Round Table on Therapeutic Antibodies Cetuximab Paolo Marchetti Oncologia Medica II Facoltà di Medicina Università La Sapienza & IDI IRCCS Roma.

Round Table on “Therapeutic Antibodies”

CetuximabPaolo Marchetti

Oncologia MedicaII Facoltà di Medicina

Università “La Sapienza”&

IDI IRCCSRoma

Targets of Cancer Therapy

Cell Growth Motility Survival Proliferation Angiogenesis

P

P

P

P

PDK1,2Growth Factor

Signaling

Gene Transcription DNA Replication and Repair

1

6 3

5

8

9

10

11

2Plasma Membrane

Nuclear Membrane

127

4

7

7 1. 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)

TMDomain

Cytoplasmic Domain(Kinase Activity)

Strategies to Inhibit ErbB

• MoAbs to blockligand binding orreceptor dimerization

• Small-moleculekinase inhibitors

• Competitivereceptor antagonists

• Ligand-toxin orAb-toxin conjugates

• Antisense oligonucleotides

• Vaccines

AntagonistMoAb KinaseInhibitor

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 respondto 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

Molecular targeted categories

• Antibodies (MoAb)

• Antisense Oligonucleotides (AO)

• Small Molecules (SM)

• Others

Terapia antitumorale

MAb TKI CT RT

Specificità per il

bersaglio assoluta variabile Bassa Bassa

Tossicità BassaBassa/

moderataAlta Moderata

Valutazione MTD

“Pending” Sì Sì Sì

Via di somminist

r.e.v. e.v./orale e.v./orale Locale

Emivita ggsett Oregg Oregg NA

MAbs e TKIs: “gemelli diversi”

Cetuximab=IMC-C225=Erbitux™Gefitinib=ZD1839=Iressa®Erlotinib-OSI774-Tarceva™

Molecola Mab (IgG1 chimerico) TKI

Meccanismo d’azione

Bloccano 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+metastasi

-Si 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

Cetuximab=IMC-C225=Erbitux™GefitinibErlotinib

Bassa incidenza di effetti tossici seri

Dose e via di somm.

400 mg/mq 250 mg/mq e.v. sett250-500 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.solidiFase II mono k rene

Fase II comb HNC, NSCLC, CRCFase 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: MAbs e TKIs: “gemelli diversi” “gemelli diversi”

Murine MAb

• Hypersensitivity• High levels of

neutralizing antibodies

Chimeric MAb

• Hypersensitivity• Low levels of

neutralizing antibodies

Humanized MAb

• Hypersensitivity• Low levels of

neutralizing antibodies

Human MAb

• Hypersensitivity• Low levels of

neutralizing antibodies

Monoclonal Antibody History

Goldsby RA, Kindt TJ, Osborne BA, et al. Kuby’s Immunology. New York, NY:WH Freeman and Company; 2003. Roth RI. J Am Pharm Assoc. 2001;41:383-391.

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 ofEGF Receptors

Ligands Bind

EGF ReceptorDimerization

TGF-

EGF

Extracellular Binding Domain

TransmembraneLipophilic Segment

Intracellular ProteinTyrosine Kinase Domain

Activation of Signal Transduction

ERBITUX Package Insert, June 2004.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

Autore N° di pzterapi

a fase RP/SD

Sopravv.

mediana

Linea di terapia

Commenti

Saltz 2001121

(EGFR+)

C225+

CPT-11

II19.2%/14.2

7+ mesi

II (resistente a CPT-11/FU)

RR = 27.7%

(rash+) vs 3.8%

(rash-)

Saltz 200257

(EGFR+)

C225 II10.5%/36.8

8+ mesi

II (resistente a CPT-11/FU)

Buona toll.

Rosenberg 2002

27(EGFR+

)

C225+CPT-11+

5FU+LV

II44.0%(RP)

NR I linea

89% pz riduzione dosi CPT-11 e 5-FU

Schoffski/Kohne,200

2

19 (EGFR+

)

C225+CPT-11+

5FU+LV

II73.7%(ORR)

NR I linea ?

BOND 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/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. 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.

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 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).

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 )