Presentation on theme: "Round Table on “Therapeutic Antibodies” Cetuximab"— Presentation transcript:
1Round Table on “Therapeutic Antibodies” Cetuximab Paolo MarchettiOncologia MedicaII Facoltà di MedicinaUniversità “La Sapienza”&IDI IRCCSRoma
2Targets of Cancer Therapy 1P254Plasma Membrane367Microtubule Dynamics1. Growth factors2. Growth factor receptors3. Adaptor proteins4. Docking proteins/binding proteins5. Guanine nucleotide exchange factors6. Phosphatases and phospholipases7. Signaling kinases8. Ribosomes9. Transcription factors10. Histones11. DNA12. MicrotubulesPDK1,27Growth Factor Signaling12RNA Translation78Nuclear MembraneThe specific intracellular targets are the enzymatic activities that mediate the essential processes:Growth factor receptor activation and signaling1. Growth factors2. Growth factor receptorsSignal transduction: kinase activation cascades3. Adaptor proteins4. Docking proteins/binding proteins5. Guanine nucleotide exchange factors6. Phosphatases and phospholipases7. Signaling kinasesIntracellular signaling response elements8. Ribosomes (translation of mRNA into protein)9. Transcription factors (TFs, transcription of genes for essential processes)10. Histones (regulation of gene transcription)11. DNA (replication and repair)12. Microtubules (cell structure, cell division, and cell motility)91110Gene TranscriptionDNA Replication and RepairCell Growth Motility Survival Proliferation Angiogenesis
3Simplified diagram of the EGFR pathway consisting of the EGFR signal transduction cascade, and cellular effects of stimulation through the EGFR. The ligand binding site serves as the receptor for ligands such as EGF and TGF-. Upon ligand binding, subsequent receptor signaling, including autophosphorylation of the receptor and phosphorylation of target proteins, occurs downstream in the signal transduction cascade.2EGFR plays a critical role in cellular growth and repair and has been shown to function as a key pathway for the regulation of growth.2
4ErbB Family of Tyrosine Kinase Receptors Extracellular Domain(Binds Ligand)Family of evolutionarily conserved type I receptor tyrosine kinasesFour members:ErbB-1 (EGFR/HER1)ErbB-2 (HER2)ErbB-3 (HER3)ErbB-4 (HER4)TMDomainCytoplasmic Domain(Kinase Activity)The ErbB family is composed of 4 evolutionarily related receptor tyrosine kinases: ErbB-1 (also known as the epidermal growth factor receptor [EGFR] or HER1), ErbB-2 (also known as HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). The 4 members of this family share a similar conserved structure––an extracellular ligand-binding domain, a single transmembrane-spanning domain, and an intracellular tyrosine kinase domain.
5Strategies to Inhibit ErbB MoAbs to block ligand binding or receptor dimerizationSmall-molecule kinase inhibitorsCompetitive receptor antagonistsLigand-toxin or Ab-toxin conjugatesAntisense oligonucleotidesVaccinesThere are multiple strategies that could potentially be used to block signaling through the ErbB receptors:Monoclonal antibodies (MoAbs) directed toward the extracellular domain of the receptor can be used to prevent interactions with ligands. This approach might also modulate signaling, dimerization, or receptor expression on the cell surface, as well as potentially triggering antibody-dependent cellular cytotoxicity or complement-mediated cytotoxicity.Small molecules directed toward the kinase domain can inhibit phosphorylation and activation of downstream signaling pathways.Receptor antagonists can be used to competitively block ligand binding.Ligands or receptor-specific antibodies can be conjugated to lethal toxins. Following binding to the receptor, the toxin is internalized and kills the tumor cells.Antisense oligonucleotides can be used to downregulate the expression of ErbB receptors or ligands.Vaccines can be made to trigger the immune system to attack tumor cells overexpressing normal or mutant ErbB receptors.While all of these strategies could potentially be used to inhibit ErbB receptors, so far MoAbs and small-molecule kinase inhibitors have been developed to the greatest extent in a clinical setting.MoAbKinaseInhibitorAntagonistLigand-toxin
6ErbB Inhibition as a Therapeutic Strategy ErbB receptors play key roles in cell growth and survival.Overexpression and/or mutation of ErbB receptors is commonly seen in human tumors and is associated with poorer patient outcome and decreased survival.Overexpressed and mutant receptors can still respond to regulation.ErbB receptor inhibition is associated with decreased proliferation and increased apoptosis of tumor cells as well as regression of metastases.Members of the ErbB receptor family play integral roles in normal cell growth and survival.1,2 They have also been associated with negative outcomes and decreased survival rates in patients with a variety of tumor types, making ErbB family members attractive candidates for therapeutic intervention.3,4 In vitro studies have demonstrated that blockade of the ErbB-1 pathway can induce growth arrest, while inhibiting signaling through ErbB-2 leads to apoptosis in certain transformed cell lines.5,6Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19:2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:3. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001; 37(suppl 4):S9-15.4. Nahta R, Hortobágyi GN, Esteva FJ. Growth factor receptors in breast cancer: potential for therapeutic intervention. Oncologist 2003; 8:5-17.5. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002; 21:6. Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001; 1:85-94.
7Erb B family as a target for anti-cancer therapy Gefitinib in NSCLC, H/N cancerTrastuzumab in Breast cancerErlotinib in NSCLC, H/N cancerCetuximab in Colorectal cancer
9Specificità per il bersaglio Terapia antitumoraleMAbTKICTRTSpecificità per il bersaglioassolutavariabileBassaTossicitàBassa/moderataAltaModerataValutazione MTD“Pending”SìVia di somministr.e.v.e.v./oraleLocaleEmivitaggsettOreggNA
10MAbs e TKIs: “gemelli diversi” Cetuximab=IMC-C225=Erbitux™Gefitinib=ZD1839=Iressa®Erlotinib-OSI774-Tarceva™MolecolaMab (IgG1 chimerico)TKIMeccanismo d’azioneBloccano l’attivazione dell’EGFR e delle vie di trasduzione del segnale a valle (MAPK,PIK3,Akt,JAK-STAT) arresto del ciclo cell, apoptosi, angiogenesi+invasività+metastasiSi lega al dominio extracellulare dell’EGFR e blocca il legame del ligando.- Induce down-regulation del recettore (internalizzazione )- ADCC- Competono con l’ATP per il legame al sito della tirosino-chinasi.- Formano omodimeri EGFR ed eterodimeri EGFR/erbB2 inattivi- Possono bloccare l’attività catalitica di EGFR ed erbB2 (80% omologia)- Possono bloccare l’attività catalitica di rec x EGF che hanno perso il dominio extracellulare
11MAbs e TKIs: “gemelli diversi” Cetuximab=IMC-C225=Erbitux™GefitinibErlotinibBassa incidenza di effetti tossici seriDose e via di somm.400 mg/mq 250 mg/mq e.v. settmg/die p.o.100/150mg/die p.o.TossicitàCutanea (flushing,rash acneiforme,follicolite), febbre,astenia,reazioni allergicheCutanea, diarrea, pneumopat. interst. (iressa)Fase di sviluppo clinicoFase I mono diversi t.solidiFase II mono k reneFase II comb HNC, NSCLC, CRCFase III comb CRC,HNCGef.: F II/III mono/comb NSCLC, prostata,stomacoErl.:F II/III mono/comb NSCLC, pancreas,HNC,ovaio
13EGFR inhibitory agents and chemotherapy For those patients (individual tumors) in which EGFR signaling represents a dominant driving force for tumor progression, EGFR inhibitor strategies will likely prove of considerable value.However, for those patients (tumors) in which EGFR signaling represents just one of several aberrant molecular growth pathways conferring growth advantage, it would seem unlikely that EGFR inhibition strategies alone will provide substantial therapeutic benefit.(Lynch et al. 2004, Paez et al. 2004)
14CETUXIMABCetuximab is a chimeric human/murine immunoglobulin G1 (IgG1) MAB targeting the EGFR, that was initially developed from the murine antibody m225.The drug achieves its anticancer effect by binding to the extracellular endogenous binding domain of EGFR with an affinity greater than natural EGFR ligands.Subsequently, cetuximab downregulates EGFR expression and interferes with a number of signaling pathways, including Ras-Raf-MAP, phosphatidylinositol 3-kinase, Akt, JAK/STAT kinases, and protein kinase C.Prevents binding of EGF or TGF- to EGFR and prevents activation of intracellular tyrosine kinaseSimultaneous receptor internalization
15CETUXIMABCetuximab blocks tumorigenesis through a number of mechanisms by triggering G1 phase cell cycle arrest (via retinoblastoma protein hypophosphorylation), activation of proapoptotic molecules, inhibition of angiogenesis, and the downregulation of VEGF expression.Cetuximab may also limit metastatic spread by curbing the expression of matrix metalloproteinases.Shows sinergistic activity with anticancer drugs (irinotecan and platinum compounds) and radiation in-vitro and in-vivo models.
16ERBITUX (Cetuximab) Mechanism of Action The EGF Receptor: An Important Target for Cancer TherapyExpression of EGF ReceptorsLigands BindEGF Receptor DimerizationTGF- EGFExtracellular Binding DomainTransmembrane Lipophilic SegmentIntracellular Protein Tyrosine Kinase DomainActivation of Signal TransductionThe epidermal growth factor receptor (EGFR, HER1 or c-ErbB-1) is a transmembrane that is a member of a subfamily of type I receptor tyrosine kinases.1The EGF receptor is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of the EGF receptor is also detected in many human cancers including those of the colon and rectum.1Binding of EGF or transforming growth factor-alpha (TGF-) results in receptor dimerization. Tyrosine kinase autophosphorylation initiates intracellular signaling, resulting in a variety of effects that may increase tumor cell growth.1,3ERBITUX Package Insert, June Baselga J. J Clin Oncol. 2001;18s:41s-44s.
17ERBITUX (Cetuximab) Mechanism of Action Antibody BindsReceptor InternalizedERBITUX binds specifically to the EGFR (HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of EGF and other ligands, such as TGF-. By preferentially binding to the EGF receptor, ERBITUX inhibits ligand-induced tyrosine kinase autophosphorylation, affecting multiple mechanisms of action1:Inhibition of cell growth.Induction of apoptosis.Decreased production of matrix metalloproteinase (MMP).Decreased production of vascular endothelial growth factor (VEGF).
18SIDE EFFECTS OF mAbs THERAPY Side effects depend on the chimeric characteristics of the mAbs:FeverAllergic or anaphylactic reactionsAstheniaProduction of human anti-chimeric antibodiesAcne-like rash related to the expression of EGFR in the cells of the epidermides
19Cetuximab nel carcinoma del colon retto AutoreN° di pzterapiafaseRP/SDSopravv. medianaLinea di terapiaCommentiSaltz 2001121(EGFR+)C225+CPT-11II19.2%/14.27+ mesiII (resistente a CPT-11/FU)RR = 27.7% (rash+) vs 3.8%(rash-)Saltz 200257C22510.5%/36.88+ mesiBuona toll.Rosenberg 200227CPT-11+5FU+LV44.0%(RP)NRI linea89% pz riduzione dosi CPT-11 e 5-FUSchoffski/Kohne,200219 (EGFR+)73.7%(ORR)?
20BOND STUDY Cunningham D et al. N Engl J Med. 2004 Cetuximab was investigated in the BOND study as monotherapy or in combination with irinotecan in 329 patients whose CRC had progressed despite prior irinotecan treatment.Bolus 400 mg/m2 dose of cetuximab was given in Week 1, followed by subsequent weekly administration of 250 mg/m2.Alone and in combination with irinotecan, cetuximab produced a response rate of 11% and 23%, respectively, although the response was significantly higher in the combination group (P = .007).Higher rates of stable disease were also noted for the irinotecan/cetuximabcombination (32% vs 22%).However, there were no significant differences in overall survival, which may be explained by the fact that patients were allowed to cross over to the other treatment arm.Results from this study led to FDA approval of cetuximab for CRC.
21BOND STUDY Cunningham D et al. N Engl J Med. 2004 The study investigators also suggested that cetuximab’s clinical activity may be attributed to more than just chemotherapy sensitization.Safety data from this study showed that the agent was generally well tolerated, with grade 3/4 hypersensitivity reactions, nausea/vomiting, and diarrhea observed in only 1.2%, 6.1, and 14.4% of patients, respectively.The great majority of patients, approximately 80% of patients in each group, developed an acne-like rash, although it was not severe enough to result in the cessation of therapy.
22BOND-2 trialThe BOND-2 trial evaluated the combination of cetuximab plus bevacizumab alone versus cetuximab plus bevacizumab combined with irinotecan.Patients had not received bevacizumab previously.Response rates were 20% and 37%, respectively, with a median progression-free survival of 7.9 months for patients treated with the two biologic agents plus chemotherapy
23Expanding the treatment continuum with second-line targeted therapies
24Cetuximab first-line therapy in patients with advanced colorectal cancer Cetuximab has also been evaluated as a component of first-line therapy in patients with advanced colorectal cancer.A randomized phase III trial of cetuximab plus FOLFIRI versus FOLFIRI alone as initial treatment for mCRC (CRYSTAL) is ongoing.Preliminary results of a phase II study of cetuximab in combination with FOLFOX first-line (ACROBAT) showed a response rate of 70% in 20 evaluable patients [Tabernero JM et al., ASCO 2004].Early results from a phase I/II study of cetuximab plus FOLFIRI first-line showed an objective response in 14 of 21 patients (67%) [Folprecht G et al., ASCO 2005].
25Cetuximab first-line therapy in patients with advanced colorectal cancer In addition, a current phase III Gastrointestinal Intergroup study, led by Cancer and Leukemia Group B and Southwest Oncology Group C80405, is investigating the combination of cetuximab plus bevacizumab, versus each agent alone, as first line treatment in combination with either FOLFOX or FOLFIRI chemotherapy.
26Irinotecan & EGFR overexpression Although cetuximab targets the EGFR and is approved for use in combination with irinotecan for tumors that overexpress EGFR, it remains unclear whether cetuximab has activity in tumors that do not overexpress EGFR.Chung and colleagues (JCO, 2005) have reported that lack of EGFR expression (as determined by imunohistochemistry) was not predictive of response to cetuximab therapy in a series of 16 patients. In fact, partial responses were noted in 4 patients, and 3 patients exhibited stable disease without expression of EGFR.These results echo the findings of the BOND study.Similar findings with cetuximab and panitumumab have been reported by other researchers (Lenz HJ et al. JCO 2006; Hecht J et al. ASCO)
27Irinotecan & EGFR overexpression To date, we are unable to clearly identify EGFR mutations that correlate with response to EGFR-targeting therapy.It is unclear whether this reflects an inadequacy in current testing methods for EGFR, methodologic limitations in the acquisition and evaluation of EGFR, or cetuximab’s ability to affect tumor growth by alternative mechanisms of action.Some preliminary findings from a study using fluorescence in-situ hybridization to assess response have suggested that patients could be selected for therapy based on EGFR copy number (Moroni M et al. Lancet Oncol. 2005).
28Irinotecan & EGFR overexpression Clearly, there is no specific indicator of activity for cetuximab.However, some data have suggested that the development of a rash may be a marker for inhibition of EGFR phosphorylation, implying drug activity (Mohamed MK et al. Ann Oncol. 2005).There have been reports that the severity of the rash in some cetuximab-treated CRC correlates with better survival outcome. Based on this finding, investigators have hypothesized that higher doses of cetuximab may result in improved clinical outcome, a theory that is currently being tested in a randomized study.
29The Continuum of Care: A Paradigm for the Management of Metastatic Colorectal Cancer Currently, first- and second-line therapies are often given in isolation. Yet the choices of first and subsequent lines of therapy are actually interrelated, with the selection of a first-line regimen in part determining the choices available for subsequent treatment.Currently, patients are typically treated with a particular chemotherapy regimen until disease progression; however, emerging data suggest that the distinction between lines of therapy may not be absolute. Patients may move on to a subsequent treatment regimen prior to disease progression and/or return to a previously used drug or regimen later.Treatment breaks or phases of maintenance therapy after response induction may be interspersed with more aggressive therapy during the management of individual patients.Patients with potentially resectable liver metastases may be treated with a regimen or regimens designed to optimize tumor shrinkage and increase the opportunity for curative resection.Goldberg, Rothenberg, Van Cutsem et al. The Oncologist, 2007
30Management of Metastatic Colorectal Cancer: Intensive Therapy Goldberg, Rothenberg, Van Cutsem et al. The Oncologist, 2007
31Management of Metastatic Colorectal Cancer: Less Intensive Therapy Goldberg, Rothenberg, Van Cutsem et al. The Oncologist, 2007
32Bioweapons of Tumor Mass Distruction ? You see we must take aim –aim by chemical variation! The marvellous effect of an antibody in the serum is due to the fact that in no case it has affinity for the body substances but files straight onward without deviation, on the parasites.The antibodies are therefore MAGIC BULLETS which find the targets themselves…. We must therefore concentrate all our powers and abilities on making the aim as accurate as we contrive, so as to strike the parasites as hard and the body cells as lightly as possible.Paul Erlich, circa 1904( Martin J.S. Dyer JCO August 2003 )