Presentation on theme: "Round Table on Therapeutic Antibodies Cetuximab Paolo Marchetti Oncologia Medica II Facoltà di Medicina Università La Sapienza & IDI IRCCS Roma."— Presentation transcript:
Round Table on Therapeutic Antibodies Cetuximab Paolo Marchetti Oncologia Medica II Facoltà di Medicina Università La Sapienza & IDI IRCCS Roma
Targets of Cancer Therapy Cell Growth Motility Survival Proliferation Angiogenesis P P P P PDK1,2 Growth Factor Signaling Gene Transcription DNA Replication and Repair Plasma Membrane Nuclear Membrane Growth factors 2.Growth factor receptors 3.Adaptor proteins 4.Docking proteins/binding proteins 5.Guanine nucleotide exchange factors 6.Phosphatases and phospholipases 7.Signaling kinases 8.Ribosomes 9.Transcription factors 10.Histones 11.DNA 12.Microtubules Microtubule Dynamics RNA Translation
ErbB Family of Tyrosine Kinase Receptors Family of evolutionarily conserved type I receptor tyrosine kinases Four members: –ErbB-1 (EGFR/HER1) –ErbB-2 (HER2) –ErbB-3 (HER3) –ErbB-4 (HER4) Extracellular Domain (Binds Ligand) TM Domain Cytoplasmic Domain (Kinase Activity)
Strategies to Inhibit ErbB MoAbs to block ligand binding or receptor dimerization Small-molecule kinase inhibitors Competitive receptor antagonists Ligand-toxin or Ab-toxin conjugates Antisense oligonucleotides Vaccines AntagonistMoAbKinase Inhibitor Ligand- toxin
ErbB 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.
Erb B family as a target for anti-cancer therapy Gefitinib in NSCLC, H/N cancer Trastuzumab in Breast cancer Erlotinib in NSCLC, H/N cancer Cetuximab in Colorectal cancer
Terapia antitumorale MAbTKICTRT Specificità per il bersaglio assolutavariabileBassa TossicitàBassa Bassa/ moderata AltaModerata Valutazione MTD PendingSì Via di somministr. e.v.e.v./orale Locale Emivitagg settOre gg NA
MAbs e TKIs: gemelli diversi Cetuximab=IMC-C225=Erbitux Gefitinib=ZD1839=Iressa® Erlotinib-OSI774-Tarceva MolecolaMab (IgG1 chimerico)TKI Meccanismo dazione Bloccano lattivazione dellEGFR e delle vie di trasduzione del segnale a valle (MAPK,PIK3,Akt,JAK-STAT) arresto del ciclo cell, apoptosi, angiogenesi+invasività+metastasi -Si lega al dominio extracellulare dellEGFR e blocca il legame del ligando. - Induce down-regulation del recettore (internalizzazione ) - ADCC - Competono con lATP per il legame al sito della tirosino- chinasi. - Formano omodimeri EGFR ed eterodimeri EGFR/erbB2 inattivi - Possono bloccare lattività catalitica di EGFR ed erbB2 (80% omologia) - Possono bloccare lattività catalitica di rec x EGF che hanno perso il dominio extracellulare
Cetuximab=IMC-C225=Erbitux Gefitinib Erlotinib Bassa incidenza di effetti tossici seri Dose e via di somm. 400 mg/mq 250 mg/mq e.v. sett mg/die p.o. 100/150mg/die p.o. Tossicità Cutanea (flushing,rash acneiforme,follicolite), febbre,astenia, reazioni allergiche Cutanea, diarrea, pneumopat. interst. (iressa) Fase di sviluppo clinico Fase I mono diversi t.solidi Fase II mono k rene Fase II comb HNC, NSCLC, CRC Fase III comb CRC,HNC Gef.: F II/III mono/comb NSCLC, prostata,stomaco Erl.:F II/III mono/comb NSCLC, pancreas,HNC,ovaio MAbs e TKIs: gemelli diversi
EGFR 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)
Cetuximab 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 kinase Simultaneous receptor internalization CETUXIMAB
Cetuximab 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. CETUXIMAB
ERBITUX (Cetuximab) Mechanism of Action The EGF Receptor: An Important Target for Cancer Therapy Expression of EGF Receptors Ligands Bind EGF Receptor Dimerization TGF- EGF Extracellular Binding Domain Transmembrane Lipophilic Segment Intracellular Protein Tyrosine Kinase Domain Activation of Signal Transduction ERBITUX Package Insert, June Baselga J. J Clin Oncol. 2001;18s:41s-44s.
ERBITUX (Cetuximab) Mechanism of Action Antibody Binds Receptor Internalized
Side effects depend on the chimeric characteristics of the mAbs: Fever Allergic or anaphylactic reactions Asthenia Production of human anti-chimeric antibodies Acne-like rash related to the expression of EGFR in the cells of the epidermides SIDE EFFECTS OF mAbs THERAPY
Cetuximab nel carcinoma del colon retto AutoreN° di pz terapia faseRP/SD Sopravv. mediana Linea di terapia Commenti Saltz (EGFR+) C225+ CPT-11 II 19.2% / mesi II (resistente a CPT-11/FU) RR = 27.7% (rash+) vs 3.8%(rash-) Saltz (EGFR+) C225II 10.5% / mesi II (resistente a CPT-11/FU) Buona toll. Rosenberg (EGFR+) C225+ CPT-11+ 5FU+LV II 44.0% (RP) NRI linea 89% pz riduzione dosi CPT-11 e 5-FU Schoffski/ Kohne, (EGFR+) C225+ CPT-11+ 5FU+LV II 73.7% (ORR) NRI linea?
BOND STUDY Cunningham D et al. N Engl J Med 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/cetuximab combination (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.
BOND STUDY Cunningham D et al. N Engl J Med The study investigators also suggested that cetuximabs 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.
BOND-2 trial The 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
Expanding the treatment continuum with second-line targeted therapies
Cetuximab 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].
Cetuximab 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.
Irinotecan & 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)
Irinotecan & 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 cetuximabs 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).
Irinotecan & 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.
The 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
Management of Metastatic Colorectal Cancer: Intensive Therapy Goldberg, Rothenberg, Van Cutsem et al. The Oncologist, 2007
Management of Metastatic Colorectal Cancer: Less Intensive Therapy Goldberg, Rothenberg, Van Cutsem et al. The Oncologist, 2007
Bioweapons 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 )