Tarceva (erlotinib) is an oral targeted therapy approved for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after chemotherapy. It works by inhibiting the HER1/EGFR tyrosine kinase receptor, blocking cancer cell proliferation. Clinical trials showed Tarceva improved progression-free and overall survival compared to placebo in NSCLC patients, with common side effects including rash and diarrhea.

1. Tarceva®
( erlotinib )
By
Sirinoot Jantharangkul

2. Tarceva
• Generic name: Erlotinib
• Brand name: Tarceva®
• FDA Approval Date: November 18,
2004

3. 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

4. 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

5. 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

6. Main types of NSCLC
• There are three main
types of NSCLC:
– Adenocarcinoma
(including
bronchioloalveolar
carcinoma)
– Squamous cell
carcinoma
– Large cell
undifferentiated
carcinoma
Introduction

7. Stage of Non-Small Cell Lung
Cancer (NSCLC)
Introduction

8. Stage of Non-Small Cell Lung
Cancer (NSCLC)
Introduction

9. 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

10. Cancer cell proliferationCancer cell proliferation
Introduction

11. HER family of receptorsHER family of receptors
Introduction

12. The role of EGFR
The role of
EGFR
The role of
EGFR
Introduction

13. HER1/EGFR
dysregulation
HER1/EGFR
dysregulation

14. Tarceva: mechanism of
inhibition
Tarceva: mechanism of
inhibition
Introduction

16. Tarceva
O
O
H3C
H3C
O
O
NH
N
N
Tarceva (erlotinib)
• Small-molecule inhibitor
of HER1/EGFR
• Molecular wight 429.90
• Orally available

17. 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

18. 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%

19. 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]

20. 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)

21. 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

22. Clinical studies :Tarceva: BR.21
Tarceva: BR.21
Target
enrolment
700 patients; stage IIIB or IV NSCLC
Prior therapy 1 or 2 chemotherapy regimens
Design Randomised 2:1
Tarceva 150mg/day plus BSC vs Placebo
plus BSC
Primary
endpoint
Overall survival
Secondary
endpoints
Progression-free survival
Symptom deterioration
Response rate
Tolerability
Tissue HER1/EGFR vs outcome/safety

23. BR.21 Progression Free Survival
Percentage
0
20
40
60
80
100
0.0
488
243
5.0
153
34
10.0
52
6
15.0
8
1
Months
___ Erlotinib: 2.2 m
___ Placebo: 1.8 m
*HR 0.61, p
<0.0001

24. BR.21 Overall Survival
Percentage
0
20
40
60
80
100
0.0
488
243
10.0
188
59
20.0
12
4
___ Erlotinib: 6.7 m
___ Placebo: 4.7 m
*HR 0.71, p
<0.0001
Months

25. BR.21 Survival by Smoking
History
Percentage
0
20
40
60
80
100
0.0
358
187
10.0
116
46
20.0
7
3
_____ Erlotinib Never Smoked
_____ Erlotinib Current/past Smoker
_____ Placebo Never Smoked
_____ Placebo Current/past smoker
Months

26. Selected BR.21 Adverse Events
76
17
55
19
40
34
19
3
0
10
20
30
40
50
60
70
80
AllGrades,%
Rash Diarrhea Nausea Stomatitis
erlotinib
placebo

27. Prolonged Time to Deterioration of QoL
Symptoms
Percentage
0
20
40
60
80
100
Time (months)
# At Risk(OSI-774)
# At Risk(Placebo)
0.0
298
153
5.0
59
20
10.0
20
6
15.0
6
0
20.0
0
0
Percentage
0
20
40
60
80
100
Time(months)
#AtRisk(OSI-774)
0.0
348
179
5.0
65
16
10.0
26
5
15.0
3
0
SUMMARYSTATISTICS:
Log-Ranktestforequalityofgroups: p=0.0098
OSI-774 PlaceboPercentage
0
20
40
60
80
100
Time(months)
#AtRisk(OSI-774)
#AtRisk(Placebo)
0.0
353
179
5.0
78
20
10.0
28
5
15.0
5
0
___ Erlotinib
___ Placebo
Cough : p=0.04
Dyspnea : p=0.01
Pain : p=0.02

28. 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

29. 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.

30. 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.

31. 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

32. Common Approaches to Targeting
HER1/EGFR
Introduction
Anti-HER1/EGFR-
blocking antibodies
Anti-ligand-
blocking
antibodies
TK
inhibitors
Ligand–
toxin
conjugates
Antibody–
toxin
conjugates

34. Mechanism