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The Rationale for EGFR Inhibition in Advanced Lung Cancer Alan Sandler, MD.
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Transcript of The Rationale for EGFR Inhibition in Advanced Lung Cancer Alan Sandler, MD.
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
10%<5%0%2-Yr:
30%20%10%1-Yr:
8 mo6 mo4 moMST:
New:Old:BSC:Surv:
NSCLC SurvivalState of the Art 2003
NSCLC TherapyState 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 TumorsSignal 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
Pre-malignancy
Localizeddisease
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. Sirotnak FM et al. Clin Cancer ResClin Cancer Res. 2000;6:4885-4892; Ciardiello F et al. . 2000;6:4885-4892; Ciardiello F et al. Clin Cancer ResClin Cancer Res. 2000;6:2053-2063. . 2000;6:2053-2063. Ciardiello F et al. Ciardiello F et al. Clin Cancer ResClin Cancer Res. 2001;7:1459-1465; Williams KJ et al. . 2001;7:1459-1465; Williams KJ et al. Proc AACRProc AACR. 2001;42:715. Abstract 3840.. 2001;42:715. Abstract 3840.McClelland RA et al. McClelland RA et al. EndocrinologyEndocrinology. 2001;142:2776-2788; Gee JM et al. . 2001;142:2776-2788; Gee JM et al. ProcProc ASCOASCO. 2001;20:71a. Abstract 282. . 2001;20:71a. Abstract 282. Fujimura M et al. Fujimura M et al. Proc AACRProc AACR. 2001;42:804. Abstract 4317; Chan KC et al. . 2001;42:804. Abstract 4317; Chan KC et al. Br J SurgBr J Surg. 2001;88:412-418.. 2001;88:412-418.
Targeting EGFR in NSCLCPhase I Results - EGFR Blockade
Yes
No
No
Rash, Diarrhea
Emesis
Rash
Rash
Hypersensitivity
250 mg daily PO
500 mg daily PO
Under study
1600 mg IV weekly
ZD1839
ABX-EGF
EMD7200
NoRash, Diarrhea150 mg daily POErlotinib
NoRash, diarrhea, hypersensitivity, thrombocytopenia, emesis,stomatitis
Under studyCI-1033
NoRash
Hypersensitivity
400 mg IV load
250 mg IV weekly
IMC-C225
Response in NSCLC
Adverse EffectsPhase II DoseAgent
EGFR Receptor Targeted Therapies Currently in Clinical DevelopmentCompound 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
• 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
• 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%
Trial Design Clinical Data
Perez-Solar et. Al, ASCO 2001
Schema of IDEAL Trials
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
Eligible Patients:• Recurrent NSCLC• 1-2 prior CT
(& 1 platinum CT)
R
A
N
D
O
M
I
Z
E
ZD 1839:• 250 mg / day
ZD 1839:• 500 mg / day
ZD1839 in Recurrent NSCLCIDEAL Phase II Trial Results
5.9 mo6.5 mo8.0 mo7.6 moMST:
35%43%37%40%SxRR:
9%12%19%18.4%ORR:
100%100%43%44%3rd Line:
114102106104Pt No:
500 mg:250 mg:500 mg:250 mg:
Kris et al:(ASCO 2002 abst #1166)
Fukuoka et al:(ASCO 2002 abst #1188)Factor:
Phase II Trial of ZD1839 in NSCLCCharacteristics Associated with Response
30 4Other
4313Adenocarcinoma
31 3Men
4919Women
32154 Prior regimens
44103 Prior regimens
39 82 Prior regimens
3614PS 2
40 9PS 0-1
Symptom Improvement Rate (%)
Response Rate (%)
ZD1839 in NSCLCObservations 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)
Stage III/IV NSCLC N=1029/Trial *Gemcitabine/cisplatin (trial 14) *Paclitaxel/carboplatin (trial 17)
Randomize
Chemotherapy * x6 cycles + 250 mg ZD1839
Chemotherapy * x6 cycles + 500 mg ZD1839
Chemotherapy * x6 cycles + Placebo
Continue ZD1839 or placebo until disease progression
Primary endpoint: Survival
ZD1839 Randomized Trials With Chemotherapy in Advanced NSCLC
Randomized ZD 1839 Trials
Intact-1 Intact-2Chemotx CG 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
0.62.3 1
31.5 32.7 32.5
0
5
10
15
20
25
30
35
40
45
50
Res
pons
e R
ates
(%
)
CR
PR
Placebo(n=289)
250 mg/day(n=306)
500 mg/day(n=308)
Intact-2: Response Rates
Population = evaluable for response
TTP - INTACT 2TTP - INTACT 2
Group 500 mg/day
Group 250 mg/day
Placebo
Population: intention-to-treatTick marks indicate censored observationsPopulation: intention-to-treatTick marks indicate censored observations
11111212
44244244
25025066
27271010
64164122
1037103700
At risk:At risk:Months:Months:
919188
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 12 1610 14Survival time (months)
Pro
po
rtio
n e
ven
t fr
ee
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)
Population: intention-to-treatTick marks indicate censored observationsPopulation: intention-to-treatTick marks indicate censored observations
Survival - INTACT 2Survival - INTACT 2
58858888
4154151212
1411411616
18182020
81481444
1037103700
At risk:At risk:Months:Months:
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival time (months)0 4 8 12 16 20 24
Pro
po
rtio
n e
ven
t fr
ee
Group 500 mg/day
Group 250 mg/day
Placebo
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)
Survival - INTACT 2Landmark Analyses
Survival - INTACT 2Landmark 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 2CT 90 days + Adeno
Survival - INTACT 2CT 90 days + Adeno
ZD1839
Paclitaxel/Carboplatin X 4
(PS 0-1, IIIB-pl eff, IV) Placebo ZD1839
Primary Endpoint: PFSPaclitaxel: 225 mg/m2 & Carboplatin: AUC = 6, ZD1839: 250mg/d Correlative Studies: Tumor: p27, EGFR pathway
S0318: Phase III Trial of Paclitaxel/Carboplatin Early vs Late
ZD1839 in Advanced NSCLCRANDOMIZE
CRPRSD PD
PI: R Herbst
*S0023: ZD1839 following Chemoradiotherapy
(N=840)
ZD1839 Chemoradiation(PE/RT -> Docetaxel) as in S9504 Placebo
Correlative Studies: Tumor tissue: p27, EGFR, K-RAS, B-tubulin
Plasma: K-RAS *SWOG, NCI-C, NCCTG
RANDOMIZE
NSCLCno previous
chemotherapy(N=1050)
OSI 774 150 mg/d* PO+ Chemotherapy
Placebo 150 mg/d* PO+ Chemotherapy
vs*study drug continued at disease progression
Chemotherapy = paclitaxel/carboplatin or gemcitabine/cisplatin80% power to detect a 25% survival benefit, =0.05Similar power to detect a 33% 1-year survival benefit
Chemotherapy +/- OSI 774
Ongoing Trials: C-225
Docetaxel + C225
Carboplatin/Paclitaxel + C225
Gem/Carboplatin + C225
Second-line
First-line
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 OSI-774 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