Tarceva® ( erlotinib )

By

Sirinoot Jantharangkul

Tarceva• Generic name: Erlotinib

• Brand name: Tarceva® • FDA Approval Date: November 18,

2004

Tarceva• Indicated for :the treatment of locally

advanced or metastatic non-small cell lung cancer that has failed prior chemotherapy

• Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor

• Inhibits intracellular phosphorylation of tyrosine kinase associated with EGFR

Introduction

Introduction• Lung Cancer

– Non-Small Cell Lung Cancer

– Stage of Non-Small Cell Lung Cancer

• Tarceva in action – Cancer cell proliferation

– HER family of receptors and the role of

HER1/EGFR– Dysregulation of HER1/EGFR– Tarceva mechanism of inhibition

Introduction

Lung Cancer

• Two general types of lung cancer exist:

– Non-small cell lung cancer (NSCLC) – Small cell lung cancer

• The most common type of lung cancer is NSCLC. Approximately 147,000 new cases of NSCLC were reported in the United States in 2004.

Introduction

Main types of NSCLC• There are three main

types of NSCLC: – Adenocarcinoma (including

bronchioloalveolar carcinoma)

– Squamous cell carcinoma

– Large cell undifferentiated carcinoma

Introduction

Stage of Non-Small Cell Lung Cancer (NSCLC)

Introduction

Stage of Non-Small Cell Lung Cancer (NSCLC)

Introduction

Tarceva in action

• Cancer cell proliferation

• The Human Epidermal Receptor (HER) family of receptors

and the role of HER1/Epidermal Growth Factor Receptor (EGFR)

• Dysregulation of HER1/EGFR

• Tarceva mechanism of inhibition

Introduction

Cancer cell proliferationCancer cell proliferation Introduction

HER family of receptorsHER family of receptors Introduction

The role of EGFR

The role of EGFRThe role of EGFR

Introduction

HER1/EGFR dysregulationHER1/EGFR dysregulation

Tarceva: mechanism of inhibitionTarceva: mechanism of inhibition

Introduction

Tarceva

O

O

H3C

H3CO

O

NH

N

N

Tarceva (erlotinib)

• Small-molecule inhibitor of HER1/EGFR• Molecular wight 429.90• Orally available

Pharmacokinetics

• A: bioavailability ≈ 60%; food ↑ bioavailability to almost 100%

• D: ≈ 93% protein bound to albumin and alpha-1 acid glycoprotein

• M: primarily by CYP3A4 and to a lesser extent by CYP1A2

• E: mainly fecal (> 80%); t½= 36h

Introduction

Drug Interactions

• CYP3A4 inhibitors expected to increase exposure to erlotinib: ketoconazole increased AUC by 67%

• CYP3A4 inducers expected to decrease exposure to erlotinib: rifampicin increased clearance by 3-fold and reduced AUC by 67%

Adverse Effects

• Common adverse effects– Rash (75) [17]– Diarrhea (54) [18]– Anorexia (52) [38]– Dyspnea (41) [35]– Infection (24) [15]– Stomatitis (17) [3]– Pruritus (13) [5]

*(treatment) [placebo]

Monitoring

• Monitor for acute onset of new or progressive pulmonary symptoms such as dyspnea, cough, or fever

• If interstitial lung disease is diagnosed, discontinue erlotinib

• Consider dose adjustment with severe LFT changes (AST,ALT, Bili, Alk Phos)

Prescription Information

• Standard dose is 150 mg po daily taken at least one hour before or two hours after the ingestion of food

• Cost: #30 150 mg tablets $2125.02

Clinical studies :Tarceva: BR.21Tarceva: BR.21

Target enrolment

700 patients; stage IIIB or IV NSCLC

Prior therapy 1 or 2 chemotherapy regimensDesign Randomised 2:1

Tarceva 150mg/day plus BSC vs Placebo plus BSC

Primary endpoint

Overall survival

Secondary endpoints

Progression-free survivalSymptom deteriorationResponse rateTolerabilityTissue HER1/EGFR vs outcome/safety

BR.21 Progression Free Survival

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0000Wilcoxon test for equality of groups: p=0.0000Survival rate at 12 months for OSI-774: 8% - % C.I. ( 5%, 10%)Survival rate at 12 months for Placebo: 2% - % C.I. ( 0%, 4%)Hazard Ratio of Placebo/OSI-774: 1.572 - 95 % C.I. (1.337, 1.848)

OSI-774 Placebo

Perc

enta

ge

0

20

40

60

80

100

Time (months) # At Risk(OSI-774) # At Risk(Placebo)

0.0488243

5.015334

10.0526

15.081

20.010

Months

___ Erlotinib: 2.2 m

___ Placebo: 1.8 m

*HR 0.61, p <0.0001

BR.21 Overall Survival

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0018Wilcoxon test for equality of groups: p=0.0143Survival rate at 12 months for OSI-774: 31% - % C.I. ( 27%, 35%)Survival rate at 12 months for Placebo: 22% - % C.I. ( 16%, 27%)Hazard Ratio of Placebo/OSI-774: 1.309 - 95 % C.I. (1.105, 1.551)

OSI-774 Placebo

Perc

enta

ge

0

20

40

60

80

100

Time (months) # At Risk(OSI-774) # At Risk(Placebo)

0.0488243

10.018859

20.0124

30.000

___ Erlotinib: 6.7 m

___ Placebo: 4.7 m

*HR 0.71, p <0.0001

Months

BR.21 Survival by Smoking History

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0000

Smoked/OSI-774 Smoked/PlaceboNever Smoked/OSI-774 Never Smoked/Placebo

Perc

enta

ge

0

20

40

60

80

100

Time (months) # At Risk(Smoked/OSI-774) # At Risk(Smoked/Placebo)

# At Risk(Never Smoked/OSI-774) # At Risk(Never Smoked/Placebo)

0.035818710442

10.011646639

20.07340

30.00000

_____ Erlotinib Never Smoked

_____ Erlotinib Current/past Smoker

_____ Placebo Never Smoked

_____ Placebo Current/past smoker

Months

Selected BR.21 Adverse Events

76

17

55

19

4034

19

30

10

20

30

40

50

60

70

80

All G

rade

s, %

Rash Diarrhea Nausea St omat it is

erlot inibplacebo

Prolonged Time to Deterioration of QoL Symptoms

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0386

OSI-774 Placebo

Perc

enta

ge

0

20

40

60

80

100

Time (months) # At Risk(OSI-774) # At Risk(Placebo)

0.0298153

5.05920

10.0206

15.060

20.000

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0181

OSI-774 Placebo

Perc

enta

ge

0

20

40

60

80

100

Time (months) # At Risk(OSI-774) # At Risk(Placebo)

0.0348179

5.06516

10.0265

15.030

SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0098

OSI-774 PlaceboPe

rcen

tage

0

20

40

60

80

100

Time (months) # At Risk(OSI-774) # At Risk(Placebo)

0.0353179

5.07820

10.0285

15.050

___ Erlotinib

___ Placebo

Cough : p=0.04

Dyspnea : p=0.01

Pain : p=0.02

BR.21 Summary• In patients who have failed standard

chemotherapy for NSCLC, erlotinib significantly improves– Response rates and progression free

survival– Overall survival– Disease related QoL and overall QoL

• Prolongation of survival was seen in most subsets of patients

Summary

• Tarceva™, erlotinib, is a Human Epidermal Growth Receptor Type 1/ Epidermal growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor.

• Tarceva™ is indicated for the treatment of patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen.

Summary

• Dermatologic and GI side effects are common.

• The incidence of Interstitial Lung Disease was the same as the placebo group (0.8%) in one trial.

References

1. http://www.tarceva,com. Accessed on 2/27/05

2. Tarceva™ package insert. Genentech. 2004 Downloaded from www.tarceva.com 2/27/05

3. http://www.drugstore.com. Accessed on 3/6/05

Common Approaches to Targeting HER1/EGFR

Introduction

Anti-HER1/EGFR-blocking antibodies

Anti-ligand-blocking

antibodies

TKinhibitors

Ligand–toxin

conjugates

Antibody–toxin

conjugates

Mechanism