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Imai K, Takaoka AComparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6(9): 714-727

October 2006
Nature Reviews Cancer 6(9):714-27

October 2006
6(9):714-27

DOI:10.1038/nrc1913

Source
PubMed

Authors:

Kohzoh Imai

The University of Tokyo

The 'magic bullet' concept of specifically targeting cancer cells at the same time as sparing normal tissues is now proven, as several monoclonal antibodies and targeted small-molecule compounds have been approved for cancer treatment. Both antibodies and small-molecule compounds are therefore promising tools for target-protein-based cancer therapy. We discuss and compare the distinctive properties of these two therapeutic strategies so as to provide a better view for the development of new drugs and the future direction of cancer therapy.

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The term ‘magic bullet’, coined by bacteriologist Paul

Ehrlich in the late 1800s, originally described a chemi-

cal with the ability to specifically target microorgan-

isms. His concept (specific targeting) was expanded

thereafter to include cancer treatments, and has been

successfully applied to the development of innova-

tive cancer-treatment strategies with different, more

specific mechanisms of action than conventional

chemotherapeutic agents

. Such molecular targeting

techniques

include monoclonal antibodies (mAbs),

small molecules, peptide mimetics and antisense

oligonucleotides. With the advances in understand-

ing of aberrant signalling pathways in various types

of cancer cells, many pivotal regulators of malignant

behaviour in cancer cells have emerged as candidates

for molecular target-based cancer therapy. Such strat-

egies have improved the management of cancers

A crucial challenge in the development of targeted

agents is to choose an appropriate approach. The two

main approaches discussed here are therapeutic mAbs

and small-molecule inhibitors

(TABLE 1).

Key signalling molecules, such as protein tyrosine

kinases, have proven to be good targets for small-

molecule inhibitors that compete with ATP and

inhibite kinase activity

. Such inhibitors have clini-

cally effective responses in chronic myeloid leukaemia

(

CML), gastrointestinal stromal tumours (GISTs)

and non-small-cell lung cancer (

NSCLC)

. Another

group of targets is represented by tumour-selective

cell-surface proteins, which can be recognized by

antibodies. The therapeutic application of mAbs has

improved response rates in patients with malignant

lymphomas and is currently being assessed in other

tumour types

Many small-molecule agents and mAbs that target

growth-factor receptors and their signalling pathways have

been developed and subjected to clinical trials. Some mol-

ecules are targeted by both types of inhibitors, including

members of the ErbB family of receptor tyrosine kinases

(RTKs). The ErbB family comprises four members: epider-

mal growth factor receptor (

EGFR, also known as ERBB1),

ERBB2 (also known as HER2), ERBB3 and ERBB4

(REFS 8,9). Both gene amplification and overexpression of

EGFR and ERBB2 are frequently observed in

breast, lung

and

colorectal cancers, and the deregulated activation

of intracellular mitogenic signalling by the ErbB family

has been implicated in various cancers

. Therefore, these

receptors have been a focus of molecular-targeting ther-

apy

. To compare mAbs and small-molecule inhibitors,

this Review will highlight EGFR-targeted agents that have

shown clinical success.

Accumulating clinical-trial results are showing that

monotherapy with a target-specific agent might need to

be reassessed. Most tumours, particularly solid tumours,

are multifactorial and are frequently linked to defects in

more than one signalling pathway

. Therefore, a dual-

targeting or multi-targeting therapy might be more

rational, not only to efficiently eliminate cancer cells, but

also to limit the emergence of drug resistance. Which

class of targeted agent will provide the best solution to

this problem? Considering the differences in specificity

or selectivity between mAbs and small-molecule inhibi-

tors might lead to the further improvement of targeting

strategies for cancer therapy.

In this Review we will describe the development of

mAbs and small-molecule inhibitors, and then compare

and contrast these two strategies using EGFR-targeted

agents.

*Sapporo Medical University,

South 1, West 17, Chuo-ku,

Sapporo, 060-8556, Japan.

‡

Department of Immunology,

Graduate School of Medicine

and Faculty of Medicine,

University of Tokyo,

Hongo 7-3-1, Bunkyo-ku,

Tokyo, 113-0033, Japan.

Correspondence to K.I.

e-mail: imai@sapmed.ac.jp

doi:10.1038/nrc1913

Comparing antibody and

small-molecule therapies for cancer

Kohzoh Imai* and Akinori Takaoka

‡

Abstract | The ‘magic bullet’ concept of specifically targeting cancer cells at the same time

as sparing normal tissues is now proven, as several monoclonal antibodies and targeted

small-molecule compounds have been approved for cancer treatment. Both antibodies and

small-molecule compounds are therefore promising tools for target-protein-based cancer

therapy. We discuss and compare the distinctive properties of these two therapeutic

strategies so as to provide a better view for the development of new drugs and the future

direction of cancer therapy.

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Bacteriophage display

A display method for

identifying proteins or peptides

that recognize and bind to a

target molecule(s).

Bacteriophages that display

the antibody of interest are

selected by antigen binding

and are propagated in

bacteria. This helps identify

therapeutic antibodies with

high binding affinity.

Shedding

The release of the extracellular

domain of a cell-membrane

protein, such as a growth-

factor receptor, from the cell

surface. ERBB2 is

proteolytically cleaved,

possibly by a matrix

metalloproteinase activator,

although this proteolysis does

not seem to be mediated by a

general shedding system that

can be activated by protein

kinase C. ERBB2 cleavage

generates a membrane-

associated receptor fragment

with potentially increased

tyrosine kinase activity.

Monoclonal antibodies for cancer therapy

The ‘magic bullet’ concept became a reality a quarter of

a century after the discovery of somatic cell hybridiza-

tion, a technique for generating mAbs pioneered by

Milstein and Köhler in 1975

(REF. 11). Early clinical trials

with murine mAbs failed owing to their short half-life,

xenogenicity and limited activity

. During this interven-

ing period, the application of genetic recombination for

humanizing rodent mAbs

made large-scale production

feasible, and enabled mAbs to be designed with better

affinities, efficient selection, decreased immunogenic-

ity and optimized effector functions. Furthermore,

proteomics and genomics combined with

bacteriophage

display

enabled the rapid selection of high-affinity

mAbs. Genetic engineering has made it possible to

design chimeric mouse–human mAbs, among which

the anti-

CD20 mAb rituximab (Rituxan) has revolu-

tionized lymphoma treatment

(TABLE 1 and FIG. 1). A

humanized mAb has provided new prospects for the

treatment of breast cancer. Trastuzumab (Herceptin) is

the first clinically approved mAb against an ErbB family

member (ERBB2)

(TABLE 1 and FIG. 1). It has excellent

anti-tumour activity, particularly when combined with

the cytotoxic agents doxorubicin and paclitaxel

Trastuzumab is approved for the treatment of

patients with metastatic breast cancer who carry an

increased ERBB2 copy number. Another anti-ERBB2

mAb, pertuzumab (Omnitarg), is also under evaluation

in phase II trials

. Unlike trastuzumab, which affects

ERBB2

shedding

, pertuzumab sterically interferes

with ERBB2 homo- and heterodimerization and sub-

sequent signalling events

. On the other hand, trastu-

zumab cannot prevent the formation of ligand-induced

ERBB2-containing heterodimers

. So, pertuzumab is

effective against trastuzumab-insensitive tumours that

do not have ERBB2 amplification

18,19

. Therefore, pertu-

zumab might be effective over a broad range of cancers

with either normal or increased ERBB2 levels.

In parallel with the development of trastuzumab, our

group also developed CH401, a mouse–human chimeric

mAb directed against ERBB2

, by a unique procedure

that used a mouse-mutant hybridoma with no mouse

immunoglobulin (Ig) heavy chains and a human Ig

expression vector. CH401 has been evaluated in a pre-

clinical study, and it significantly reduced the in vivo

growth of various ERBB2-expressing tumour cells

21,22

Of note, CH401 has shown an apoptosis-inducing effect,

presumably through the activation of p38 mitogen-

activated protein kinase (MAPK) and c-Jun N-terminal

kinase (

JNK)

21,22

. Our results showed that it is significantly

more effective than trastuzumab

These ERBB2-targeted therapeutic mAbs have used

three distinct strategies for signal blockade includ-

ing interference with ligand interactions and receptor

downregulation (trastuzumab), inhibition of receptor

dimerization (pertuzumab), and induction of apoptosis

(CH401).

EGFR is also overexpressed in various cancers, includ-

ing colon and breast, and mAbs directed against EGFR

have also been developed

. Cetuximab (also known as

At a glance

• The concept of specific molecular targeting has been applied to the development of innovative cancer-treatment

strategies. At present, two main approaches are available for use in clinical practice: therapeutic monoclonal

antibodies (mAbs) and small-molecule agents.

• We focus on the ErbB receptor family, particularly epidermal growth factor receptor (EGFR, also known as ERBB1) as

an example of a target in our comparison of mAbs and small-molecule inhibitors. Cetuximab, a mAb, and gefitinib

and erlotinib, which are small-molecule inhibitors, differ markedly in their basic properties and their underlying

mechanisms of action.

• The presence of activating mutations within the ATP-binding cleft of the EGFR kinase domain is associated with the

sensitivity of non-small-cell lung cancer (NSCLC) to gefitinib, but not to cetuximab. By contrast, cetuximab shows

a clinical benefit for colorectal cancers that overexpress EGFR in a manner independent of EGFR mutations.

In malignant glioma, the sensitivity to gefitinib is closely related to deletions within the ectodomain of EGFR.

In contrast to these drug-sensitivity mutations, the appearance of the T790M mutation confers resistance to

gefitinib in NSCLC.

• There are unique immune-effector mechanisms that are only triggered by therapeutic mAbs, such as antibody-

dependent cellular cytotoxicity, complement-dependent cytotoxicity and complement-dependent cell-mediated

cytotoxicity. By contrast, the effects of small-molecule agents are not directly linked to the activation of an immune

response against tumour cells.

• In general, mild adverse effects such as dermatological complications are commonly observed with these two classes

of EGFR inhibitors. Although interstitial lung diseases or diarrhoea are more commonly associated with small-

molecule therapies, therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, leading to the production

of human anti-mouse antibodies or human antichimeric antibodies, respectively.

• It has been shown that mAbs such as trastuzumab and cetuximab exert synergistic anti-tumour effects in combination

with chemotherapeutic agents more frequently than small-molecule inhibitors.

• The combination of distinct classes of EGFR inhibitors could not only increase their efficacy, but also contribute to

overcoming resistance to one class of EGFR inhibitor.

• Further investigation into the distinct properties of these two classes of targeted agents should not only contribute

to the development of new targeted agents but also provide an optimal therapeutic strategy for cancer treatment,

thereby leading to the improvement of dual-targeted or multi-targeted therapy.

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Complement-dependent

cytotoxicity

This is one of the antigen-

elimination processes that is

mediated by immunoglobulins

(Ig). When IgM and certain IgG

subclasses (IgG1 and IgG3)

bind to an antigen, one of the

complement factors is strongly

activated. Then, a sequence of

cleavage reactions of other

complement factors (classical

pathway of complement

activation) is triggered to

activate their cytotoxic

function, which leads to the

destruction of the target cells.

C225; Erbitux) is a chimeric IgG1-isotype mAb that binds

to EGFR with high affinity and abrogates ligand-induced

EGFR phosphorylation

25,26

. In addition, panitumumab

(ABX-EGF) was developed as a fully human IgG2-isotype

mAb against EGFR, and a recent randomized phase

III trial has shown that panitumumab monotherapy

improved the progression-free survival of patients with

previously treated metastatic colorectal cancer

Putative mechanisms of mAb-based cancer therapy

can be classified into two categories. The first is direct

action, which can be further subcategorized into three

modes of action. One mode of action is blocking the

function of target signalling molecules or receptors.

This can occur by blocking ligand binding, inhibiting

cell-cycle progression or DNA repair

, inducing the

regression of angiogenesis

, increasing the internaliza-

tion of receptors

30,31

or reducing proteolytic cleavage of

receptors

. Other modes of direct action are stimulat-

ing function, which induces apoptosis, and targeting

function. In the case of targeting function, mAbs can be

conjugated with toxins, radioisotopes, cytokines, DNA

molecules or even small-molecule agents

7,32,33

to selec-

tively target tumour cells (

TABLE 1 and FIG. 1). The second

mechanism of mAb therapy is indirect action mediated

by the immune system. The elimination of tumour cells

using mAbs depends on Ig-mediated mechanisms,

including

complement-dependent cytotoxicity (CDC) and

antibody-dependent cellular cytotoxicity (ADCC), to activate

immune-effector cells

(FIG. 2).

Small-molecule agents for cancer therapy

RTKs and non-RTKs are crucial mediators in signalling

pathways of cell proliferation, differentiation, migra-

tion, angiogenesis, cell-cycle regulation and others

4,34,35

and many are deregulated during tumorigenesis.

Small-molecule inhibitors target these kinases by direct

effects on tumour cells, rather than by causing immune

responses as mAbs do. Most small-molecule inhibitors

of tyrosine kinases are

ATP mimetics. Imatinib mesylate

(Glivec), one of the first successful small-molecule

inhibitors, inactivates the kinase activity of the

BCR–

ABL fusion protein in CML

36,37

(TABLE 1). It has shown

Table 1 | Two classes of FDA-approved targeted agents and the spectrum of targeted cancers

Agent Target for agent

Targeted cancer

Solid tumours Haematological tumours

NSCLC

Breast

cancer

CRC

GIST

Renal

cancer

Pancreatic

cancer

HNSCC

AML

B-cell

CLL

CML

B-cell

lymphoma

Multiple

myeloma

mAbs

Cetuximab (Erbitux) EGFR

✓

‡

✓

Trastuzumab (Herceptin)

ERBB2

✓

Bevacizumab (Avastin)

VEGF

✓

Rituximab (Rituxan)** CD20

✓

Ibritumomab tiuxetan

(Zevalin)*

CD20

✓

Tositumomab-I

131

(Bexxar)* CD20

✓

Gemtuzumab ozogamicin

(Mylotarg)

‡‡

CD33

✓

Alemtuzumab (Campath) CD52

✓

Small-molecule inhibitors

Imatinib mesylate (Glivec) TKs (BCR-ABL, KIT, PDGFR)

✓✓

Gefitinib (Iressa) TK (EGFR)

✓

Erlotinib (Tarceva) TK (EGFR)

✓✓

§§

Sunitinib (Sutent ) TKs (VEGFR, PDGFR, KIT, FLT3)

✓✓

Sorafenib (Nexavar) Kinases (B-Raf, VEGFR2, EGFR,

PDGFR)

✓

Bortezomib (Velcade) 28S protease

✓

Agents are shown as generic names with trade names in parentheses. The table lists cancers to which each targeted agent is approved. *Radiolabelled with

Yttrium

or Iodine

131

‡

In combination with irinotecan or administered as a single agent.

In combination with radiation therapy or administered as a single agent.

In combination with paclitaxel or administered as a single agent.

In combination with 5-fluorouracil-based chemotherapy. ** In combination with CHOP

(cyclophosphamide, doxorubicin, vincristine and prednisolone) or other anthracycline-based chemotherapy regimens.

‡‡

This mAb is linked to N-acetyl-γ

calicheamicin, a bacterial toxin. After internalization of the mAb, the released toxin binds to DNA and causes double-strand DNA breaks.

§§

In combination with

gemcitabine. AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia; CRC, colorectal cancer; EGFR, epidermal

growth factor receptor; FLT3, Fms-like tyrosine kinase 3; GIST, gastrointestinal stromal tumour; NSCLC, non-small-cell lung cancer; PDGFR, platelet-derived growth

factor receptor; HNSCC, head and neck squamous-cell carcinoma; TK, tyrosine kinase; VEGFR, vascular endothelial growth factor receptor.

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Fab

CDR

Ibritumomab tiuxetan

(CD20); IgG1κ

Tositumomab-I

131

(CD20); IgG2aλ

Cetuximab (EGFR);

IgG1κ

Panitumumab (EGFR);

IgG2

Rituximab (CD20);

IgG1κ

Trastuzumab (ERBB2);

IgG1κ

Bevacizumab (VEGF); IgG1

Alemtuzumab (CD52); IgG1κ

Gemtuzumab ozogamicin

(CD33); IgG4κ

Murine Chimeric Humanized HumanType of mAb

Antibody-dependent

cellular cytotoxicity

This reaction can be initiated

by the Fc portion of

immunoglobulins (Ig).

Phagocytes such as

monocytes/macrophages,

dendritic cells, natural killer

cells and neutrophils take up

IgG-coated target cells through

binding with Fcγ-receptors on

the surface of the phagocytes.

This is eventually followed by

the elimination of target cells.

ATP mimetics

These small-molecule inhibitors

competitively bind to the ATP-

binding cleft at the activation

loop of target kinases, thereby

inhibiting their kinase activity.

remarkable efficacy for the treatment of patients with

Philadelphia chromosome-positive CML

. It is also a

multi-targeted inhibitor of other tyrosine kinases, includ-

ing

KIT, which is key to the pathogenesis of metastatic

GISTs, and the platelet-derived growth factor receptors

PDGFRα and PDGFRβ, which are key to the patho-

genesis of PDGF-driven tumours such as glioblastoma

and dermatofibrosarcoma protuberans

EGFR is also a rational target for small-molecule

inhibitors

. Gefitinib (Iressa)

and erlotinib (Tarceva)

selectively inhibit EGFR, and both are efficacious against

EGFR-expressing cancers such as NSCLC and head and

neck squamous-cell carcinoma (

HNSCC) (TABLE 1).

Phase II studies of these agents have also shown their

efficacy with or without concurrent chemotherapy

in HNSCC, and several phase III trials of gefitinib

are ongoing

. Erlotinib in combination with an anti-

metabolite, gemcitabine, is also approved for treating

advanced pancreatic cancer.

Unlike mAbs, small-molecule agents can trans-

locate through plasma membranes and interact with

the cytoplasmic domain of cell-surface receptors and

intracellular signalling molecules. Therefore, various

small-molecule inhibitors have been generated to target

cancer-cell proliferation and survival by inhibiting Ras

prenylation

, Raf–MEK kinase

, phosphatidylinositol

3-kinase (

PI3K), the mammalian target of rapamycin

(

mTOR) pathway or heat shock protein 90 (HSP90)

(REF. 45); cancer-cell adhesion and invasion by inhibiting

SRC kinase

or matrix metalloproteinases (MMPs)

; or

neovascularization by inhibiting the vascular endothelial

growth factor RTK (

VEGFR).

As a new type of small-molecule agent, sorafenib

(Nexavar) is known to exert its inhibitory effect on not

only different isoforms of Raf serine kinase but also

various RTKs such as VEGFR, EGFR and PDGFR

. This

dual-action kinase inihibitor shows broad-spectrum anti-

tumour activity by inhibiting tumour proliferation and

angiogenesis

. Another new anti-angiogenesis small-

molecule drug, sunitinib malate (Sutent), is also a multi-

targeted tyrosine kinase inhibitor of VEGFR, PDGFR,

KIT and Fms-like tyrosine kinase 3 (

FLT3)

. Potential

targets for the development of small-molecule agents

have also been identified in the ubiquitin–proteasome

Figure 1 | The classification of therapeutic monoclonal antibodies (mAbs) by the different antibody types —

murine, chimeric, humanized and human. Advances in genetic engineering techniques have contributed to the

development of humanized therapeutic mAbs. The fundamental structure of an intact, single immunoglobulin G (IgG)

molecule has a pair of light chains (orange/red) and a pair of heavy chains (yellow/pink). Light chains are composed of two

separate regions (one variable region (V

) and one constant region (C

)), whereas heavy chains are composed of four regions

, C

1, C

2 and C

3). The complementarity-determining regions (CDRs) are found in the variable fragment (Fv) portion of

the antigen-binding fragment (Fab). Chimeric mAbs such as cetuximab and rituximab are constructed with variable regions

and V

) derived from a murine source and constant regions derived from a human source. Humanized therapeutic mAbs

are predominantly derived from a human source except for the CDRs, which are murine. There are currently four approved

humanized mAbs. Both murine and human mAbs are entirely derived from mouse and human sources, respectively.

Panitumumab (ABX–EGF) is a fully human anti-epidermal growth factor receptor (EGFR) mAb, but has not yet been

approved. Furthermore, several mAbs (marked with an asterisk) are armed with cytotoxins including radionucleotides or a

bacterial toxin (see text for further details). There is a significant difference between the IgG subclasses in terms of their

half-lives in the blood (IgG1, IgG2 and IgG4 approximately 21 days; IgG3 approximately 7 days) and in terms of their

capability to activate the classical complement pathway and to bind Fcγ-receptors (see the legend of

FIG. 2). The choice of

an IgG subclass is a key factor in determining the efficacy of therapeutic mAbs. Most of the approved mAbs shown here

belong to the IgG1 subclass, which has a long half-life and triggers potent immune-effector functions such as complement-

dependent cytotoxicity (CDC), complement-dependent cell-mediated cytotoxicity (CDCC) and antibody-dependent

cellular cytotoxicity (ADCC). On the other hand, panitumumab is an IgG2 subclass that does not show potent CDC and

ADCC, but it has recently shown its efficacy in a phase III trial as a monotherapy for the treatment of metastatic colorectal

cancer. VEGF, vascular endothelial growth factor.

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CDCC

CDC

C3b

MAC

C3bR

Macrophage/

natural killer cell

Target tumour cell

Phagocytosis

FcγRIIIa

FcγRIIb

C1q

Natural killer

cell

Macrophage

ADCC

Lysis

mAbs (IgG1 subtype)

mAb

target

FcγRIIIa

Chymotryptic protease in

the 26S proteasome

The 26S proteasome is a

multicatalytic complex, which

is composed of the 20S

catalytic core subunit and the

19S regulatory subunit that

recognize and degrade

ubiquitylated proteins. A

chymotrypsin-like proteolytic

activity is one of the catalytic

activities of this core subunit

for the hydrolysis of peptide

substrates.

pathway, which is crucial in processes including cell-

cycle arrest and apoptosis. Bortezomib (Velcade), which

was first developed as a selective, reversible inhibitor

of the

chymotryptic protease in the 26S proteasome, has

been reported to be effective against various cancers,

particularly haematological malignancies

(TABLE 1).

Comparison between mAbs and small-molecules

Many preclinical and clinical studies have indicated that

targeting EGFR could represent a significant contribu-

tion to cancer therapy. Because both mAb and small-

molecule EGFR inhibitors have been approved as cancer

therapies, we will use them as our primary example to

compare mAbs and small-molecule inhibitors. There is

no clear difference in the spectrum of cancers targeted by

the one mAb and the two small-molecule inhibitors that

are approved by the US Food and Drug Administration

(FDA) and specifically target EGFR

(TABLE 1). Further

comparison between these two classes of targeted agents

will be discussed below.

Basic drug properties and development. The timelines

for the development of mAbs versus small-molecule

inhibitors seem to differ. Following the establishment of

mouse hybridoma technology, the mAb approach was

first applied to block EGFR-mediated signalling for can-

cer treatment in the early 1980s. About 10 years behind

this, the potential of EGFR-targeted therapy contributed

to the development of small-molecule EGFR tyrosine

kinase inhibitors (TKIs)

Although therapeutic mAb development requires

relatively complex processes with huge monetary costs

compared with small-molecule inhibitors, many bio-

tech and pharmaceutical firms are vying to develop

therapeutic mAbs after the advent of humanization

techniques and human antibodies

. Furthermore,

chimeric and humanized mAbs, which have been the

predominant mAbs entering clinical studies, have

higher approval success rates (18% and 24%, respec-

tively)

than new chemical entities (NCEs) including

small-molecule agents (5%)

, especially in the field of

oncology

. On the other hand, small-molecule agents

are less expensive and more convenient to administer

than mAbs.

mAbs and small-molecule inhibitors differ in sev-

eral pharmacological properties. Anti-EGFR mAbs

are large proteins (around 150 kDa) and are generally

intravenously administered, whereas EGFR TKIs are

orally available, synthetic chemicals (approximately

500 Da). The large molecular weight of mAbs is

probably the cause of their inefficient delivery into

brain tissues because of the blood–brain barrier, so

therapeutic mAbs for brain cancer are usually deliv-

ered intra-tumorally

. In addition, we speculate that

owing to the difference in molecular size, intact Igs

such as IgG subclasses might be less efficient for tis-

sue penetration, tumour retention and blood clearance

than small-molecule agents. In fact, there are marked

differences between these two classes of agents in

several pharmacokinetic properties. According to

FDA labelling, the mAb half-lives (that is, cetuximab:

3.1–7.8 days, allowing for once-weekly dosing) are

much longer than those of small-molecule agents (that

is, gefitinib, approximately 48 hrs; erlotinib, approxi-

mately 36 hrs; allowing for once-daily dosing). Also,

pharmacokinetic studies showed that plasma concen-

trations of small-molecule agents can vary at a given

dose between patients

. This might be explained by the

oral administration of small-molecule agents versus

the intravenous administration of mAbs. Furthermore,

it might also be speculated that the degradation sys-

tem for small-molecule agents (chemicals) might vary

more in individuals than that for mAbs (proteins).

Because of their inability to pass through the cellular

membrane, mAbs can only act on molecules that are

expressed on the cell surface or secreted

. Bevacizumab

Figure 2 | Schematic model of antibody action by immune mechanisms.

Following the binding of monoclonal antibodies (mAbs) to a specific target on a tumour

cell, C1q complement factor interacts with the C

2 constant region of the mAb, which

leads to the activation of a proteolytic cascade of the complement classical pathway and

consequently induces the formation of a membrane-attack complex (MAC) for the lysis

of tumour cells; this effect is termed complement-dependent cytotoxicity (CDC). C3b,

which is generated during this cascade reaction, functions as an

opsonin to facilitate

phagocytosis and cytolysis through its interaction with the C3b receptor (C3bR) on a

macrophage or natural killer (NK) cell

118

; this activity is termed complement-dependent

cell-mediated cytotoxicity

(CDCC). In addition, mAb-binding to tumour cells induces

antibody-dependent cellular cytotoxicity (ADCC); immune-effector cells such as

macrophages and NK cells are recruited and interact with the C

3 region of the mAbs

through FcγRIIIa expressed by both effector cells. Then, mAb-coated tumour cells are

phagocytosed by macrophages or undergo cytolysis by NK cells. On the other hand,

there is a negative regulation to modulate the cytotoxic response against tumours

through FcγRIIb, which is expressed on the cell surface of macrophages. Immunoglobulin

G1 (IgG1) and IgG3 can activate the classical complement pathway and interact with Fcγ

receptors more potently than IgG2 or IgG4. In particular, IgG4 cannot activate the

classical complement pathway.

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Abnormal activities

Proliferation/diﬀerentiation

Invasion and metastasis

Angiogenesis

Cell survival

Cell-cycle progression

Deregulated

activation

of downstream

signalling

pathways

SOS

Y Y

CR1

ATP

Excess ligand

(EGF) or ligand-

independent

activation

CR2

STAT3

GRB2

MEK

MAPK

Tyrosine

kinase domain

Y Y

ATP

TKI TKI

TKI

TKI TKI

TKI

Inhibition of

tyrosine

phosphorylation

of the receptor

Inhibition of

downstream

signalling

Inhibition of

downstream

signalling

Small-molecule

inhibitor

Therapeutic mAb

Receptor

internalization

Inhibition of tyrosine

phosphorylation of

the receptor

Activation of immune

responses (ADCC

and CDC)

mAb

TKI

RTK (EGFR)

Raf

Ras

PI3K

AKT

Complement-dependent

cellular cytotoxicity

This is a cell-mediated effector

mechanism for target cell

killing. As similarly observed in

CDC, complement activation is

triggered in CDCC by the

interaction of C1 q to the Fc

regions of antibodies bound to

target antigens. During this

process, several complement

components, such as C3b, are

generated and recognized by

effector immune cells through

their complementary

receptors, which leads to

phagocytosis and cytotoxicity.

Opsonins

Opsonins are any molecules

with which antigens are coated,

such as IgG and components of

complement factors (C1 q,

C3b, iC3b, and C4b), to

become more susceptible to

phagocytosis by macrophages

or neutrophils.These

phagocytes bind opsonin

molecules through Fcγ

receptors or complement

receptors that are expressed

on their surface membrane.

(Avastin) is the main mAb agent to have been developed

against the secreted pro-angiogenic protein VEGF, and

it improves survival when combined with 5-fluorourocil

(5-FU)-based chemotherapy in patients with meta-

static colorectal cancer (

TABLE 1 and FIG. 1). However,

small-molecule inhibitors can pass into the cytoplasm,

and can therefore be developed to target any molecules

regardless of their cellular location

. So, mAbs possess

biological activities that are not shared by small-molecule

inhibitors, and vice versa.

Typically, the advantage of therapeutic mAbs in can-

cer treatment is thought to depend on their capability to

bind antigens expressed on the tumour-cell surface with

a highly specific selectivity. The antigen-binding affin-

ity of an antibody is also associated with its biological

potency

. Therefore, it is presumed that mAbs might

Figure 3 | Distinct mechanisms of small-molecule inhibitors and monoclonal antibodies for targeting receptor

tyrosine kinases in cancer cells. a | Epidermal growth factor receptor (EGFR) and receptor tyrosine kinase (RTK)-

dependent growth signalling in cancer cells. The extracellular region of EGFR consists of four domains, the ligand-binding

domains (L1 and L2) and the cysteine-rich domains (CR1 and CR2), and the C-terminal domain of EGFR contains six

tyrosine residues (Y; only two are depicted here for simplicity). Following the activation of EGFR by ligand binding or

ligand-independent dimerization, the Ras–Raf–MEK–MAPK pathway is activated through the growth factor receptor-

bound protein 2 (GRB2)–SOS complex. EGFR-mediated signalling also activates the phosphatidylinositol 3-kinase (PI3K)–

AKT pathway, which contributes to anti-apoptotic effects of EGFR activation. Additionally, signal transducer and activator

of transcription (Stat) proteins (STAT1, STAT3 and STAT5) are also activated. The coordinated effects of these EGFR

downstream signalling pathways lead to the induction of cellular responses including proliferation, differentiation, cell

motility, adhesion and angiogenesis. The deregulation of EGFR-mediated signalling in some cancer cells leads to aberrant

proliferation, invasion, metastasis and neovascularization

. b | Small-molecule tyrosine kinase inhibitors (TKIs) such as

gefitinib function as ATP analogues and inhibit EGFR signalling by competing with ATP binding within the catalytic kinase

domain of RTKs. As a result, the activation of various downstream signalling pathways is blocked. Each TKI has a different

selectivity for RTKs, and some are dual- or multi-selective, which might provide a therapeutic advantage. c | By contrast,

therapeutic monoclonal antibodies (mAbs) bind to the ectodomain of the RTK with high specificity (for example,

cetuximab binds to the L2 domain of EGFR, and thereby inhibits its downstream signalling by triggering receptor

internalization and hindering ligand–receptor interaction. Unlike small-molecule inhibitors, mAbs also activate Fcγ-

receptor-dependent phagocytosis or cytolysis by immune-effector cells such as neutrophils, macrophages and natural

killer cells by inducing complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC)

107

MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase.

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TKI

EGFR

CR1

NSCLC Glioblastoma

CR2

Transmembrane

domain

∆6–273

(EGFRvIII)

(∆6–185)

∆521–603

ATP-binding cle

of the kinase

ATP

EGF

P-loop

A-loop

G719S,G719C

L858R, L861Q

∆E746–A750

∆L747–P753insS

∆L747–T751insS

T790M

Tyrosine

kinase

domain

be more effective against circulating cancer cells than

against solid tumours, possibly because of their poor

ability to penetrate into tissues and tumours, although

there might be other contributing factors such as the

availability of effector cells. This might be partly linked

to the high approval rates and marketing successes of

both armed and unarmed mAbs for haematological

malignancies

(TABLE 1). However, three mAbs have been

approved by the FDA for the treatment of solid tumours.

Most of the FDA-approved small-molecule agents are

more frequently used for the treatment of solid tumours,

whereas only two small-molecule agents are indicated

for use against haematological tumours.

Anti-EGFR mAbs and EGFR TKIs target distinct

domains of EGFR, the extracellular ligand-binding

domain and intracellular tyrosine kinase domain of

the receptor, respectively

(FIG. 3). Following interaction

with the receptor, the small-molecule TKIs gefitinib and

erlotinib specifically inhibit EGFR phosphorylation and

downstream signalling pathways. By contrast, recent

structural analysis by Li et al. showed that the interac-

tion of the mAb cetuximab with EGFR results in the

partial occlusion of the ligand-binding region (L2) and

steric hindrance preventing the receptor from adopting

the extended conformation required for dimerization

In another example, trastuzumab, the mAb directed

against ERBB2, distinctively binds to the juxtamem-

brane domain (CR2) of ERBB2, eventually leading to the

inhibition of downstream signalling

Specificity. Small-molecule inhibitors are generally

thought to be less specific than therapeutic mAbs

However, this lower specificity is potentially advanta-

geous, albeit with some risk of increased toxicity, in

that it confers the ability to inhibit several signalling

pathways at plasma concentrations that are clinically

possible

. In particular, small-molecule EGFR TKIs

show varying degrees of cross-reactivity for the ErbB

family members, which might account for their potent

anti-tumour effects when used in combination with a

more selective mAb against EGFR

. Supporting this,

Huang et al.

showed significant tumour regression

following treatment with cetuximab plus gefitinib or

erlotinib in a xenograft model with a human NSCLC

cell line. Both combinations reduced tumour volume

by approximately 75%, whereas monotherapy with

cetuximab or the EGFR TKIs reduced tumour volume

by approximately 50% or 20%. Similarly, another study

by Matar et al.

with an epithelial carcinoma cell line

showed that combination treatment increased the inhi-

bition of cell and tumour xenograft growth, possibly

through shared and complementary mechanisms of

action with gefitinib and cetuximab.

Although gefitinib is relatively mono-selective, with

a 200-fold greater affinity for EGFR than for ERBB2

34,60

several multi-selective EGFR inhibitors have been devel-

oped. Canertinib (CI-1033)

is a multi-selective EGFR

inhibitor that rapidly and irreversibly inhibits all ErbB

family members. Another multi-selective EGFR inhibi-

tor is lapatinib (GW-572016)

, which reversibly and

specifically inhibits both EGFR and ERBB2. A phase III

study in patients with advanced trastuzumab-resistant

breast cancer indicated that lapatinib might offer sig-

nificant benefits in combination with capecitabine. The

median progression-free survival was twice as long (36.9

weeks) with combination therapy than with capecitabine

monotherapy

. Based on the acceptable tolerability and

efficacy of this combination therapy, a Biologics License

Application (BLA) submission is currently pending

The efficacy of lapatinib has also been reported in

advanced renal cancer (phase III study)

and HNSCC

(phase I study)

. The cooperative inhibitory effects of

multi-targeting might enable broader anti-tumour activ-

ity and improve efficacy. In addition, it might follow that

the development of resistance is less likely. On the other

hand, no therapeutic mAbs with such cross-reactivity

have yet been reported.

Figure 4 | EGFR mutations correlated with clinical response to EGFR inhibitors.

Two types of EGFR (epidermal growth factor receptor) mutations have been reported so

far in relation to the sensitivity and resistance to gefitinib of non-small-cell lung cancer

(NSCLC; left)

75,76,86

, both of which occur in the ATP-binding cleft. First, missense

mutations that are detected within the nucleotide triphosphate binding domain (P-loop,

exon 18; red) of the tyrosine kinase (G719S and G719C); or within the activating loop

(A-loop, exon 21; yellow) (L858R and L861Q). Second, in-frame deletions with or without

the insertion of a serine residue (exon 19), which are clustered in the region between

codon 746–759; for example, ∆E746–A750, ∆L747–T751insS, ∆L747–P753insS.

Mutations clustered within the ATP-binding cleft would be predicted to stabilize the

interaction of ATP or an inhibitor molecule with this pocket, consequently leading to the

more intense and sustained activation or inhibition of EGFR than that of the wild-type

receptor. However, a recent report

163

has shown that such mutations of EGFR do not

affect the binding affinity of gefitinib or erlotinib to the ATP-binding pocket of the

receptor, which contrasts with other activating catalytic domain mutations that have a

profound effect on the interaction with imatinib mesylate, another small-molecule

inhibitor. On the other hand, a resistance-related mutation, T790M, was also found within

the ATP-binding cleft of the EGFR kinase domain. This mutation leads to steric hindrance

to the accessibility of an inhibitor into the cleft due to the bulkiness of the methionine

side chain. Unlike NSCLC, glioblastomas (right) do not frequently have mutations in the

EGFR kinase domain but rather in the extracellular domain of EGFR

. A recent study

showed that in glioblastomas, EGFRvIII, a constitutively active genomic-deletion variant

of EGFR (∆6–273), preferentially activates the phosphatidylinositol 3-kinase (PI3K)– AKT

pathway and, in tumours with intact PTEN expression, confers sensitivity to EGFR kinase

inhibitors

. Other EGFR mutations reported in glioblastomas include the deletion of

exons 14–15, which leads to the expression of a short-form mutant partly lacking the CR2

domain (∆521–603)

. However, the functional role of this mutant form remains unknown.

CR1, cysteine-rich domain 1; L1, ligand-binding domain 1; TKI, tyrosine kinase inhibitor.

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Sensitivity and resistance mechanisms. An important

issue remains whether a relationship exists between EGFR

expression and clinical outcome with EGFR-targeted

agents. Several preclinical studies with cetuximab

and gefitinib showed that both were potent in human

cancer cells with highly variable EGFR levels

67–69

. In a

retrospective evaluation, there was no significant asso-

ciation between EGFR expression and clinical response

to gefitinib in NSCLC

. In addition, the results of a ran-

domized, placebo-controlled phase III study in patients

with advanced NSCLC showed that EGFR expression

did not predict survival benefit with erlotinib

. Several

factors other than the level of EGFR expression have

therefore been shown to be involved in predicting the

clinical response to EGFR-targeted therapeutics

72–74

Certain subsets of patients also seem to be refractory to

EGFR-inhibitor treatment despite high levels of EGFR

expression in their tumours. Furthermore, cancer cells

often acquire resistance to EGFR inhibitors, but different

mechanisms seem to underlie sensitivity to mAbs and

EGFR TKIs.

Recent clinical studies have shown that mutations

in EGFR significantly affect, with a positive or negative

correlation, clinical responses to small-molecule TKIs

in patients with NSCLC

75,76

. Highly responsive NSCLC

contains somatic mutations of EGFR, including small

deletions (amino acids 747–750) or point mutations (most

commonly a L858R replacement)

75–82

(FIG. 4). These muta-

tions seem to result in the repositioning of crucial residues

that surround the ATP-binding cleft of the EGFR tyrosine

kinase domain, thereby stabilizing the interactions of the

inhibitor with the kinase domain

. Therefore, these muta-

tion types increase the sensitivity of tumour cells to gefit-

inib; the autophosphorylation of mutant EGFR is inhibited

at gefitinib concentrations 10–100-fold lower than those

necessary to inhibit wild-type EGFR

. Furthermore,

NSCLC cells with the L858R mutation undergo apoptosis

following gefitinib treatment, whereas cells that contain

wild-type EGFR undergo cell-cycle arrest

. In addition,

more recent reports have indicated that other factors

have a role in determining responsiveness to gefitinib in

patients with NSCLC, including amplifications of EGFR

and ERBB2

(REFS 84,85), as the ERBB2 status (determined

by the use of fluorescence in situ hybridization (FISH)) is

a validated marker for the clinical benefit of trastuzumab

for breast cancer

Despite the positive correlation between EGFR muta-

tions and sensitivity to TKIs, it seems that most patients

with NSCLC who are treated with these compounds

develop resistance, in part because of additional EGFR

mutations, particularly the T790M mutation, which

leads to the steric hindrance of gefitinib or erlotinib

binding due to the presence of the bulkier methionine

in the catalytic cleft

(FIG. 4). By contrast, malignant

glioma frequently shows deletions within the extra-

cellular domain of EGFR but infrequent mutations in the

kinase domain. The presence of these deletions might

increase the sensitivity of gliomas to gefitinib therapy

wherein the co-expression of EGFR deletion mutant

variant III and the tumour-suppressor protein

PTEN

affect sensitivity

It is unclear whether mutations in the intracellular

domains of EGFR affect the response to therapeutic

mAbs. Mukohara et al.

compared the efficacy of gefitinib

and cetuximab on NSCLC with EGFR mutations.

Gefitinib was more effective than cetuximab at inhibit-

ing not only in vitro growth, but also the induction of

apoptosis in EGFR-mutant NSCLC cell lines. Gefitinib

consistently suppressed EGFR phosphorylation in

EGFR-mutant cell lines, whereas cetuximab had less of

an inhibitory effect. Of note, even high concentrations of

cetuximab failed to show any inhibitory effect on EGFR

phosphorylation in EGFR-mutant cells

89, 90

. Clinical

data indicate that mutant EGFRs are more sensitive to

gefitinib than to cetuximab, which suggests that EGFR

mutations in NSCLC cells are associated with gefitinib,

but not cetuximab, sensitivity.

In colorectal cancers it has been reported that EGFR

mAbs are more effective than small-molecule inhibi-

tors

91–94

. The difference in the effectiveness of the two

classes of agents on colorectal cancer might therefore

be partially explained by the lower frequency of activat-

ing EGFR mutations

such as those found in NSCLC.

However, the efficacy of therapeutic mAbs in colorectal

cancer does not seem to correlate with EGFR expres-

sion

. Cetuximab has been shown to be effective even

in patients with EGFR-negative colorectal cancer,

as determined by immunohistochemistry

. In fact,

this remains an emerging issue for cetuximab-based

therapy for colorectal cancer; there are currently no

adequate markers that can efficiently predict the benefit

from EGFR-targeted therapy. This issue might be partly

related to the limited ability of the immunohistochemi-

cal detection method. Moroni et al.

showed that eight

out of nine panitumumab or cetuximab responders with

colorectal cancer had an increased EGFR copy number.

Therefore, the evaluation of EGFR amplification status

by FISH could help select patients for cetuximab therapy

in colorectal cancer.

EGFR phosphorylation does not seem to correlate

exactly with the effect of cetuximab on tumour-cell

growth. Despite no inhibitory effect on EGFR phospho-

rylation

89,90

, cetuximab potently inhibited the growth of

HCC827 NSCLC cells, which contain a deletion muta-

tion in exon 19 of EGFR. By contrast, the growth of

three different EGFR-mutant NSCLC cell lines was not

inhibited by cetuximab

. Therefore, factors other than

the modification of EGFR phosphorylation by mutations

might affect the anti-tumour efficacy of mAbs in some

types of NSCLC. If EGFR phosphorylation is not always

coupled with the sensitivity of these inhibitors, then it is

possible that cetuximab could have an inhibitory effect

on the activation of downstream pathways mediated

by ERK1/2 and AKT, thereby producing anti-tumour

effects. Several lines of evidence support the impor-

tant role of AKT in EGFR-mediated cell survival

98–100

Furthermore, Amann et al.

suggest that in addition to

EGFR mutations, other factors in NSCLC cells such as

high expression levels of other ErbB family members

might contribute to the sensitivity to both types of EGFR

inhibitors, possibly through the deregulated activation of

the AKT pathway downstream of EGFR. The possible

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Cancer stem cells

A small subpopulation of

quiescent tumour cells within a

tumour that have properties

similar to normal stem cells,

such as the capability to

undergo self-renewal and to

maintain tumour growth and

heterogeneity. According to the

stem-cell-based model,

conventional therapies

typically target actively

proliferating cells but spare

drug-resistant cancer stem

cells, which might contribute to

therapeutic failure and

eventual relapses.

Pruritus

A dermatological symptom

(itching) that is often observed

in cutaneous lesions caused by

allergy and infections.

Asthenia

A general feeling of weakness

or lack of vigour, which can be

associated with various

diseases.

involvement of determinants other than EGFR muta-

tions needs to be addressed to clarify the mechanism(s)

that underlie resistance to EGFR inhibitors, as supported

by several recent reports

98,99,101,102

Cancer stem cells could be a source of tumour relapse

and drug resistance during treatment with targeted

therapies

103,104

. Recent CML studies quantitatively vali-

date the model whereby imatinib affects differentiated

leukaemic cells but not leukaemic stem cells, which are

eventually linked to relapse

105

. No such stem-cell-related

resistance has been reported for mAb-based therapies.

On the other hand, the resistance mechanisms to mAbs

not shared by TKIs are intrinsically host related. For

instance, the impairment of ADCC, possibly through

a defective immune system or other mechanisms, could

result in resistance to treatment with mAbs

106

because

ADCC is a unique in vivo mechanism of action for

these agents.

Immune mechanisms. There are important differ-

ences between the effects of mAbs and small-molecule

inhibitors on immune responses. The mechanisms that

underlie the therapeutic effects of small-molecule agents

are not directly linked to the activation of the immune

response against tumour cells, whereas mAbs exert not

only direct inhibitory effects on tumour growth but

also have the ability to activate indirect accessory anti-

tumour activities such as ADCC and CDC

107

(FIG. 2).

Because of these properties, one can envisage that

in vitro growth inhibition by mAbs might not accurately

reflect the in vivo efficacy of mAb treatment compared

with small-molecule agents. In fact, cetuximab is less

effective at inhibiting the proliferation of NSCLC cell

lines than gefitinib, whereas the inhibitory effect of

cetuximab on in vivo tumour growth seems to be more

significant than that of gefitinib

57,89

. Although no effect

of gefitinib on immunological responses has, to our

knowledge, been described, the engagement of the acti-

vation antibody receptor (FcγRIII) on effector cells such

as natural killer (NK) cells or monocytes/macrophages

(FIG. 2) is a dominant component of in vivo cytotoxic

activity mediated by cetuximab against tumours. There

have also been reports on the pharmacogenetic associa-

tion of FcγR polymorphisms and the clinical response

to rituximab in patients with follicular

non-Hodgkin

lymphoma

108,109

, which supports the contribution of

FcγR-mediated ADCC to the clinical effect of mAbs.

However, an F(ab´)

form of cetuximab that lacks FcRγ-

chain interaction still has an inhibitory effect on in vivo

tumour growth, although half of the activity is induced

by native cetuximab

110

. A partially reduced response

was also observed in FcRγ-chain-deficient mice

106

By contrast, a regulatory mechanism by the inhibitory

antibody receptor (FcγRIIb) was also reported

(FIG. 2).

In syngeneic and xenograft models with three different

tumours, Clynes et al. clearly showed more robust anti-

tumour effects of the therapeutic mAbs trastuzumab

and rituximab in FcγRIIb-deficient mice

106

. Therefore,

Fc-receptor-dependent mechanisms contribute substan-

tially to the anti-tumour activities of mAbs, but their

interference with signalling pathways and the engagement

of other immune-effector mechanisms including CDC

are also putatively involved.

Regarding the contribution of CDC to immune

mechanisms, the role of complement factors as an

effector mechanism

is still controversial. The observa-

tion that at least 10 times more mAbs are required to

trigger CDC on the

cell surface than to trigger ADCC

111

suggests that most mAbs are engaged in an ADCC event

during treatment, whereas mAbs are unlikely to reach

the surface density on target cells sufficient

to activate

the classical complement pathway. In support of this, the

therapeutic activity

of rituximab does not correlate with

either the susceptibility of lymphoma cells to in vitro

complement-mediated lysis induced by rituximab or

the expression levels

of the complement-regulatory

proteins

112

. On the other hand, some evidence supports

the involvement of CDC in mAb-mediated immune

mechanisms

113–115

. In vivo data showed that rituximab,

which redistributes CD20 into membrane rafts

116

, is

bound efficiently by C1q and deposits C3b, which acti-

vates CDC

117

. In addition, the in vivo role of CDC in the

action of rituximab is suggested by evidence that com-

plement depletion

115

or C1q-deficient mice

114

showed

reduced or abolished efficacy of rituximab in lymphoma

models. Complement-dependent cellular cytotoxicity

(CDCC) might also be a mechanism of tumour-cell

killing

118

(FIG. 2). During the complement activation

cascade, C3b generation triggers phagocytosis and cel-

lular lysis through the engagement with C3b-receptor

macrophages, NK cells and polymorphonuclear leuko-

cytes. Other activated complement factors such as CD3a

and C5a might also facilitate inflammatory responses to

efficiently eliminate tumour cells.

Several strategies have been explored to increase

antibody-mediated effector functions and optimize effi-

cacy

. To increase FcγR-mediated ADCC activity, the

amino-acid sequence or glycosylation of the C

2 region

of mAbs has been manipulated by computational design

or mutational analysis to improve its interaction with

FcγRs

119–121

. New CD20 mAbs with strikingly potent CDC

activity have also been developed using human Ig trans-

genic mice

122

or through engineering the amino-acid

sequence of the C1q-binding site

123

Adverse effects. In general, the adverse effects associ-

ated with small-molecule inhibitors are mild. The most

frequently observed adverse effects of gefitinib are cuta-

neous (for example, rash, acne, dry skin and

pruritus)

and gastrointestinal symptoms (for example, diarrhoea,

nausea, vomiting and anorexia)

34, 124

. Similar to small-

molecule agents, most of the observed adverse effects of

mAb therapies are mild, including dermatological (for

example, acne, rash, dry skin and pruritus) and other

manifestations (for example, fever, chill and

asthenia),

without the bone-marrow suppressive properties of

chemotherapy.

The most common symptom associated with both

classes of anti-EGFR agents is an acneiform skin rash

resulting from the effects of EGFR inhibition, not from

a drug-related allergic reaction

125

, possibly due to the

expression of EGFRs in the epidermis. Interestingly, a

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Anaphylactoid reactions

Systemic immunological hyper-

responses that mimic

anaphylaxis. In contrast to IgE-

mediated anaphylactic

reactions, these are triggered

by an IgE-independent

mechanism, frequently appear

as allergic reactions to drugs,

foods and exercise, and

manifest as potentially life-

threatening symptoms such as

hypotension, bronchospasm

and laryngeal oedema.

Urticaria

A cutaneous symptom that

primarily manifests as a rash

and pruritus. This manifestation

is caused by IgE- or non-IgE

hypersensitivity with histamine

and other vasoactive

chemicals released from mast

cells as a result of exposure to

drugs and foods.

Interstitial pneumonitis

A form of pneumonia that is

characterized by non-infectious

inflammation and fibrosis in

the space between the

epithelial and endothelial

basement membranes of the

lower respiratory tract. This is

caused by unknown and known

factors such as drugs (gefitinib,

lefluomide or irinotecan) or

environmental factors, and can

be observed in association with

other diseases (for example,

connective tissue diseases).

Patients with this disorder

typically present with cough

and shortness of breath.

Human anti-mouse

antibodies

HAMAs are antibodies that are

produced by the human

immune system against

therapeutic murine monoclonal

antibodies (mAbs)

Human anti-chimeric

antibodies

HACAs are antibodies that are

produced against murine

components of chimeric or

humanized mAbs. HAMAs and

HACAs are often related to

immunogenicity problems

associated with a lack of

efficacy and rapid clearance

during mAb therapy.

growing number of reports show a positive correlation

between skin rash and clinical outcome in EGFR-targeted

therapies with cetuximab and erlotinib, although this

effect is less consistent for gefitinib

126

. Therefore, skin

rash might be a possible marker for evaluating and mon-

itoring the efficacy of anti-EGFR agents. This skin rash is

not thought to be dose-limiting, and completely resolves

following treatment cessation

25,60

. Dermatological toxic-

ity is not significantly different between both types of

inhibitors. On the other hand, diarrhoea is not com-

mon in patients treated with mAbs but is in patients

treated with small-molecule inhibitors

71,127,128

, and it can

be dose-limiting

34,53

. This might be linked to the oral

administration of small-molecule inhibitors, although

direct evidence has not been provided for such an asso-

ciation. Unlike small-molecule inhibitors, mAbs can

trigger allergic reactions such as

anaphylactoid reactions

and

urticaria

129

, but these are manageable by conventional

treatments and are not clinically limiting

The only severe toxicity reported to date with any of

these agents is gefitinib-related

interstitial pneumonitis,

the highest incidence of which was observed in Japanese

patients at 1–2% (3–4 times higher than that for patients

worldwide)

130

. Over 170 patients died from this pul-

monary disease after treatment with gefitinib

. Recent

analyses of chest radiographic and computer tomography

(CT) findings showed that the imaging of gefitinib-related

interstitial lung disease is similar to that of pulmonary

damage caused by conventional antineoplastic agents

131

We speculate that pulmonary toxicity with gefitinib might

be due to a direct cytotoxic effect, although its aetiology

is not yet clear. Japanese patients with NSCLC also show

a higher response to gefitinib, which is associated with a

more frequent detection of EGFR mutations

132

. Therefore,

differences in genetic background could underlie the high

incidence of gefitinib-induced interstitial lung disease

among Japanese patients. Furthermore, gefitinib inter-

acts with the ATP-binding cassette transporter

ABCG2,

which might be involved in the efflux of gefitinib from

cells

133

. Therefore, the genetic alteration of ABCG2 might

affect the absorption, tissue distribution and toxicities of

gefitinib. The development of new inhibitors that can

discriminate between wild-type and tumour-specific

mutant EGFRs might provide a solution to the adverse

effects described above.

Distinct from small-molecule agents, any protein

therapeutic is potentially immunogenic. Previously, the

development of therapeutic murine mAbs was hindered

by problems such as a lack of efficacy and rapid clear-

ance by

human anti-mouse antibodies (HAMAs). Such an

immunogenicity problem does not disappear by using

chimeric or humanized mAbs, and even human mAbs

pose this problem. As cetuximab is a mouse–human

chimeric mAb containing 5–10% murine protein it has,

although less frequently than fully murine mAbs

25,134

, the

potential to induce the production of

human anti-chimeric

antibodies

(HACAs), which might interfere with its

efficacy. However, the generation of HACAs occurs

in only a small fraction (3%) of patients treated with

cetuximab, so HACA responses are not thought to be

clinically limiting

Response rates. In a series of clinical trials, gefitinib

and erlotinib caused objective responses in 10–20%

of previously treated patients with NSCLC

135–138

. In a

recent placebo-controlled phase III clinical trial

71,128

erlotinib significantly prolonged the survival of

patients with NSCLC, whereas gefitinib did not sig-

nificantly improve survival. As for monotherapy with

therapeutic mAbs, both preclinical and clinical studies

have shown efficacy in some patients with colorectal

cancer, NSCLC and other solid tumours

139,140

. No

remarkable difference in the overall rate of response

to monotherapy is apparent between these two classes

of agents, which is supported by previous preclinical

data that show that the induction of cell-cycle arrest

and cytotoxic activity is almost the same between

small-molecule inhibitors and mAbs. To improve

the efficacy of these agents, therapeutic strategies in

combination with chemotherapy or radiotherapy have

been investigated.

Combination with chemotherapy or radiotherapy.

Clinical trials using mAbs or small-molecule inhibitors

combined with chemotherapy have shown a paradoxical

distinction between these two classes of agents in lung

cancer. The combination of gefitinib with two different

chemotherapy regimens in advanced NSCLC did not result

in any additive effects over chemotherapy alone in two

large randomized studies

141,142

. By contrast, anti-tumour

effects were increased by the addition of cetuximab

to chemotherapy in advanced NSCLC

143,144

. We think

that the underlying mechanisms for this synergy might

include the interruption of EGFR-activated survival

and proliferation signalling

145

, which makes tumour

cells more vulnerable to chemotherapy, but this cannot

account for the distinction between these two classes of

targeted agents. The discrepancy might be explained

partly by some positive, direct action of mAbs on apop-

totic pathways. In addition, some in vivo, specific role of

therapeutic mAbs might also contribute to a synergistic

effect with cytotoxic chemotherapeutic agents. In this

regard, we presume that mAbs but not small-molecule

inhibitors show advantageous activity because of their

indirect actions, for example, the activation of immune

responses such as ADCC. This activity might be fur-

ther increased by some immunostimulatory process,

such as the activation of macrophages, in response to

cytotoxic-agent-induced cell death.

A difference in responsiveness to these two types of

inhibitors is not observed in every type of cancer. Several

clinical trials have shown the effectiveness of cetuximab

combined with irinotecan-based chemotherapy in

metastatic colorectal cancer

92,94,145

. However, in contrast

to the lack of synergy in NSCLC, it has been reported

that gefitinib has a synergistic effect in combination

with chemotherapy in metastatic colorectal cancer

146

Kuo and Fisher argued that the differences between

NSCLC and colorectal cancer with respect to EGFR

expression and mutation status do not completely

explain this dichotomy

146

. Therefore, the mechanism that

underlies the synergistic effects of these EGFR inhibitors

seems to be multifactorial.

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723

In HNSCC, accumulating preclinical and clinical

studies have shown an increased effect of cetuximab in

combination with radiotherapy

147

, therefore contribut-

ing to its approval by the FDA. In addition, a recent

early-phase trial has also shown encouraging data for

the combination of gefitinib with chemoradiation

148

In metastatic colorectal cancer, another FDA-approved

mAb, bevacizumab, also significantly improved

response rates and overall survival of patients in com-

bination with 5-FU-based chemotherapy

149

. Although

the underlying mechanism is still unclear, we specu-

late that these augmentative effects of mAbs might be

partially due to their possible role in increasing p53-

dependent apoptosis, which is an important apoptotic

pathway activated by genotoxic agents

150

. Analogous

to this, we reported a similar mechanism for the syn-

ergistic effect of interferon-α (IFNα) and IFNβ with

genotoxic stresses such as 5-FU or γ-irradiation: IFNα

and IFNβ treatment contributes to the increase of DNA-

damage-induced apoptosis by activating TP53 expres-

sion

151

. Nevertheless, the association of TP53 status with

responsiveness to the combination of bevacizumab and

5-FU-based chemotherapy in colorectal cancer remains

controversial

152,153

, whereas p53 loss of function seems

to predict resistance to the combination of gefitinib with

chemotherapy, particularly in colorectal cancers with

intact p21 expression

Synergistic effects of the combination of monoclonal

antibodies with small-molecule inhibitors. When one

envisages potential synergism of the non-redundant

properties of targeted mAbs and small-molecule

inhibitors, another interesting question is raised: can

the combination of distinct classes of inhibitors to the

same target molecule, for example, anti-EGFR mAbs

and EGFR TKIs, augment their efficacy for cancer

therapy compared with using a single EGFR inhibitor?

Huang et al. studied the effect of combination treat-

ment with cetuximab and either gefitinib or erlotinib

They found that the phosphorylation of EGFR and its

downstream signalling molecules, ERK and AKT, is

more severely inhibited by combined treatment, which

induced apoptosis in HNSCC cell lines. In addition,

gefitinib or erlotinib still retained the capacity to inhibit

EGFR-mediated signalling and in vitro proliferation of

lung and HNSCC cells, which are highly resistant to

cetuximab. Furthermore, combined treatment with

cetuximab and gefitinib or erlotinib significantly inhib-

ited the growth of human tumour xenografts, whereas

treatment with a single agent produced only modest

growth inhibition. Their findings suggest that the com-

bination of distinct classes of EGFR inhibitors might not

only increase their efficacy through non-overlapping

mechanisms of action, but also assist in overcoming

resistance to one class of EGFR inhibitor

. Consistent

with this, other groups have shown that therapeutic

mAbs can lower the effective dose of small-molecule

inhibitors such as gefitinib or lapatinib, which might

contribute to the reduction of toxicity without compro-

mising efficacy

154,155

. Preclinical studies

58,156

have shown

increased efficacy when trastuzumab is combined with

lapatinib in ERBB2-positive breast cancer cells, which

might support the encouraging phase I study results

of these agents in a combined regimen

157

. Although

antibody-related immune activation might explain this

synergy, several reports showed direct actions against

cancer cells. Treatment with lapatinib and trastuzumab

increased apoptosis of ERBB2-overexpressing breast

cancer cells

, and trastuzumab might sensitize cancer

cells to treatment with lapatinib during combination

therapy

156

. Further clarification of the mechanism of

action of each class of agents will be required to validate

the efficacy of combinations.

Conclusion and future directions

The recent clinical successes of therapeutic mAbs and

small molecules in cancer treatment have established

these agents as the first cornerstone of molecular target-

ing therapy for cancers. However, the issues that have

arisen during the development of targeted agents must

be addressed, and on the basis of these data an appro-

priate approach should be chosen to develop targeted

drugs with greater efficacy and safety. In particular, dur-

ing preclinical drug development it is crucial to predict

how potent and selectively targeted drugs will function

in eventual clinical applications. However, the biochemi-

cal criteria for target validation

158

have yet to be decided.

Knight et al. have recently used a systematic approach

for parallel evaluation using a chemically diverse panel

of small-molecule inhibitors that target the PI3K fam-

ily

159

. Such integrated approaches should be useful for

the mapping of drug targets.

The activation of anti-tumour immunity is probably

crucial for efficiently eliminating tumour cells. In this

regard, small-molecule agents that do not directly act

on the immune system should be combined with drugs

with immunostimulatory activities to maximize thera-

peutic effects. As such, efforts have been made to target

a molecule with combinations of different classes of

agents, and several reports have provided evidence for

the potential synergistic effects of mAb therapies and

small-molecule inhibitors for cancer treatment

57,59,154,160

Although the efficient doses or schedules for combina-

tion therapies need to be optimized, and the predictive

criteria for the selection of patients that might benefit

from dual-agent therapy need to be established, a role

for therapeutic mAbs and small-molecule inhibitors

in combination therapies is emerging. Therefore, the

simultaneous use of distinct classes of agents that tar-

get one specific molecule could be thought of as one

of the promising strategies for maximally inhibiting

target molecule(s) and overcoming the limitations of

any single blockade.

However, in most solid tumours oncogenic progres-

sion is a multistep process and molecular pathogenesis

is not linked to the defect of a single target. In this con-

text, a single targeted therapy seems theoretically to

be an unfavourable strategy and cannot be expected

to yield optimal outcomes, which is paradoxical to the

original concept that a single targeted therapy would be

ideal, with fewer side effects due to its high specificity.

Therefore, the establishment of multi-targeted therapies

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Acknowledgements

We would like to thank T. Ishida for his continuous support of

the work in our laboratory described in this Review. The work

in our laboratory was supported in part by a grant for

Advanced Research on Cancer from the Ministry of Education,

Culture, Sports, Science, and Technology of Japan. We also

thank Z. Wang for his assistance with this manuscript.

Competing interests statement

The authors declare no competing financial interests.

DATABASES

The following terms in this article are linked online to:

Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.

fcgi?db=gene

FLT3 | HNSCC | HSP90 | JNK | KIT | MTOR | PI3K | PTEN | SRC |

VEGF | VEGFR

National Cancer Institute: http://www.cancer.gov

non-Hodgkin lymphoma

FURTHER INFORMATION

US FDA-approved drug information: http://www.

accessdata.fda.gov/scripts/cder/drugsatfda

Access to this links box is available online.

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5543 Background: Concurrent chemotherapy/radiation therapy (RT) improves treatment outcome in pts with locally advanced unresectable squamous cancers of the head and neck. We previously reported a 51% 3-year disease-free survival with induction paclitaxel/carboplatin/5-FU followed by concurrent paclitaxel/carboplatin/RT. In this phase II trial, we added gefitinib, an EGFR inhibitor, to a similar chemoradiation regimen. Methods: All pts had squamous carcinoma of the head and neck, with at least one of the following: N 1 -N 3 disease, T 3 or T 4 primary lesion, nasopharynx primary (except T 1 N 0 M 0 ). Additional eligibility: no previous therapy, ECOG PS 0 or 1, adequate bone marrow, kidney, liver function; informed consent. All pts received initial docetaxel 60mg/m ² D1, 22; carboplatin AUC 5.0 D1, 22; 5-FU 200mg/m ² , 24-hour CI, D1–43; gefitinib 250mg PO qd, D1–43. Beginning week 8, pts received RT, 1.8Gy single daily dose to total 68.4 Gy, and concurrent docetaxel 20mg/m ² weekly × 6 doses + gefitinib 250mg PO daily. At completion of therapy, pts were reevaluated with CT scans and endoscopy. Results: 45 pts entered this trial between 8/04 and 8/05. Pertinent clinical characteristics: clinical T 3 /T 4 , 17; N 2 /N 3 , 23. 42 pts (93%) completed induction chemotherapy. 34 pts (76%) have completed combined modality therapy and have been restaged. Response to treatment: 11 CR (32%); 18 PR (53%); 5 stable/progression (15%). After median follow-up 7 months, 9 patients (20%) have developed progressive cancer. Actuarial PFS and OS at 1 year are 68% and 86%, respectively. Grade 3/4 myelosuppression was common, and grade 3/4 mucositis occurred in all pts during combined modality therapy. One pt had a treatment-related death during combined modality therapy. The addition of gefitinib did not substantially increase toxicity. Conclusions: This combined modality regimen was feasible and produced high response rates in pts with locally advanced head and neck cancer. Toxicity was consistent with other effective combined modality regimens for these pts. Further follow-up is needed to better assess the benefit of this approach. [Table: see text]

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4502 Background: Lapatinib is an orally-active, reversible inhibitor of EGFR/ErbB2 tyrosine kinases. In Phase I/II trials, lapatinib has demonstrated activity in patients (pts) with advanced breast cancer. We report the first results of a randomized open-label Phase III trial ( EGF20001 ) of lapatinib vs. hormone therapy (HT) in pts with advanced RCC that express EGFR and/or ErbB2 by immunohistochemistry (IHC). The main endpoints were time to progression (TTP) and overall survival (OS). Methods: Pts with advanced RCC of any histology who had failed first-line cytokine therapy were stratified by Karnofsky performance score (KPS) and number of metastatic sites. Pts were randomized to receive oral lapatinib 1250 mg OD or HT. The primary efficacy endpoint was TTP, with 90% power to detect a 50% increase (i.e. 4 vs. 6 months) at a two-sided 5% significance level. All pt scans were interpreted by independent radiologic review. Results: At the time of the TTP analysis, 417 pts were randomized and 298 TTP events were reported. Demographic and baseline characteristics were similar between both arms; pooled results were: median age: 61 yrs; Stage IV disease: 97%, KPS 90–100: 59%, metastatic sites >2: 49%, prior nephrectomy: 94%, prior interferon therapy: 64%. No unexpected toxicities were observed, and drug-related AE (all grades) for lapatinib vs. HT included rash (44%:3%), diarrhoea (40%:3%). When results from all pts were analysed, median TTP was 15.3 weeks for lapatinib vs. 15.4 weeks for HT (hazard ratio (HR) = 0.94; p = 0.60), and median OS was 46.9 weeks for lapatinib vs. 43.1 weeks for HT (HR=0.88; p=0.29). In the major subgroup of 241 pts with EGFR overexpressed disease (3+ by IHC), median TTP was 15.1 weeks for lapatinib vs. 10.9 weeks for HT (HR = 0.76; p = 0.06), and median OS was 46.0 weeks for lapatinib vs. 37.9 weeks for HT (HR = 0.69; p = 0.02). These results were confirmed by Cox Regression analysis, and additional biomarker evaluation, including FISH, is underway. Conclusions: The EGFR/ErbB2 dual targeted inhibitor, lapatinib, appears to prolong overall survival compared to hormone therapy in advanced RCC pts with overexpressed EGFR who failed prior therapy. [Table: see text]

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5553 Background: Lapatinib is a selective and potent dual, competitive inhibitor of EGFR and ErbB2. A high level of expression of EGFR is reported in SCCHN (ranging from 55% to 90%), which is a negative prognostic factor, whereas ErbB2 expression ranges between 40% to 60%. The rationale for EGFR inhibition in combination with fractionated radiotherapy is to enhance radiosensitivity and inhibit cellular proliferation, including accelerated repopulation, during treatment. Methods: Patients (pts) with locally advanced SCCHN were enrolled at escalating dose levels of lapatinib (500–1,500 mg/d) in combination with radiotherapy (66–70 Gy/6–7 weeks given 5 days a week in 2 Gy daily fractions) and intravenous cisplatin (100 mg/m ² , days 1, 22 and 43 of radiotherapy). Each cohort was to include 3 pts, with expansion to 6 in the event of dose-limiting toxicity (DLT). Main eligibility criteria were confirmed SCCHN, excluding nasopharynx, stage III, IVa,b, and adequate organ function. Regular safety assessments were performed during therapy and follow-up period. Cardiac assessments using MUGA or ECHO scans were also performed. Results: Seventeen pts were treated (500 mg - 7; 1,000 mg - 7; 1,500 mg - 3; expanded cohort of 9 additional pts is currently recruiting). The most common side effects were Grade 1-3 dysphagia, mucositis and dermatitis, typically observed with cisplatin and radiotherapy in this population. Lapatinib-related adverse events were minor. In the 500mg cohort: 2 pts had diarrhea (Gr 1), 1 pt had tinnitus (Gr 1); in the 1,000mg cohort: 2 pts had nausea (Gr 2) and vomiting (Gr 2), 1 pt had transient elevated liver enzymes (Gr 3); in the 1,500mg cohort 2 pts had nausea (Gr 1) and 3 pts vomiting (1 pt Gr 1, and 2 pts Gr 2). One DLT was reported both at 500 mg and 1,000 mg dose levels; no further DLT were reported at the final 1,500 mg dose level. The optimally tolerated regimen was lapatinib 1,500 mg OD, given concurrently with conventional radiotherapy and cisplatin. Preliminary evidence of clinical activity was encouraging. Conclusions: The combination of lapatinib and concomitant chemoradiation is well tolerated, has demonstrated encouraging clinical activity in this population of locally advanced SCCHN patients, and warrants phase II studies in this disease. [Table: see text]

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Article

Sep 1997

IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell–specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab

Article

Jul 2004

A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1 st line or 2 nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial

Article

Jul 2004

7022 Background: In phase II studies, erlotinib has shown single agent activity in a number of tumor types, including NSCLC. NCIC CTG BR.21 is a randomized, placebo-controlled trial undertaken to determine if the Epidermal Growth Factor Receptor (EGFR) inhibitor erlotinib (Tarceva) prolongs survival in NSCLC patients after 1st or 2nd line chemotherapy. Methods: Eligibility criteria included stage IIIB/IV NSCLC, PS 0–3, 1–2 chemotherapy regimens (at least 1 combination regimen if < 70 yrs). Patients were stratified by center, PS (0,1 v 2,3), response to chemo (CR, PR v SD v PD), number of prior regimens (1 v 2), platinum (yes v no), and were randomized 2:1 to receive erlotinib 150 mg po/day or placebo. The 10 endpoint was survival with 20 endpoints of progression free survival (PFS), response, toxicity and QOL. Results: From Nov/01-Feb/03, 731 pts entered the study (median age 61y; 64% male; 67% PS 0,1). 50% had received 2 prior regimens, 93% had received platinum and 37% prior taxanes. Patient characteris...

Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab

Article

Jul 2004

5507 Background: The majority of head and neck cancers overexpress the epidermal growth factor receptor (EGFR), which is associated with aggressive tumor behavior and poor clinical outcome. Preclinical in vitro and in vivo model systems demonstrate radiosensitization following molecular inhibition of EGFR signaling. Promising phase I/II clinical results were achieved when radiation was combined with the EGFR blocking antibody, cetuximab, in patients with locoregionally advanced squamous cell carcinoma (SCC) of the head and neck (H&N). This phase III international trial was designed to examine the impact of combining cetuximab with high dose radiation on locoregional disease control and survival in patients with locally advanced H&N cancer. Methods: Patients with locoregionally advanced SCC of the oropharynx, hypopharynx or larynx with measurable disease were eligible to enroll. Patients were stratified by Karnofsky score 60–80 vs. 90–100, node positive vs. negative, T1–3 vs. T4, radiation fractionation re...

A phase II trial of cetuximab as therapy for recurrent non-small cell lung cancer (NSCLC)

Article

Jul 2004

A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen

Article

Jun 2005

Imai K, Takaoka AComparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6(9): 714-727

Abstract

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