Transcript Document

The Rationale for
EGFR Inhibition in
Advanced Lung Cancer
Alan Sandler, MD
Outline
• NSCLC - background
• EGFR inhibition
– Preclinical
– Previously treated patients
– Chemotherapy-naïve patients
• Questions and future directions
Non-small Cell Lung Cancer:
Metastatic Disease
• NSCLC accounts for ~135,000 cases of lung
cancer annually
• Approximately 30-40% of these patients will
have metastatic disease
• Untreated patients have a median survival of
~4 - 5 months
NSCLC Survival
State of the Art 2003
Surv: BSC:
Old:
New:
MST:
4 mo
6 mo
8 mo
1-Yr:
10%
20%
30%
2-Yr:
0%
<5%
10%
NSCLC Therapy
State of the Art
• Chemotherapy > BSC
• 2 drugs > 1 drug regimens
• 3 drugs  2 drug regimens
– more toxic & more expensive
• Second-line therapy “works”
• Quality of life is improved
– 1st & 2nd line CT improve Q of L
Targeted Therapy in Oncology
•
Goals
– Identify agents that target tumor-specific molecules,
thus sparing normal cells
• Increased specificity leads to decreased toxicity
– Identify ideal drug target
•
•
•
•
•
Drives tumor growth
Turns on key mechanisms of cancer progression
Reversible by inhibition with agent
Dispensable in normal cells
Target measurable in tumor tissue
Biological Agents for Solid Tumors
Signal Transduction/Cell-Cycle
Inhibitors
–
–
–
–
Farnesyl transferase
Flavopiridol
Retinoids
UCN-101
Gene Therapy
–
–
–
GM-CSF
Wild-type p53
Antisense
– c-myc
– PKC
Vaccines
–
–
–
–
Tumor cells
Peptides
Dendritic cells
Viral vaccines
Angiogenesis Inhibitors
–
–
–
–
–
–
–
–
SU5416/SU6668
Anti-VEGF antibodies
Interferon-a/b
Marimastat
ZD6474
LY317615
TNP-470
Endostatin/angiostatin
Receptor-Targeted Therapy
–
–
Trastuzumab
Anti-EGFR
– ZD1839
– C225
– OSI-774
Potential Treatment Options for NSCLC:
Integration With Current Therapies
Premalignancy
Localized
disease
Locally or
regionally
advanced
disease
Advanced/
metastatic
disease
S (RT)
CT + RT
CT
Biological agents
Preclinical Anti-Tumor Activity
of EGFR-TK Inhibitors1-8
• Growth inhibition/regression observed in
multiple tumor types in xenografts
• Enhanced growth inhibition/regression
observed with both chemotherapy and radiation
• Activity observed in hormone-resistant tumor
cell models
Sirotnak FM et al. Clin Cancer Res. 2000;6:4885-4892; Ciardiello F et al. Clin Cancer Res. 2000;6:2053-2063.
Ciardiello F et al. Clin Cancer Res. 2001;7:1459-1465; Williams KJ et al. Proc AACR. 2001;42:715. Abstract 3840.
McClelland RA et al. Endocrinology. 2001;142:2776-2788; Gee JM et al. Proc ASCO. 2001;20:71a. Abstract 282.
Fujimura M et al. Proc AACR. 2001;42:804. Abstract 4317; Chan KC et al. Br J Surg. 2001;88:412-418.
Targeting EGFR in NSCLC
Phase I Results - EGFR Blockade
Agent
Phase II Dose
Adverse Effects
Response
in NSCLC
IMC-C225
400 mg IV load
250 mg IV weekly
Rash
Hypersensitivity
No
CI-1033
Under study
Rash, diarrhea,
No
hypersensitivity,
thrombocytopenia,
emesis,stomatitis
Erlotinib
150 mg daily PO
Rash, Diarrhea
No
Rash, Diarrhea
Emesis
Rash
Rash
Hypersensitivity
Yes
No
No
ZD1839
250 mg daily PO
500 mg daily PO
ABX-EGF Under study
EMD7200 1600 mg IV weekly
EGFR Receptor Targeted Therapies
Currently in Clinical Development
Compound
Description
Phase
Herceptin
Genentech/Roche
ErbB-2 monoclonal
antibody
Approved
IMC-C225
Imclone
ErbB-1 monoclonal
antibody
Phase II/III
ZD1839
AstraZeneca
ErbB-1 tyrosine kinase
inhibitor
Phase III
OSI-774
OSI Pharmaceuticals
ErbB-1 tyrosine kinase
inhibitor
Phase lll
PKI-166
Novartis
ErbB-1 tyrosine kinase
inhibitor
Phase I
CI-1033
Pfizer
Pan-ErbB tyrosine kinase
inactivator
Phase I
EGFR Blockade
Previously Treated Patients
OSI-774
Trial Design
• NSCLC positive for EGFR
(>10% cells by IHC)
• Progression/relapse after
platinum-based therapy
• All patients with at least
one prior chemotherapy
regimen (most with more)
• No active brain metastasis
allowed
• 150 mg/day set dose
Clinical Data
• 1 CR (1.8%), 7 PR
(12.5%); 15 stable
disease (26.8%)
• ORR = 14.3%
• Median survival = 257
days
• 1-Year survival of 48%
Perez-Solar et. Al, ASCO 2001
Schema of IDEAL Trials
R
A
N
Eligible Patients:
• Recurrent NSCLC
• 1-2 prior CT
(& 1 platinum CT)
D
ZD 1839:
• 250 mg / day
O
M
I
ZD 1839:
• 500 mg / day
Z
E
Continue ZD1839 until PD or
intolerable toxicity.
Primary Endpoints:
• ORR
• Safety profile
Secondary Endpoints:
• Sx improvement rate
• Disease control rate
• PFS & OS
• Change in Q of L
ZD1839 in Recurrent NSCLC
IDEAL Phase II Trial Results
Factor:
Fukuoka et al:
Kris et al:
(ASCO 2002 abst #1188)
(ASCO 2002 abst #1166)
250 mg:
500 mg:
250 mg:
500 mg:
Pt No:
104
106
102
114
3rd Line:
44%
43%
100%
100%
ORR:
18.4%
19%
12%
9%
SxRR:
40%
37%
43%
35%
MST:
7.6 mo
8.0 mo
6.5 mo
5.9 mo
Phase II Trial of ZD1839 in NSCLC
Characteristics Associated with Response
Response
Rate (%)
9
14
Symptom
Improvement Rate (%)
40
36
2 Prior regimens
3 Prior regimens
4 Prior regimens
8
10
15
39
44
32
Women
Men
19
3
49
31
Adenocarcinoma
Other
13
4
43
30
PS 0-1
PS 2
ZD1839 in NSCLC
Observations from Monotherapy Trials
• RR in women > men
• RR in Adeno > SqCCa
– “Best” RR in BAC?
• RR unrelated to ECOG PS?
• RR not affected by number of
previous therapies
EGFR Blockade
Chemotherapy-Naïve Patients
Targeting EGFR in NSCLC
ZD1839: Phase I Combinations in
NSCLC Patients

Combinations of ZD1839 plus



carboplatin/paclitaxel – 6/24 Partial Responses
gemcitabine/cisplatin - 9/18 Partial Responses
No new or increased toxicities or significant
drug-drug interactions
Gonzalez-Larriba JL et al. Proc ASCO 2002, 21:95a (abs 376)
Miller VA et al. Proc ASCO 2001; 20 : 326a (abs 1301)
ZD1839 Randomized Trials With
Chemotherapy in Advanced NSCLC
Chemotherapy *
+ 250 mg ZD1839
x6 cycles
Randomize
Chemotherapy *
+ 500 mg ZD1839
x6 cycles
Chemotherapy *
+ Placebo
x6 cycles
Continue
ZD1839 or
placebo
until disease
progression
Stage III/IV NSCLC N=1029/Trial
*Gemcitabine/cisplatin (trial 14)
*Paclitaxel/carboplatin (trial 17)
Primary endpoint: Survival
Randomized ZD 1839 Trials
Chemotx
Intact-1
CG
Intact-2
PC
Patients
1093
1037
*M/F
74/26
60/40
Age
61 (32-86)
63 (27-87)
*PS 0/1/2
33/57/10
36/53/11
*IIIA/IIIB/IV
3/27/70
4/17/79
*per cent
Intact-2: Response Rates
50
CR
45
PR
Response Rates (%)
40
35
32.7
31.5
32.5
30
25
20
15
10
5
0.6
2.3
1
250 mg/day
(n=306)
Placebo
(n=289)
0
500 mg/day
(n=308)
Population = evaluable for response
Proportion event free
TTP - INTACT 2
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
500 mg:
250 mg:
Placebo:
PFS:
4.67 mo
5.32 mo
5.06 mo
Log rank:
-1.6338
-1.5833
(p=0.1023)
(p=0.1133)
Group 500 mg/day
Group 250 mg/day
Placebo
0
2
4
6
8
10
Survival time (months)
Months:
0
2
4
6
At risk:
1037
641
442
250
Population: intention-to-treat
Tick marks indicate censored observations
8
91
10
27
12
12
11
14
16
Proportion event free
Survival - INTACT 2
Months:
At risk:
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
500 mg:
250 mg:
Placebo:
MST:
8.74 mo
9.82 mo
9.92 mo
1-Year:
0.37
0.41
0.42
Log rank:
0.4641
-0.4254
(p=0.6425)
(p=0.6705)
Group 500 mg/day
Group 250 mg/day
Placebo
0
4
0
1037
4
814
8
12
16
Survival time (months)
20
8
588
20
18
Population: intention-to-treat
Tick marks indicate censored observations
12
415
16
141
24
Survival - INTACT 2
Landmark Analyses
Chemotherapy:
No:
Median Survival (mo):
500 mg: 250 mg: Placebo:
• 90 days:
599
14.1
14.9
13.0
• 90 d + Adeno:
334
16.1
17.1
13.6
• 90 d + Stage IV:
458
12.0
15.1
12.6
• 90 d + Adeno + IV:
260
13.7
19.7
12.5
• 120 days:
510
15.0
15.5
13.6
• 120 d + Adeno:
287
18.3
17.3
14.3
Survival - INTACT 2
CT 90 days + Adeno
S0318: Phase III Trial of
Paclitaxel/Carboplatin  Early vs Late
ZD1839 in Advanced NSCLC
Paclitaxel/Carboplatin X 4
(PS 0-1, IIIB-pl eff, IV)
R
A
N
D
O
M
I
Z
E
 ZD1839
CR
PR
SD
PD
 Placebo  ZD1839
Primary Endpoint: PFS
Paclitaxel: 225 mg/m2 & Carboplatin: AUC = 6, ZD1839: 250mg/d
Correlative Studies: Tumor: p27, EGFR pathway
PI: R Herbst
*S0023: ZD1839 following
Chemoradiotherapy
(N=840)
Chemoradiation
(PE/RT -> Docetaxel)
as in S9504
R
A
N
D
O
M
I
Z
E
 ZD1839
 Placebo
Correlative Studies: Tumor tissue: p27, EGFR, K-RAS,
B-tubulin
Plasma: K-RAS
*SWOG, NCI-C, NCCTG
Chemotherapy +/- OSI 774
NSCLC
no previous
chemotherapy
(N=1050)
OSI 774 150 mg/d* PO
+ Chemotherapy
vs
*study drug continued
at disease progression
Placebo 150 mg/d* PO
+ Chemotherapy
Chemotherapy = paclitaxel/carboplatin or gemcitabine/cisplatin
80% power to detect a 25% survival benefit, =0.05
Similar power to detect a 33% 1-year survival benefit
Ongoing Trials: C-225
Docetaxel + C225
Second-line
Carboplatin/Paclitaxel + C225
First-line
Gem/Carboplatin + C225
First-line
ABX-EGF: PHASE I STUDY
ABX-EGF Human Monoclonal Antibody to EGFR
Biological activity at 1mg/kg/wk.
DLT ‘Cutaneous Toxicity’
Studies Planned:
PC +/- ABX-EGF: Random. Phase II
Docetaxel +/- ABX-EGF
Figlin et al, Proc Am Soc Clin Oncol, 20:276a(#1102), 2001
Future Directions and
Questions:
EGFR Inhibitors in NSCLC
• Standardize definitions of EGFR + and
their role
• Validate Abs for p-EGFR (and
downstream components)
• Characterize molecular profile of
responding patient and validate
prospectively
Future Directions and
Questions:
EGFR Inhibitors in NSCLC
• Optimize schedule of EGFR-inhibitors
and chemotherapy
– Sequential?
• Studies with XRT, locoregional disease
• Develop rational molecularly targeted
doublets
Targeted Therapy Combinations
• Overexpression of EGFR results in
increased VEGF expression
• Blockade of EGFR results in decreased
VEGF production
• Co-blockade of EGFR and VEGF
results in increased cure rates in murine
models
Ant-VEGF plus OSI-774
• Phase I/II study of anti-VEGF and OSI774 in previously treated NSCLC
– MDACC and Vanderbilt
– Establish MTD with correlative studies
• EGFR and HER-2 (IHC and FISH)
• Angiogenesis - endothelial cell apoptosis
and microvessel density
Mininberg, et al Submitted ASCO, 2003