Advanced Lung Cancer. Alan Sandler, MD. Outline. NSCLC

1
The Rationale for EGFR Inhibition in Advanced
Lung Cancer

• Alan Sandler, MD

2
Outline

• NSCLC - background
• EGFR inhibition
• Preclinical
• Previously treated patients
• Chemotherapy-naïve patients
• Questions and future directions

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Non-small Cell Lung CancerMetastatic 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

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NSCLC SurvivalState of the Art 2003
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NSCLC TherapyState of the Art

• Chemotherapy gt BSC
• 2 drugs gt 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

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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

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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

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Potential Treatment Options for
NSCLCIntegration With Current Therapies
Locally or regionally advanced disease
Advanced/ metastatic disease
Pre-malignancy
Localized disease
S
(RT)
CT RT
CT
Biological agents
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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.
200064885-4892 Ciardiello F et al. Clin Cancer
Res. 200062053-2063. Ciardiello F et al. Clin
Cancer Res. 200171459-1465 Williams KJ et al.
Proc AACR. 200142715. Abstract 3840.McClelland
RA et al. Endocrinology. 20011422776-2788 Gee
JM et al. Proc ASCO. 20012071a. Abstract 282.
Fujimura M et al. Proc AACR. 200142804.
Abstract 4317 Chan KC et al. Br J Surg.
200188412-418.
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Targeting EGFR in NSCLCPhase I Results - EGFR
Blockade
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EGFR Receptor Targeted Therapies Currently in
Clinical Development
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EGFR Blockade

• Previously Treated Patients

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OSI-774
Trial Design
Clinical Data

• NSCLC positive for EGFR (gt10 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

Perez-Solar et. Al, ASCO 2001
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Schema of IDEAL Trials
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ZD1839 in Recurrent NSCLCIDEAL Phase II Trial
Results
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Phase II Trial of ZD1839 in NSCLCCharacteristics
Associated with Response
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ZD1839 in NSCLCObservations from Monotherapy
Trials

• RR in women gt men
• RR in Adeno gt SqCCa
• Best RR in BAC?
• RR unrelated to ECOG PS?
• RR not affected by number of previous therapies

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EGFR Blockade

• Chemotherapy-Naïve Patients

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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,
2195a (abs 376) Miller VA et al. Proc ASCO
2001 20 326a (abs 1301)
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ZD1839 Randomized Trials With Chemotherapy in
Advanced NSCLC
Chemotherapy x6 cycles
250 mg ZD1839
Continue ZD1839 or placebo until disease
progression
Chemotherapy x6 cycles
Randomize
500 mg ZD1839
Chemotherapy x6 cycles
Placebo
Stage III/IV NSCLC N1029/Trial
Gemcitabine/cisplatin (trial 14)
Paclitaxel/carboplatin (trial 17)
Primary endpoint Survival
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Randomized ZD 1839 Trials
Intact-1 Intact-2 Chemotx 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
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Intact-2 Response Rates
Placebo(n289)
250 mg/day (n306)
500 mg/day (n308)
Population evaluable for response
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TTP - INTACT 2
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Survival - INTACT 2
1.0
0.9
0.8
0.7
0.6
Proportion event free
0.5
0.4
0.3
0.2
0.1
0.0
0
4
8
12
16
20
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Survival time (months)
Population intention-to-treat Tick marks
indicate censored observations
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Survival - INTACT 2Landmark Analyses
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Survival - INTACT 2CT ?90 days Adeno
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S0318 Phase III Trial of Paclitaxel/Carboplatin
? Early vs Late ZD1839 in Advanced NSCLC

• 
  
• ? ZD1839
• Paclitaxel/Carboplatin X 4
• (PS 0-1, IIIB-pl eff, IV) ? Placebo ? ZD1839
  
• Primary Endpoint PFS
• Paclitaxel 225 mg/m2 Carboplatin AUC 6,
  ZD1839 250mg/d
• Correlative Studies Tumor p27, EGFR
  pathway

CR PR SD
PD
PI R Herbst
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S0023 ZD1839 following Chemoradiotherapy
(N840)

• ? ZD1839
• Chemoradiation
• (PE/RT -gt Docetaxel)
• as in S9504 ? Placebo
• Correlative Studies Tumor tissue p27, EGFR,
  K-RAS, B-tubulin
• Plasma K-RAS
• SWOG, NCI-C, NCCTG

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Chemotherapy /- OSI 774
OSI 774 150 mg/d PO Chemotherapy
NSCLC no previous chemotherapy (N1050)
study drug continued at disease progression
vs
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
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Ongoing Trials C-225
Docetaxel C225 Carboplatin/Paclitaxel
C225 Gem/Carboplatin C225
Second-line First-line First-line
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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,
20276a(1102), 2001
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Future Directions and QuestionsEGFR 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

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Future Directions and QuestionsEGFR Inhibitors
in NSCLC

• Optimize schedule of EGFR-inhibitors and
  chemotherapy
• Sequential?
• Studies with XRT, locoregional disease
• Develop rational molecularly targeted doublets

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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

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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