Title: Targeted Therapy in Cancer
1Targeted Therapy in Cancer
- Iressa an EGFR Tyrosine Kinase Inhibitor
- Hematology Grand Rounds
- September 13, 2002
- Maggi Coplin,M.D.
2Case Study
- 11/01 66 yr old male w/10 pk yr hz (quit 1969)
- nonremitting pneumonia
- - CXR 5 cm LLL mass.
- - Bronch washings positive for
adenocarcinoma - - CT was suspicious for hilar and
subcarinal disease - - PET scan (-).
- - LLL lobectomy done without preop
mediastinoscopy - - Hilar, subcarinal nodes ()
- - Diaphragm involved and pleural studding,
mult nodules. - - Dx with T4N2MO Stage IIIb NSCLC
- - Told he was incurable and to see a
med/rad oncologist - 12/01 saw outside medical and radiation
oncologist. - - Told he wasnt a candidate secondary to
extensive involvement - 1/02 - saw outside medical oncologist again
- - Decision was made to observe and
re-scan in 4 wks
3Case Study
- 2/02 Sought second opinion at BJC weight 189
at first visit - - Developed pleural effusion/CT/pleurodesi
s/ - - Scans now () for adrenal met (1.3cm)
and mets to T spine - 3/02 Phase II irinotecan/carboplatin
- - 2 cycles then PS 3 (fatigue, malaise,
bed 90 of time, 11lb loss) - 4/02 Restaging CT showed adrenal lesion now
1.6cm, paraesophageal - LNs, more bone mets
- 5/02 Iressa for compassionate use protocol
- 6/02 Feel great, has a bounce in his step, 6 lb
weight gain, requesting - Viagra
- 7/02 Getting back to my old self, wt now 197
- 7/02 Restaging CT decrease in adrenal mass to
1.2cm (2 months of Iressa) - 8/02 Just got back from Cancun
4The erB Family
- 4 tyrosine kinase receptors
- act as signal transductors for cell proliferation
and differentiation via the MAPK path - erB-1 aka EGFR and HER1
- erB-2 aka HER2 (no ligands potent signal)
- erB-3 aka HER3 (no TK uses PI3K/AKT)
- erb-4 aka HER4
5The ErbB Family and Ligands
EGF TGF-? Amphiregulin ?-cellulin HB-EGF Epireguli
n
HB-EGF Heregulins ?-cellulin
No KnownLigands
Heregulins
Extracellular
Tyrosine Kinase Domain
Intracellular
ErbB-1HER1 EGFR
ErbB-2 HER2 neu
ErbB-3 HER3
ErbB-4 HER4
6Activated EGFR-TKA Pivotal Driver of Malignancy
1-6
R
R
RAS
RAF
SOS
K
K
PI3-K
pY
pY
MEK
GRB2
pY
STAT
MAPK
PTEN
Akt
Gene transcription Cell cycle progression
P
P
Cyclin D1
myc
cyclin D1
Proliferation/ Maturation
DNA
Jun
Fos
Myc
Chemotherapy/ Radiotherapy resistance
Survival (Anti-apoptosis)
Angiogenesis
Metastasis
Adapted with permission from Baselga J. Signal.
2000112-21. 1. Raymond E et al. Drugs.
200060(suppl 1)15-23. 2. Woodburn JR. Pharmacol
Ther. 199982241-250. 3. Wells A. Int J Biochem
Cell Biol. 199931637-643. 4. Hanahan D,
Weinberg RA. Cell. 200010057-70. 5. Balaban N
et al. Biochim Biophys Acta. 19961314147-156.
6. Akimoto T et al. Clin Cancer Res.
199952884-2890.
7EGFR Expression in Selected Human Tumors
8Prognostic Significance of EGFR Expression in
Selected Cancers
Risk of Metastases
Tumor Type
Prognosis
Survival
Reference
Volm (1998)Veale (1993)Ohsaki (2000) Nicholson
(2001)Perez (2001) Nicholson (2001)Mayer
(1993)Hemming (1992) Grandis (1998)Maurizi
(1996)
OS OS OS DFSOS
NSCLC Breast Colorectal Head and neck
Poor Poor Poor Poor
DFS disease-free survival OS overall
survival.
9Multiple Activation Mechanisms for EGFR-TK1-4
- 1. Overexpression of EGFR protein
- 2. Increased ligand expression/autocrine loop
- 3. Heterodimerization
- Lateral signal propagation, cross talk (G-protein
- coupled receptors, cytokine receptors,
cell stress) - 5. Mutant EGFR constitutive activation
- 6. Decreased phosphatase
- 7. Altered downstream signal function
1. Raymond E et al. Drugs. 200060(suppl
1)15-23. 2. Velu TJ. Mol Cell Endocrinol.
199070205-216. 3. Wells A. Int J Biochem Cell
Biol. 199931637-643. 4. Moghal N et al. Curr
Opin Cell Biol. 199911190-196.
10Turning Off the EGFR-TK Signal Outside1-3
- Monoclonal antibodiescan block the
EGFR-TKsignal from the outside
- The EGFR-TK signal can be turned on by many other
triggers inside the cell
1. Huang S-M, Harari PM. Invest New Drugs.
199917259-269. 2. Baselga J. J Clin Oncol.
200018(suppl)54s-59s.3. Wells A. Int J Biochem
Cell Biol. 199931637-643.
11Turning Off the EGFR-TK SignalAt the Source1-3
- Inhibition of the EGFR-TK itselfinside the
cellcompletely inhibits EGFR-TK signaling
regardless of the triggering event
1. Leserer M et al. IUBMB Life. 200049405-409.
2. Raymond E et al. Drugs. 200060(suppl
1)15-23. 3. Prenzel N et al. Endocr Relat
Cancer. 2001811-31.
12Preclinical Anti-Tumor Activity of EGFR-TK
Inhibitors1-8
- Dose dependent activity seen in xenografts (lung,
breast, CR, prostate, gastric, ovarian) even if
low EGFR expression (cytostatic) - Growth inhibition/regression observedwith
chemotherapy or radiation (even after drug) - Activity observed in hormone-resistant tumorcell
models
1. Sirotnak FM et al. Clin Cancer Res.
200064885-4892. 2. Ciardiello F et al. Clin
Cancer Res. 200062053-2063. 3. Ciardiello F et
al. Clin Cancer Res. 200171459-1465. 4.
Williams KJ et al. Proc AACR. 200142715.
Abstract 3840.5. McClelland RA et al.
Endocrinology. 20011422776-2788. 6. Gee JM et
al. Proc ASCO. 20012071a. Abstract 282. 7.
Fujimura M et al. Proc AACR. 200142804.
Abstract 4317. 8. Chan KC et al. Br J Surg.
200188412-418.
13IRESSA Inhibits Growth of A549Xenograft Tumors
(NSCLC)
0.8
Vehicle IRESSA 200 mg/kg,days 10-30 IRESSA 200
mg/kg,days 10-72
0.7
0.6
MeanTumor Volume(cm3)
0.5
0.4
0.3
0.2
0.1
0
10
30
50
70
Day
Data on file, AstraZeneca Pharmaceuticals LP.
14Inhibition of Xenograft Tumor GrowthIRESSA With
Paclitaxel
PC-3 Prostate
LX-1 Lung
1200
1200
1000
1000
800
800
TumorMass (mg)
600
600
400
400
200
200
TumorMass (mg)
0
0
0
4
8
12
16
20
24
28
32
36
0
4
8
12
16
20
24
28
32
36
Time (days)
Time (days)
Control
Paclitaxel
IRESSA
IRESSA paclitaxel
Adapted with permission from Sirotnak FM et al.
Clin Cancer Res. 200064885-4892.
15IRESSA Phase I Trials Patient Demographics
Patient characteristic
Total (N)
Enrolled Nonsmall-cell lung cancer
(NSCLC) Median age (range) years Performance
Status 0/1/2 ()
252 100 59 (28-91) 31/67/2
NSCLC, hormone-refractory prostate, head and
neck, colorectal, ovarian,and other cancers.
Data on file, AstraZeneca Pharmaceuticals, LP.
16IRESSA Phase I Monotherapy TrialsSafety Data1- 4
- Grade 1-2 adverse events common in first 2 months
- Most common events
- grade 1-2 diarrhea (dose limiting at 700mg)
- acneiform rash1,2 (grade 3 in 1 patient at
400mg) - Grade 3-4 adverse events were rare, even at high
doses2,4 - Noncumulative toxicity
- No cardiac, hematologic, or renal toxicity
1. Baselga J et al. Proc ASCO. 200019177a.
Abstract 686. 2. Ferry D et al. Proc ASCO. 2000.
Abstract 5E. 3. Goss GD et al. Proc ASCO. 2001.
Ab 335. 4. Negoro S et al. Proc ASCO.
200120(part 1)324a. Abstract 1292.
17IRESSA Phase INSCLC Anti-Tumor Activity1-3
- Overall response rate in NSCLC ?10
- Patients on therapy for ?6 months ?18
- Stable disease for ?3 months in 33 of patients
- 8 patients on study drug for 11 to 26 months
1. Data on file, AstraZeneca Pharmaceuticals LP.
2. Negoro S et al. Proc ASCO. 200120324a.
Abstract 1292.3. Kris M et al. Clin Cancer Res.
19995(suppl)3749s. Abstract 99.
18IRESSA Acneiform Rash
Skin rash in patient with NSCLC receiving IRESSA
400 mg/day
- Rash on an erythematous base
- Rarely results in discontinuation of therapy
Adapted with permission from Baselga J et al.
Clin Cancer Res. 19995(suppl)3735s. Abstract
29.
19IRESSA Pharmacodynamics
25
Plt.001
30
Plt.001
20
KI67Positive
ActivatedMAPKPositive
20
15
10
10
5
0
0
Pre
On
Pre
On
Pre-IRESSA
On IRESSA 28d
50
30
Plt.001
Plt.001
25
40
Phospho-STAT3Positive
20
p27KIP1Positive
30
15
20
10
10
5
0
0
Pre
On
Pre
On
- Skin biomarkers in 104 pretherapy and on-therapy
skin biopsies in 65 pts - Profound effects at doses well below MTD
Activated MAPK expression reducedduring IRESSA
treatment (reduced proliferation of stratum
corneum)
Adapted with permission from Albanell J et al. J
Clin Oncol. 200220110-124.
20Pharmacokinetic studies
- 250mg dose is 50 bioavailable
- Peak concentrations within 3-7 hours
- Half life of 27-41 hours
- Steady state achieved in 7-10 days
- IC90 achievable at doses gt100mg/d
- Metabolized in the liver via the cytochrome P450
3A4 isoenzyme, excreted in feces
21IRESSA Phase IObserved Anti-Tumor Response
3 Months on IRESSA
2 Months on IRESSA
Pretreatment
CT Scans of NSCLC patient IRESSA 525 mg/day
Adapted with permission from Kris M et al. Clin
Cancer Res. 19995(suppl)3749s. Abstract 99.
22IRESSA Phase I TrialsConclusions
- Anti-tumor activity across different types of
advanced solid tumors, most notably NSCLC - Durable PR and disease control observed across a
range of doses (150 mg/day to 700 mg/day) - Symptom improvement correlated with responses
- 30 had SD for gt3months 4pts with SD gt1yr
- DLT at 800 mg/day, 250 mg/day and 500 mg/day
doses selected for phase II/III trials
23Phase II trials with IRESSA in NSCLCIDEAL Trials
- IDEAL-1 (Trial 16)phase II, global multicenter
trial (210 patients) - IDEAL-2 (Trial 39)phase II, US multicenter
trial (221 patients)
IDEAL IRESSA Dose Evaluation in Advanced Lung
Cancer.
24IDEAL-1 and IDEAL-2 Study Objectives
- Primary
- Objective tumor response rate
- Symptom improvement rate (IDEAL-2)
- Safety profile (IDEAL-1)
- Secondary
- Disease control rates progression-free survival
- Time to symptom worsening and quality of life
(Functional Assessment of Cancer TherapyLung
Cancer Scale) - Safety, population pharmacokinetics (IDEAL-2)
25IRESSA Monotherapy TrialsPhase II Design Schema
IDEAL-1 (Trial 16) Patients (N210) 1-2
previous platinumchemotherapy regimens
Primary end points
250 mg IRESSA once daily
- Objectivetumorresponse
- Safety profile(IDEAL-1 only)
- Symptom improvement (IDEAL-2 only)
Randomize
IDEAL-2 (Trial 39) Patients (N216) ³2
previous chemotherapy regimens including
platinum and docetaxel, symptoms
500 mg IRESSA once daily
Continue IRESSA until diseaseprogression or
intolerable toxicity
26Phase II - IDEAL-1 Patient Demographics
Total
Patient Characteristic
Patients, N Male/Female, Age, mean (range),
yr Performance Status 0/1/2,
210 70/30 59.6 (28-85) 18/69/13
Baselga J et al. Presented at AARC-NCI-EORTC
October 29-November 2, 2001 Miami Beach, Fla.
27IDEAL-1 Response Rates by Dose
60
54.4
IRESSA 250 mg/day
51.4
IRESSA 500 mg/day
50
40
Patients,
30
19.0
18.4
20
10
0
CRPR
CRPRSD
n208. Close agreement with independent response
evaluation committee. Adapted with permission
from Baselga J et al. Presented at
AACR-NCI-EORTC. October 29-November 2, 2001
Miami Beach, Fla.
28IDEAL-1 Efficacy
- Objective response rate (CR PR) 18.7 (95
CI 13.724.7) - Overall disease control rate (CR PR SD)
52.9 (95 CI 45.959.8) - Median progression-free survival 12 weeks
- Progression-free survival at 4 months 34
- No difference between 250 mg/day and 500 mg/day
doses for any of these efficacy end points
Baselga et al. Presented at AARC-NCI-EORTC.
October 29-November 2, 2001 Miami Beach, Fla.
29IDEAL I - overall survival
Dose250 mg/day 500 mg/day
Patients(n)103 106
Deaths(n)62 64
Median (mos)7.6 7.9
Proportion event free
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
Overall survival (mos)
30IDEAL IDrug-related toxicities by dose
ZD1839 250 mg/day
ZD1839 500 mg/day
Grade 1273326251011109
Grade 3/41 0 00 012 0
Grade 1313634235171415
Grade 3/47 7 1 021 6 3
Grade 2208533112
Grade 23518388756
Rash Diarrhea PruritusDry skin Acne Nausea
ALT increasedAST increased
Values are patients
31IDEAL IDrug-related withdrawals, dose
reductions, interruptions
ZD1839 dose
250 mg/day (n103)
500 mg/day (n106)
Withdrawals Dose reductions Dose interruptions
2 (2) 0 (0) 16 (16)
10 (9) 11 (10) 30 (28)
32IDEAL-1 Conclusions
- Both doses of IRESSA were equally efficacious
when given as once-daily chronic treatment - RR 18.7 overall
- symptom improvement 39 overall
- OS 7.8 months overall
- Single-agent activity confirmed in large,
international,phase II trial - Symptomatic relief correlated with stable and
responsive disease IRESSA showed anti-tumor
activity and provided symptom relief as second-
and third-line treatment
Baselga J et al. Presented at AACR-NCI-EORTC.
October 29-November 2, 2001 Miami Beach, Fla.
33IDEAL IIStudy Aims
- To determine the radiographic response rate and
symptom improvement rate for ZD1839 when used in
patients with NSCLC after both docetaxel
cisplatin/carboplatin - To compare efficacy and toxicities between 250 mg
and 500 mg daily oral doses - To correlate response and symptom improvement
34IDEAL II Eligibility
- Locally advanced or metastatic NSCLC
- At least 2 prior chemotherapy regimens including
docetaxel and cisplatin or carboplatin - Disease progression or unacceptable toxicity
within 90 days of last chemotherapy - Symptomatic NSCLC (LCS score lt24)
- Performance Status 0, 1 or 2
35IDEAL IIMeasuring Symptoms by LCS
What is the LCS? What lung cancer symptoms
are measured? Definition of symptom improvement
7-item subscale of FACT-L. A validated,
reliable and feasible questionnaire to measure
symptoms of lung cancer. Zero the worst score
28 the best Shortness of breath, weight loss,
clarity of thought, cough, appetite, tightness in
the chest, ease of breathing A two or more point
increase in LCS score sustained for at least 4
weeks
- FACT-L Functional Assessment of Cancer Therapy
Lung - (measures functional, physical, emotional, social
and symtoms)
36IDEAL IIPatients
Women () Performance Status 0-1 ()Performance
Status 2 () Stage IIIB ()Stage IV () Median
Age (range)
37Patients (contd)
ZD1839 250 mg
ZD1839 500 mg
Adenocarcinoma ()Squamous Cell ()Large Cell
and other () Prior Chemotherapy Regimens
() 2 3 4 Median Symptom Score (LCS)
(Range)
691417 403028 17(8-24)
641620 423622 16(2-27)
38IDEAL IIResponse Symptom Improvement
Response Rate (PR)
Symptom Improvement Rate
Patients ()
43
9
12
35
ZD1839250 mg
ZD1839500 mg
ZD1839250 mg
ZD1839500 mg
39IDEAL IITime to Symptom Improvement
Percent
40
30
Median 2 weeks
20
10
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Time to Improvement (Weeks)
40IDEAL IIAssociation Between Radiographic and
Symptomatic Response
with Symptom Improvement by LCS
plt0.0001
96
71
17
Test for ordered association (Terpstra-Jonckheere
)
41IDEAL IISurvival by dose
42IDEAL IISurvival by Response
1.0
0.8
Logrank plt0.0001
0.6
Proportion Alive
0.4
One year survival - 86 Partial - 44 Stable - 8
Progression
0.2
0.0
0
2
4
6
8
10
12
14
16
18
Months from Randomization
43IDEAL IISurvival by Symptom Improvement
1.0
0.8
Proportion Alive
0.6
0.4
Logrank plt0.0001
One year survival - 53 Improvement - 9 No
Improvement
0.2
0.0
0
2
4
6
8
10
12
14
16
18
Months from Randomization
44IDEAL IICharacteristics Associated with Response
PS 0-1PS 2 2 prior regimens3 prior
regimensgt4 prior regimens WomenMen Adenocarcinom
aOther
ResponseRate () 914 81015 193 134
Symptom ImprovementRate () 4036 394432 4931
4330
45IDEAL II Drug-related Withdrawals, Dose
Reductions and Interruptions, Deaths
Withdrawals Dose Reductions Dose
Interruptions Possible Drug-Related Death
One patient died on day 11 from lung hemorrhage
from a cavitating lung tumor. Considered possibly
drug-related but also reported as cancer-related
46IDEAL IIDrug-Related Toxicities by Dose
Rash/acne/pruritis/dry skin Any Grade
1 Grade 2 Grade 3/4 Diarrhea Any Grade
1 Grade 2 Grade 3/4 Nausea 1/2/3/4 Vomiting
1/2/3/4
ZD1839 250 mg( patients) 65 48 13 0 57 48 9 1
13 12
ZD1839 500 mg( patients) 81 48 22 5 75 59 20 6
18 9
p0.04
p0.006
47IDEAL IIConclusions
- Blocking the EGFR TK leads to regressions and
symptom benefits in patients with NSCLC - In these NSCLC patients who had received 2 or
more prior chemotherapy regimens - Partial responses in 11.8 overall
- PFS was 8 weeks
- Median OS was 6.5 months
- Symptom improvement in 39 pt - assoc with
- response and increased survival
- Lung cancer symptom benefit in 10 days
- Comparable efficacy less toxicity with 250 mg
48Phase III Combination Study Rationale
- Preclinical models suggest evidence of IRESSA
activity with chemotherapy1,2 - 2 pilot studies done
- Carbo/Taxol in untrt NSCLC pts
- 25pts with RR 68 (PRSD)
- Gem/cis in untrt adv or met pts
- 8pts with NSCLC had RR 100 (50PR)
- 17pts total with RR 94
- Ciardello F et al. Clin Cancer Res.
200062053-2063. 2. Sirotnak FM et al. Clin
Cancer Res. 200064885-4892. - 3. Miller VA et al. Proc ASCO. 200120326a.
Abstract 1301. 4 Giaccone et al. AACR-NCI-EORTC.
Abstract 553, 2001.
49Phase III Combination INTACT-1 and INTACT-2
Overview
- Randomized, double-blind, placebo-controlled
trials - Chemotherapy-naive patients with advanced (stage
III or IV) nonsmall-cell lung cancer - Comparative trials of 2 doses of IRESSA in
combination with chemotherapy vs placebo in
combination with chemotherapy - Gemcitabine/cisplatin INTACT-1
- Paclitaxel/carboplatin INTACT-2
50INTACT TrialsEndpoints
- Primary
- Increase in overall survival
- Secondary
- Improvement in time to worsening of
disease-related symptoms on Lung Cancer Scale - Improvement in progression-free survival
- Tertiary
- Improvements in
- ORR, disease control rate, symptom improvement
rate - Quality of life as good or better than control
51IRESSA Phase III Combination Trials in
First-Line Treatment of NSCLC INTACT-1 and
INTACT-2
- Stratification
- Weight loss in previous 6 months (?5 vs gt5)
- Stage (III vs IV)
- PS 0 - 1 vs 2
- Measurable disease (yes vs no)
- Statistics
- 90 power, 2-sided, 5 significance level
Chemotherapy x 6 cycles
250 mg IRESSA
Continue IRESSA or placebo until disease
progression
Chemotherapy x 6 cycles
Randomize
500 mg IRESSA
Chemotherapy x 6 cycles
Placebo
Stage III/IV NSCLC. Gem 1250mg d18/cis80mg d1
INTACT-1 (N1093) or Taxol 225mg d1/carbo AUC 6
INTACT-2 (N1037) INTACT IRESSA NSCLC
Trial Assessing Combination Therapy
52Conclusions
- Iressa is NOT Gleevec
- It is NOT a magic bullet
- It will NOT increase OS on its own
- BUT.
- We dont cure DM, HTN, etc..why cant we be happy
with STABLE DISEASE? - Take home message
- STABLE DISEASE IS GOOD