Transcript Document

Epidermal Growth Factor
Receptor (EGFR) Inhibitors
Dr.M.Jayanthi
Introduction
Cellular Signalling Pathways
 Vital for cell cycle progression, growth,
differentiation & death.
 Growth Factors – The key stone
 A delicate balance between activating and
inhibitory signals needs to be maintained normally
 Alteration in this balance - Dysregulated cellular
proliferation & survival of abnormal cells.
Growth Factors & Cell Cycle
Gene Transcription
+
Receptors
S
Priming
G0
G1
Cell Cycle
M
G2
Epidermal Growth Factor Receptor (EGFR)
Tumour
EGFR Expression
Rate
Breast
14 % - 91 %
Colon
25 % - 77 %
Lung Cancer
(Non small cell)
40 % - 80 %
Head & Neck
80 % - 95 %
Ovarian
35 % - 70 %
Pancreatic
30 % - 50 %
Some Landmarks in EGFR Signalling
Stanley Cohen
 EGF in mice (1960’s)
 Human EGF (1970’s)
 Isolation and cloning of EGFR (1980’s). Link
between EGFR and malignant transformation of
cells demonstrated
Mendelsohn et al.,
 Blocking EGFR signalling to treat cancer
 Murine monoclonal antibodies targeting
EGFR-TK→ Human:murine chimeric version
More than 20 anti-EGFR agents in
development
Human Epidermal Growth Factor Receptor Family
EGF, TGFa , b Cellulin
Amphiregulin, HB-EGF
TK
erbB1
HER1
EGFR
No specific
ligands often acts as
dimer partner
Heregulins
TK
erbB2
HER2
neu
NRG2
NRG3
Heregulins
β-cellulin
TK
erbB3
HER3
erbB4
HER4
EGFR Structure
Extracellular
Domain
Transmembrane
Domain
TK
Intracellular
Domain
EGFR Stimulation & dimerisation
TK
TK
TK
TK
EGFR Homo Dimerisation
erbB1
HER1
EGFR
erbB2
HER2
neu
erbB3
HER3
erbB4
HER4
EGFR stimulation cont…
TK
TK
TK
Hetero Dimerisation
erbB1
erbB2
HER1
HER2
Risk for cancerneu
EGFR
erbB3
HER3
erbB4
HER4
EGFR Function in Normal Cell
ATP
TK
TK
ATP
+
Gene Transcription
Cell Cycle Progression
Antiapoptosis
Cell Proliferation
Angiogenesis
EGFR signal transduction in tumour cells
TK
TK
PI3-K
pY
pY
GRB2
pY
RAS RAF
STAT3
PTEN
SOS
AKT
MEK
Gene transcription
G1
M
Proliferation/
maturation
Chemotherapy /
radiotherapy
resistance
MAPK
S
G2
Angiogenesis
Survival
(anti-apoptosis)
Metastasis
Other mechanisms of EGFR stimulation
MMP
Steroid
hormone
HB-EGF
+
α
P
γ β G protein
+
Ca++
Pyk2
P
+
Ras
Src
MAPK
Transcription
erbB Ligand
Gene
Steroid
hormone
receptor
How EGFR variant differs from the wild type
EGFR - Variant III
EGFR – Wild Type
No extracellular domain
Present
Ligand cannot bind
Can bind
TK constitutively active
TK activated by ligand binding
Cannot dimerise
Can dimerise
Not found in normal cells
Found normally
More propensity for cancer
Up regulation leads to cancer
ATP
TK
Gene transcription
Cell Cycle Progression
Cell Proliferation
Metastasis
Anti Apoptosis
Cancer
Mutation
Consequence of proliferation
of EGFR receptors
Normal Cell
Up Regulation
Cancerous Cell
EGFR – A good target for lung cancer ( non small cell )
 High level of receptor expression compared with
healthy tissue.
 EGFR - Key role in tumour cell growth & function.
 EGFR inhibition can inhibit downstream activity.
 EGFR inhibitors have no severe toxicity.
Rationale for EGFR Inhibitors in Head & Neck
cancer
 EGFR expressed in > 90% of head & neck cancers.
 EGFR over expression associated with decreased
survival.
 Increased EGFR expression is an early event in
carcinogenesis & even present in premalignant
lesions.
 Inhibition of EGFR – TK slows the growth of
xenograft tumour models of head & neck.
Anti-ligand
EGFR tyrosine
Anti-EGFR mAbs mAbs
kinase inhibitors
ATP
TK
-
TK
TK
-
-
Bispecific
Abs
TK
-
Immune effector cell
Strategies to inhibit EGFR signaling
Drugs Available
 Gefitinib
 Erlotinib
Highly selective, potent & reversible
EGFR Tyrosine Kinase Inhibitor
 Cetuximab – Monoclonal Anti EGFR antibody
 H 447
 MDX 210
Bispecific Anti EGFR antibody
linked to Anti CD 64
Indications
Gefitinib & Erlotinib:
Monotherapy in advanced stage of NSCLC
Cetuximab
Metastatic colorectal cancer with/without Irinotecan
Dose
Gefitinib 250 mg O.D. oral
Erlotinib 150 mg O.D. oral
Cetuximab 400 mg/ m2 i.v.→ 200 mg / m2 i.v. wkly
Side Effects
 Skin rash
 Diarrhoea ( EGFR – TKI s )
 Fever ( EGFR – mAb )
 Interstitial lung disease – 1% (only for Gefitinib)
Discontinuation rates due to adverse effects
are very low unlike chemotherapy.
Drug Interactions
 EGFR – TK Inhibitors metabolised by CYP3A4.
 Inhibitors / inducers of CYP3A4 can alter drug
levels.
 Warfarin interactions have occurred in clinical
trials of Gefitinib.
 Concomitant administration with warfarin
requires monitoring of PT, INR.
Advantages of EGFR Inhibitors
 Orally effective
 Better quality of life.
 Can be used as monotherapy.
 No need for premedication or dose monitoring.
 No hematological toxicity.
 Potential for long term treatment.
 Reduced resistance to radiation or hormone
therapy
Current Status
Gefitinib
 FDA Approved on May ,2003 for Lung cancer-NSC
(Accelerated Approval Programme)
Erlotinib
 FDA Approved on Nov, 2004 for Lung cancer –
Non Small Cell (AAP)
Cetuximab
 FDA Approved on Feb, 2004 for advanced
colorectal cancer
Clinical Trials
Gefitinib Phase II Trials
Parameter
Design
IDEAL I
IDEAL II
Randomized double blind Randomized double blind
parallel group, multicenter
Parallel Group, multicenter
Protocol
Monotherapy
Monotherapy
N of patients
209
216
Cancer
Advanced NSCLC; 1-2 prior Advanced NSCLC; >2 prior
Chemotherapy cycles
Chemotherapy cycles
Dose / regimen
250 or 500 mg/day
Adverse effects
GI, Rash
Activity
CR/PR 18% & 19%,CR/PR/SD
54 % & 51 OS 7.6 & 7.9
mnths at 250 & 500 mg/d
250 or 500 mg/day
GI, Rash
CR/PR 12% & 9%,CR/PR/SD
42 % & 36%; OS 6.5 & 5.9 mnths
at 250 & 500 mg/d
Gefitinib Phase III Trials
Parameter
Design
Protocol
N of patients
Cancer
Dose / regimen
Adverse effects
Activity
INTACT I
INTACT II
Randomized double blind Randomized double blind
placebo cont.,multicenter
Placebo cont., multicenter
Combination – gemcitabine
Combination- Carboplatin
& Paclitaxel
& cisplatin
1093
1037
Adv.NSCLC Chemotherapy
naïve stage III/IV
Adv. NSCLC; Chemotherapy
naïve stage III/IV
Std. chemo plus 250 or
500 mg/day
Diarrhoea, Rash
No difference in overall surv.,
Prog. Free surv., or time to
worsening symptoms
Std. chemo plus 250 or
500 mg/day
Diarrhoea, Rash
No difference in overall surv.,
Prog. Free surv., or time to
worsening symptoms
Erlotinib – Phase II Trials
Parameter
I
Design
Open label
Protocol
Monotherapy
II
Open label
Monotherapy
124
57
Cancer
Head & neck Ca refractory
to chemo-/radiotherapy
Advanced NSCL refractory
to platinum based therapy
Dose / regimen
150 mg/day
N of patients
Adverse effects
Diarrhoea, Rash
Activity
PR 6%; PR/SD 46 %
150 mg/day
Diarrhoea, Rash
CR/PR 12%, CR/PR/SD
51 %; OS 8.4 mnths
Outcomes with Targeted Therapy
 Progression-free survival
 Quality of life
 Response to treatment
 Safety
 Overall Survival
Unanswered Questions
 Patient selection
 How long patients should be treated
 Timing and sequencing of combination therapy
 Use in various stages of disease
 Appropriate markers for response
 Managing unique adverse events
→ ILD
→ Liver toxicity
 Best use in other solid tumours
Ongoing Trials…
 Different treatment schedules for use in
combination chemotherapy
 In other malignancies – Breast, Prostate, Head &
Neck, Colon as single / combination therapy
Strategies
 Combining EGFRI with Radiotherapy / Surgery or
other novel targeted agents like trastuzumab
 Identify subset of people who will benefit from TKI
Skin rashes, Mutation in TK, KRAS
Conclusion
Conclusion…
 EGFR inhibitors- a definite role in treatment of
cancer
 Combination chemotherapy – Further studies
needed
 Improves QOL with minimal adverse effects
 Can be administered at optimal biological
dose
 Potential for use in multiple tumors
Conclusion…
 Role in early stage of cancer needs to be
assertained
 Survival not significantly prolonged
 Costly
Reference
Review Articles
1.Soler R.P. HER1/ EGFR Targeting :Refining the strategy. Oncologist 2004
; 9 : 58 – 67.
2. Herbst R.S, Fukuoka M, Baselga J. Gefitinib – a novel targeted approach
to treating canver. Nature rev cancer 2004 ; 4 : 956 – 65.
3. Strausberg R.L, Simpson A.J.G, Old L.J, Riggins G.J. Oncogenomics and
the development of new cancer therapies. Nature 2004 ; 429 : 469 – 74.
4. Noble M.E.M, Endicott J.A, Johnson L.N. Protein kinase inhibitors :
Insights into drug design from structure. Science 2004 ; 303 : 1800 – 05.
5.Glover K.Y, Soler R.P, Papadimitradopoulou V.A. A review of small
molecule Epidermal Growth Factor Receptor specific tyrosine kinase
inhibitors in development for non small cell lung cancer. Sem. Oncol.
2004 ; 31 suppl : 83 – 92.
6. Janmaat M.L, Giaccone G. Small molecule Epidermal Growth Factor
Receptor tyrosine kinase inhibitors. Oncologist 2003 ; 8 : 576 – 86.
Review Articles – cont …
7. Yano S, Nishioka Y, Goto H, Sone S. Molecular mechanism of
angiogenesis in non small cell lung cancer and therapeutics trageting
related molecules. Cancer sci. 2003 ; 94 : 479 – 85.
8. Vlahovic G, Crawford J. Activation of tyrosine kinases in cancer.
Oncologist 2003 ; 8 : 531 – 8.
9. Spiro S.G, Porter J.C. Lung cancer – where are we today ? Current
advances in staging and non surgical treatment. Am J Respir Crit Care
Med 2002 ; 166 : 1166 – 96.
10. Arteaga C.L, Epidermal Growth Factor Receptor dependence in human
tumors : more than just expression ? Oncologist 2002 ; 7 suppl 4 : 31 – 9.
11. Raymond E, Faivre S, Armand J.P. Epidermal growth factor receptor
tyrosine kinaase as a target for anticancer therapy. Drugs 2000 ; 60 suppl
1 : 15 – 23.
Mini Review
1. Levin E.R. Bidirectional signalling between the estrogen receptor and
the epidermal growth factor receptor. Mol. Endocrinol. 2003 ; 17 : 309 –
17.
Original Articles
1.
Kelly K, Averbuch S. Gefitinib : Phase II and III results in advanced non
small cell lung cancer. Sem. Oncol. 2004 ; 31 suppl1 : 93 – 9.
2.
Pao W, Wang T, Riley G.J, Miller V.A, Pan Q, Varmus H.E et al . KRAS
mutations and primary resistance of lung adenocarcinoma to Gefitinib or
Erlotinib. PLOS Medicine 2005 ; 2 : e17.