%62%PR100% of responders in Cohort A are ErbB2 3+ and FISH +Change to 100% of responders are p-ErbB2 positive0%Cohort AErbB2+24 patientsCohort BErbB1+/ErbB2-12 patientsErbB2 (IHC 3+/FISH+)p-ErbB2 positive5 enrolled patients were not evaluable (did not express target or died prior to Day 28)
20EGF10023: Phase I, open-label study of the Safety, Tolerability and Pharmacokinetics of Lapatinib in combination with TrastuzumabThe proposed phase II and III dose for this combination is 1000 mg/day lapatinib and standard weekly trastuzumabThe most frequent AEs with this combination were diarrhea, fatigue, nausea, and anorexiaThe 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 trastuzumabAdditional randomized studies are planned with lapatinib and trastuzumabStorniolo et al., ASCO 2005 and SABCS
21STUDI IN CORSO : ADIUVANTE, METASTATICO E NEOADIUVANTE
22Heterodimers 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.PEGFR/ERbB2HER3/erbB3EGFRHER2/HER3Tortora et al., 2007
23IGF-1R and resistance MCF-7 + HER2 IGF-1 and activation of IGF-1R Lu, JNCI, 24: , 2001a-IR3(Ab anti-IGF-1R)ControlIGFBP-3MCF-7 + HER2There 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-1Rare also involved in resistance to EGFR inhibitors
24mTOR Pathway is linked to EGFR and VEGF Growth factorsIGF-1, VEGF, ErbB, etcPI3-KRas/Raf,Abl, ERPTENOxygen, energy, and nutrientsAkt/PKBVEGFTSC2TSC1HIF-1CCI-779 (temsirolimus)RAD-001 (everolimus)AP23573Ras/Raf pathway kinasesmTORIn 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.ReferencesBjornsti 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:S6K14E-BP1elF-4ES6Protein productionXCell growthAngiogenesisCell division
25Randomized Phase II Trial with Temsirolimus/CCI-779 in advanced breast cancer109 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 eventsOverall response: 9% (10 PRs), 26% MRmTTP: 3 m, mOS: 15mPhase III development ongoing in combination with letrozoleChan, S. et al. J Clin Oncol; 23:
26Progression of pro-Angiogenic activity in Breast cancer VEGFVEGFbFGFVEGFbFGFTGFbPLGFPD-ECGFEtc….VEGFbFGFTGFbVEGFbFGFTGFbPLGFVEGFbFGFTGFbPLGFPD-ECGFModified by Tortora, from Relf et al., Cancer Res. 1997
27Cross-talk tra diverse vie di segnale : base Per l’ acquisizione di resistenza a terapie selettiveTortora et al., 2006IGF-R1PDGFR,HER/erbBc-KITRPPGRB2SOSp21rasRafPPKAIPPI3KVEGFPLCgMEKMAPKPKCPTENAKTVEGFR1VEGFR2Endothelial cellsBcl-2CyclinD1mdm2E2FmTORCDKAngiogenesisp53Cell ProliferationRbApoptosisInvasionmetastasis
28Novel Paradigm :“Multi-targeted therapy” Multiple targeted cellsCancer cellsEndothelial cellsPericytesFibroblastsMultiple molecular targetsHERVEGF/VEGFRPDGF/PDGFRKIT/MET/RETOthers kinasesAngiogenesisReceptor tyrosine kinasesSerine/threonine kinasesFaivre et al. Sem Oncol, 2006
29I recettori del VEGF ANGIOGENESIS LYMPHANGIOGENESIS VEGFR-3/Flt-4 VEGFR-2/KDRLYMPHANGIOGENESISANGIOGENESIS
31ZD6474 inhibits KDR and EGFR TGFEGFRZD6474KDRRETEndothelial cellsCancer cellsVEGFAngiogenesisTortora & Ciardiello 2003Carlomagno et al, Cancer Res. 2002Ciardiello et al., Clin Cancer Res. 2003Ciardiello et al., Clin Cancer Res. 2005Damiano et al., Clin Cancer Res 2005Cell Proliferation
32A Multicenter Phase II Trial of ZD6474, a VEGFR-2 and EGFR TKI, in Patients with Previously Treated Metastatic Breast CancerKathy D.Miller, JoseManuelTrigo, Catherine Wheeler, Alan Barge, Jacqui Rowbottom, George Sledge, and Jose Baselga100mg/d n=22300mg/d n=24The 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
33The endothelial cell-pericyte network of signals Pericytes protects endothelial cells from apoptosisand overexpress PDGF-RPDGF-R is overexpressed in many tumorsPDGF-R and VEGF cooperateNature Review Cancer
35Days After Dosing Began SU11248 increased activity in combination with Docetaxel in a breast cancer modelVehicle control1,500SU mg/kg per day PODocetaxel 15 mg/kg IV once per week x 3SU mg/kg per day + docetaxel 15 mg/kgonce per week x 31,000Average Tumor Volume, mm3500Complete regression in 33% of mice, with no regrowth 3 months after dosing stopped on day 72SU11248 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 withSU11248 at 40 mg/kg per dayDocetaxel 15 mg/kg IV once weekly for 3 weeksBoth SU11248 and docetaxel at the same concentrations and on the same daily or weekly scheduleThere 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.10203040506070DocetaxelDays After Dosing BeganSU11248Abrams et al. Mol Cancer Ther. 2003;2: , with permission.
36Phase 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 Baum6 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
37Ongoing studies with Sunitinib Phase III randomized study of Sunitinib + capecitabine vs capecitabine in pretreated advanced breast cancer patients430 pts. Primary endpoint: PFSPhase 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: PFSPhase 2 randomized, double blind study of Sunitinib in combination with Trastuzumab in 1st line for MBC.Primary endpoint: Response Rate2 Phase I studies of Sunitinib in combination with Paclitaxel (or with Docetaxel) in 1st line for MBC.20 pts. each Primary endpoint: Safety
38Ongoing studies with Sunitinib Phase 1-2 study of Sunitinib in combination with Exemestanein 1st line for MBC.70 pts. Primary endpoint: PFS, SafetyPhase 2 randomized study of Sunitinib vs Standard of care in previously treated Triple receptor negative (ER, PR, HER2) BC.200 pts. Primary endpoint: PFS
39BAY 43-9006 (Sorafenib) Bisaryl urea, multiple targeted inhibitor. ClF3CNHOBisaryl 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.
40A phase I trial combining sorafenib with bevacizumab Phase II trial in metastatic breast cancer patients failing anthracycline and/or taxaneLimited 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 bevacizumabDose 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 # 3004BAY has clear activity in several tumor types and is going on to phase II studies.
41PTK787/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 MBCThe purpose of this slide is to introduce PTK/ZK as a multi-VEGF receptor inhibitorPTK/ZK is multi-VEGF receptor inhibitor that completely inhibits the activation of VEGF receptors: VEGFR-1, VEGFR-2, and VEGFR-31,2PTK/ZK also inhibits the PDGF receptor which plays a role in blood vessel stabilizationPTK/ZK is being codeveloped by Novartis Pharmaceuticals Corporation AG and Schering AG Berlin, Germany1. 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):
42International 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 inhibitorPTK/ZK is multi-VEGF receptor inhibitor that completely inhibits the activation of VEGF receptors: VEGFR-1, VEGFR-2, and VEGFR-31,2PTK/ZK also inhibits the PDGF receptor which plays a role in blood vessel stabilizationPTK/ZK is being codeveloped by Novartis Pharmaceuticals Corporation AG and Schering AG Berlin, Germany1. 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):
44Horizontal 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
45GW786034 (Pazopanib) in combination with Lapatinib in breast cancer xenografts
46Phase III Randomized double blind study with Pazopanib in combination with Lapatinib in MBCLapatinib 1500 mg/day +placeboPD*relapsed or refractory inflammatory breast cancer overexpressing ErbB2(n=320)Lapatinib 1500 mg/day +Pazopanib 800 mg/dayPDPrimary endpoint: PFSSecondary endpoint: overall Response Rate, time-to-response, response duration, quality of life, overall survival (OS), safety and tolerability, biomarkers, pharmacokinetics and pharmacogenomicsPatients in the bevacizumab plus CP arm may receive single-agent bevacizumab until disease progressionE4599 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).
47CONCLUSIONII 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.