Assessing and managing toxicities of molecularly targeted agents March 28-29, 2008 Domus Sessoriana...

Assessing and managing toxicities of molecularly targeted agents

March 28-29, 2008 Domus SessorianaMarch 28-29, 2008 Domus Sessoriana Rome, ItalyRome, Italy

Pierosandro TagliaferriUniversità Magna Græcia di CatanzaroCentro OncologicoFondazione Tommaso Campanella

An emerging problem: the clinical toxicities of targeted agents


Targeted therapies, which include monoclonal

antibodies and small molecule inhibitors, have

significantly changed

the treatment of cancer

over the past 10 years.


These drugs are now a component of therapy for many

common malignancies, including breast, colorectal, lung, and

pancreatic cancers, as well as lymphoma, leukemia, and

multiple myeloma.


Traditional cytotoxic chemotherapy works primarily through the inhibition of cell division


These drugs target rapidly dividing cells, including cancer cells and certain normal tissues.


As a result, many patients experiencethe classic toxicities of alopecia, gastrointestinalsymptoms, and myelosuppression.


In contrast, Targetedtherapy blocks the proliferation of cancer cells by interfering with specific molecules required for tumor development and growth.Some of these molecules may be present in normal tissue, but they are often mutated or overexpressed in tumors.


The molecular pathways most often targeted in the treatment of solid tumors are:- Epidermal growth factor receptor EGFR (also known as HER1)

- Vascular endothelial growth factor VEGF- HER2/neuSuch pathways can be inhibited at multiple levels: 1) By binding and neutralizing ligands (i.e., moleculesthat bind to specific receptor sites on cells)

2) By occupying receptor-binding sites (thereby preventingligand binding)

3) By blocking receptor signaling within the cancer cell4) By interfering with downstream intracellular molecules.


Targeted therapies have expanded the concept of individually tailored cancer treatment because some of these drugs maybe effective in patients whosecancers havea specific moleculartarget, but they may not be effectivein the absenceof such a target.


Some of the recently approved molecular-targeted

therapies are now being used in daily clinical practice.

These molecular targets are also expressed in normal

cells, which explains the different grades of toxicity,

resulting from the disruption of normal cellular function.


Main molecular targeted agents in the treatment of solid cancers

Gefitinib TK inhibitor of EGFR

Erlotinb TK inhibitor of EGFR

Cetuximab Block EGFR

Panitumumab Block EGFR

Trasduzumab Block HER-2

Lapatinib Inhibition of EGFR and HER-2

Bevacizumab Block VEGF

Sorafenib Inhibition of VEGFR-2, VEGFR-3, PDGFRB,

Raf, c-Kit, and Flt-3

Sunitinb Inhibition of VEGFR, PDGFR, cKit, and Flt-3


Monoclonal antibodies, which are usually water soluble and

large, target extracellular components of these pathways,

such as ligands and receptor binding domains.

In contrast, small molecule inhibitors can enter cells, thereby

blocking receptor signaling and interfering with downstream

intracellular molecules.


Ligands:

EGFTGF-aAmphiregulinBetacellulinHB-EGFEpiregulin

Heregulins

NRG2NRG3HeregulinsBetacellulin

Cysteine-richdomains

HER1/EGFRerbB1

HER2erbB2neu

HER3erbB3

HER4erbB4

Tyrosine-kinasedomains

Salomon D, Brandt R, Ciardiello F, et al. Crit Rev Oncol Hematol. 1995;19:183-232.Woodburn J. Pharmacol Ther. 1999;82:241-250.

The HER Family of Receptors


HER1/EGFR Targeted TherapyHER1/EGFR Targeted Therapy

Neutralizing Monoclonal AntibodyNeutralizing Monoclonal Antibody Cetuximab (Erbitux), Cetuximab (Erbitux),

Panitumumab (Vectibix) Panitumumab (Vectibix)

MatuzumabMatuzumab

Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitors Gefitinib (Iressa)Gefitinib (Iressa)

Erlotinib (Tarceva)Erlotinib (Tarceva)

LapatinibLapatinib


Targeted therapy has raised new questions about the

tailoring of cancer treatment to an individual patient’s

tumor, the assessment of drug effectiveness and toxicity,

and the economics of cancer care.


In general, targeted molecular therapies have good toxicity

profiles, but some patients are exquisitely sensitive

to these drugs and can develop particular and severe adverse

effects, such as acneiform rash, cardiac dysfunction,

thrombosis, hypertension and proteinuria.


Most of these side effects are directly related to the

specific molecular target in normal tissues inhibited or

modulated by the specific drug.

The paradigm of this phenomenon is the cutaneous toxicity

observed with the inhibitors of the epidermal growth factor

receptor (EGFR)


Tumors with HER1/EGFR Dysregulation

Breast

Esophagus

Gastric

PancreaticOvarian

CervicalProstateBladder

ColorectalRenal

Lung

Glioma

Head and neck


EGFR and its ligands have an important role in

the regulation of epithelial cell proliferation, survival, and

differentiation during physiological development,

Particularly in the skin and in the gastrointestinal tract,

as well as a key role in mesenchymal

and neuronal tissue formation


Currently, the main anti-EGFR therapies prescribed are Cetuximab and Panitumumab, two mAbs directed toward the extracellular ligand-binding domain of this receptor,and Gefitinib and Erlotinib, which are small molecules that inhibit the activation of the TK activity of the receptor.


Common Approaches to Targeting HER1/EGFR

Anti-HER1/EGFR-blocking antibodies

Anti-ligand-blocking

antibodies

TKinhibitors

Ligand–toxin

conjugatesAntibody–

toxinconjugates

PP P

P


Acneiform eruption, also called acne-like rash or folliculitis, which occurs in 50%–100% of patients.The pathophysiology of this acneiform rash remains unclear. It is believed that inhibition of EGFR-mediated pathways affecting basal keratinocytes induces many crucial events of growth arrest and apoptosis, decreases cell migration, and increases cell attachment and differentiation and inflammation. With the release of chemoattractants (such as CXCLs and CCLs) and recruitment of leukocytes, inflammation is primarily responsible for thecharacteristic signs and symptoms associated with the rash.

Commonly observed side effect with EGFR inhibitors


SIDE EFFECTS OF ANTI-EGFR THERAPIES

Other typical skin toxicities observed include:-Nail fragility- Hair changes- Trichomegaly- Paronychia - Pyogenic granuloma- Xerosis

Skin ToxicityGastrointestinal ToxicityInterstitial lung disease (ILD)FeverElectrolyte disorders


SIDE EFFECTS OF ANTI-EGFR THERAPIES

LONG-TERM SIDE EFFECTS SHORT-TERM SIDE EFFECTS


SHORT-TERM SIDE EFFECT SKIN TOXICITY


LONG-TERM SIDE EFFECTS OF ANTI-EGFR THERAPIES

Interstitial lung disease (ILD) is known to be an adverse event of some cancer chemotherapeutic agents and following local radiotherapy


Toxicity of molecular targeted agents (1)

Understatement

Versus

Overstatement



Understatement

It is not chemotherapy !!!!!



Overstatement

I do not know how to manage and recognise,It is not chemotherapy…..!!



Nihilist

I do not trust molecular targeted agents !!!I trust chemotherapy…!!!


GENERAL SIDE-EFFECT OF TARGETED THERAPIESversus

SPECIFIC ON-TARGET SIDE-EFFECT OF TARGETED THERAPIES


GENERAL SIDE-EFFECT OF TARGETED THERAPIES

The new england journal of medicine

In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy.

The antibodies were specific for galactose-α-1,3-galactose.

Cetuximab-Induced Anaphylaxis and IgESpecific for Galactose-α-1,3-Galactose



IgE Antibodies Binding to Cetuximab in Serum Samples from 76 Case Subjects and 462 Control Subjects.Results are shown according to whether the treating physician reported ahypersensitivity reaction (HSR) to cetuximabor no HSR reaction. Results are alsoshown for pretreatment serum samples from control subjects and from subjects who had not received cetuximab. The horizontal lines indicate geometric Mean values for the positive results. Values with multiplication signs indicate the number of negative values for each symbol.

Anti-EGFR monoclonal antibodies : molecular developement


DIRECT ON TARGET SIDE EFFECTS


march 13, 2008 1129

Brief Report

VEGF Inhibition and Renal Thrombotic Microangiopathy

This report describes six patients with proteinuria and classic pathological features

of thrombotic microangiopathy after bevacizumab therapy. The findings underscore the need for a better understanding of the renal consequences of

VEGF inhibition.

Hypothetical Model of Disruption of VEGF Signaling in Renal Thrombotic MicroangiopathyThe loss of function of vascular endothelial growth factor (VEGF) through genetic deletion (VEGF KO), pharmacologic inhibition, or an elevated level of circulating soluble fms-like tyrosine kinase 1 (sFlt-1) that binds VEGF is associated with damage to the glomerular endothelium characterized by swelling and thrombotic microangiopathy. VEGFR-2 denotes kinase insert domain receptor.


Why this happens?


Targeted therapies = Non-selective inhibitors

Wide spread effect

Side effect

Unknown kinase inibition


Activated kinases:

The “Achilles’ heel”

of targeted

therapies


Protein kinases appear to represent particularly important

targets for cancer therapy.

The fact that they are frequently activated by mutation and/or

gene amplification highlights their role in a variety of human

cancers and, consequently, they feature prominently in the

cancer drug development pipelines of many biotechnology


For example, the clinical activity of the multikinase inhibitor Imatinib led

to a paradigm shift in cancer treatment strategies, and represented some

of the first examples of oncogene addiction in the context of cancer

therapy. The apoptotic response to drug treatment, suggests that

clinical responses are likely to reflect a cancer cell-autonomous

dependency on specific activated kinases for their survival.


The genetic constitution of the tumor cell, aside from a single addicting

oncogene, will almost certainly influence the response to oncoprotein

inactivation. For example, mutations in the ARF/p53 pathway potently

attenuate the proapoptotic and/or prosenescence properties of oncogenic BCR-

ABL, and tumors harboring such mutations appear to be particularly resistant

to Imatinib. This might help to explain the failure of targeted therapies in

certain tumors despite the presence of activating mutations in oncogenes that

might otherwise confer a state of addiction.


HOW TO DETERMINE THE RISK

OF TREATMENT-RELATED TOXICITY?


Nomograms to Predict Serious Adverse Events

in Phase II

Clinical Trials of Molecularly Targeted Agents


A tool that quantifies the risk of treatment-related toxicity

based on individual patient characteristics

can augment the informed consent process and safety

monitoring in the setting of phase II

cancer treatment trials of molecularly targeted agents (MTAs).


Nomogram for predicting anyserious adverse event during

cycle 1. Nomogram for predicting any

attributableserious adverse event during

cycle. Abbreviations:ULN, upper limit of normal;

LDH,lactate dehydrogenase; RT,

radiation therapy;BSA, body-surface area.


The use of targeted therapy has markedly changed the outcome for important diseases.

In addition to prolonging survival in patients with certain cancers, targeted therapies provide treatment options for some patients who

may not otherwise be candidates for anticancer therapy.Not too optimistic….Not too pessimistic…

But not nihilist….Some time they work and are safe !!!!

CONCLUSIONS

Assessing and managing toxicities of molecularly targeted agents March 28-29, 2008 Domus Sessoriana...

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