Advanced Lung Cancer. Alan Sandler, MD. Outline. NSCLC - PowerPoint PPT Presentation

Loading...

PPT – Advanced Lung Cancer. Alan Sandler, MD. Outline. NSCLC PowerPoint presentation | free to view - id: 15fa7-NWRmM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

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

Description:

Advanced Lung Cancer. Alan Sandler, MD. Outline. NSCLC - background. EGFR inhibition. Preclinical ... Non-small Cell Lung Cancer: Metastatic Disease. NSCLC ... – PowerPoint PPT presentation

Number of Views:505
Avg rating:3.0/5.0
Slides: 37
Provided by: uws6
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: 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

3
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

4
NSCLC SurvivalState of the Art 2003
5
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

6
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

7
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

8
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
9
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.
10
Targeting EGFR in NSCLCPhase I Results - EGFR
Blockade
11
EGFR Receptor Targeted Therapies Currently in
Clinical Development
12
EGFR Blockade
  • Previously Treated Patients

13
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
14
Schema of IDEAL Trials
15
ZD1839 in Recurrent NSCLCIDEAL Phase II Trial
Results
16
Phase II Trial of ZD1839 in NSCLCCharacteristics
Associated with Response
17
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

18
EGFR Blockade
  • Chemotherapy-Naïve Patients

19
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)
20
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
21
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
22
Intact-2 Response Rates
Placebo(n289)
250 mg/day (n306)
500 mg/day (n308)
Population evaluable for response
23
TTP - INTACT 2
24
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
24
Survival time (months)
Population intention-to-treat Tick marks
indicate censored observations
25
Survival - INTACT 2Landmark Analyses
26
Survival - INTACT 2CT ?90 days Adeno
27
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
28
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

29
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
30
Ongoing Trials C-225
Docetaxel C225 Carboplatin/Paclitaxel
C225 Gem/Carboplatin C225
Second-line First-line First-line
31
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
32
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

33
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

34
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

35
(No Transcript)
36
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
About PowerShow.com