iressa zd1839 monotherapy for non small cell lung cancer nsclc l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC) PowerPoint Presentation
Download Presentation
IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC)

Loading in 2 Seconds...

play fullscreen
1 / 34

IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC) - PowerPoint PPT Presentation


  • 132 Views
  • Uploaded on

ONCOLOGY. IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC). Oncologic Drugs Advisory Committee Meeting September 24, 2002. IRESSA ® Introduction. George Blackledge, MD Clinical Vice President, Oncology AstraZeneca Pharmaceuticals. IRESSA ® Agenda for Today’s Meeting.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC)' - penn


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
iressa zd1839 monotherapy for non small cell lung cancer nsclc

ONCOLOGY

IRESSA®(ZD1839)Monotherapy for Non-Small Cell Lung Cancer (NSCLC)

Oncologic Drugs

Advisory Committee Meeting

September 24, 2002

iressa introduction

IRESSA®Introduction

George Blackledge, MD

Clinical Vice President, Oncology

AstraZeneca Pharmaceuticals

iressa agenda for today s meeting
IRESSA®Agenda for Today’s Meeting

Introduction George Blackledge, MD

Refractory NSCLC Frances A. Shepherd, MD

Clinical efficacy Ronald B. Natale, MD

Safety profile Alan B. Sandler, MD

Summary George Blackledge, MD

experts available for q a
Jose Baselga, MD

Chairman, Medical Oncology

Vall d'Hebron University Hospital

Barcelona, Spain

David Cella, PhD

Director, Center on OutcomesResearch and Education

Northwestern University

Evanston, IL

Gary Donaldson, PhD

Professor, Department of Anesthesiology

University of Utah School of Medicine

Salt Lake City, UT

Mark Kris, MD

Chief, Thoracic Oncology

Memorial Sloan-Kettering Cancer Center

New York, NY

Thomas Lynch, MD

Associate Professor of Medicine

Massachusetts General Hospital

Boston, MA

Experts Available for Q&A
experts available from astrazeneca
Experts Available From AstraZeneca

Steve Averbuch, MD

Andrea Kay, MD

David McKillop, PhD

Judith Ochs, MD

Graham Richmond, MSc

Mark Scott, PhD

Mark Steinberg, MD

Helen Swaisland, BSc

Alan Wakeling, PhD

Michael Wolf, MSc

iressa for 3rd line nsclc
IRESSA® for 3rd-Line NSCLC
  • High unmet need
    • Thousands of patients each year
    • Disease of symptoms
  • IRESSA
    • Unprecedented activity in target population
    • Symptom control
    • Excellent tolerability
demonstration of the role of iressa
Demonstration of the Role of IRESSA®

IRESSA® 250 mg po daily can be used in the 3rd-line treatment of patients with locally advanced or metastatic non-small cell lung cancer.

how did we get here iressa
How Did We Get Here? IRESSA®
  • Molecular targeted agents 1990 discovery program
  • ZD1839 molecule discovered 1994
  • Healthy volunteer trials 1997
egfr signal transduction in tumor cells

CI-9

K

K

K

K

EGFR Signal Transduction in Tumor Cells

R

R

R

R

Gene transcription and

cell cycle progression

myc

cyclin D1

Jun

Fos

egfr signal transduction in tumor cells10

CI-10

RAS

RAF

R

P

P

P

P

K

K

SOS

R

K

GRB2

PI3-K

P

P

K

MEK

AKT

MAPK

Inhibition of apoptosis

Proliferation

Metastasis

Angiogenesis

EGFR Signal Transduction in Tumor Cells

R

R

Gene transcription and

cell cycle progression

myc

cyclin D1

Jun

Fos

iressa non clinical summary
IRESSA® Non-Clinical Summary

IC50 (µM)

  • Selective enzyme inhibition
    • EGFR (ErbB-1): 0.033
    • Other cellular kinases > 3
  • EGFR autophosphorylation < 1 inhibition in tumor cell lines
  • Tumor cell growth inhibition
    • EGF stimulated 0.054
    • Basal 8.8
iressa inhibits growth of a549 xenograft tumors nsclc
IRESSA® Inhibits Growth of A549 Xenograft Tumors (NSCLC)

IRESSA 200 mg/kg, po days 10 - 72

IRESSA 200 mg/kg, po days 10 - 30

Vehicle

0.8

0.7

0.6

0.5

Mean tumor volume, cm3

0.4

0.3

0.2

0.1

0

0

20

40

60

80

Day

clinical pharmacokinetics n 535
Clinical Pharmacokinetics (N = 535)
  • Bioavailability ~ 60%
  • No clinically significant effect of food
  • Mean t½ = 41 hours
  • Steady state achieved within 7 to 10 days

Daily oral dosing administration schedule

iressa clinical development program
IRESSA® Clinical Development Program
  • Phase I clinical trials 1998
  • 3rd-line monotherapy 2000(Trials 39 and 16)§
  • 1st-line combination therapy 2000(Trials 14 and 17)§
  • Expanded Access Program (EAP) 2000
  • Phase I clinical trials 1998

§Separate Fast Track designations by FDA

iressa phase i safety and activity n 289
IRESSA® Phase I Safety and Activity (N = 289)
  • Safety profile
    • Grade 1 - 2 skin, GI toxicity common
    • Dose-limiting toxicity: reversible Grade 3 diarrhea at 800 to 1,000 mg daily
  • Striking symptom improvement in NSCLC
  • Antitumor activity in NSCLC
    • 10 objective responses in 100 patients
    • 17 on study ≥ 6 months
x rays of nsclc patient pre and post treatment with iressa 400 mg day
X-rays of NSCLC Patient Pre- and Post-Treatment With IRESSA®(400 mg/day)

Prior to treatment

After 14 days treatment

iressa clinical development program17
IRESSA® Clinical Development Program
  • Phase I clinical trials 1998
  • 3rd-line monotherapy 2000(Trials 39 and 16)§
  • 1st-line combination therapy 2000(Trials 14 and 17)§
  • Expanded Access Program (EAP) 2000

§Separate Fast Track designations by FDA

rationale for monotherapy
Rationale for Monotherapy

Trials 39 and 16

  • No approved therapy for 3rd-line NSCLC patients
  • Clinical need
    • Objective response
    • Symptom improvement
    • Well-tolerated therapy
results
Results

Trials 39 and 16

  • Response rate 10% in Trial 39 with an additional 30% stable disease
  • Associated symptom improvement
  • Similar supportive data in Trial 16
  • Highly acceptable safety profile
iressa clinical development program20
IRESSA® Clinical Development Program
  • Phase I clinical trials 1998
  • 3rd-line monotherapy 2000(Trials 39 and 16)§
  • 1st-line combination therapy 2000(Trials 14 and 17)§
  • Expanded Access Program (EAP) 2000

§Separate Fast Track designations by FDA

1st line combination therapy
1st-Line Combination Therapy

Trials 14 and 17

  • Rationale
    • Novel mechanism of action
    • Objective responses in Phase I
    • Was seen as the next logical step in improving outcome in NSCLC
  • Trial design
    • Previously untreated patients with advanced, unresectable NSCLC
    • Standard combination chemotherapy ± IRESSA®
    • Primary objective: survival
1st line combination trial results
1st-Line Combination Trial Results
  • Both trials
    • Representative of typical 1st-line populations
    • Well-balanced baseline patient and disease characteristics
  • No difference in overall survival across treatment arms in both trials
  • Analysis of response rate and time to progression showed no additional benefit for IRESSA® added to 2-drug chemotherapy
  • No additional safety issues
iressa 3rd line monotherapy benefit distinct from combination trial data
IRESSA® 3rd-Line Monotherapy Benefit Distinct From Combination Trial Data
  • Trials 14 and 17 outcomes are not germane to results demonstrated in 3rd-line NSCLC
    • Different treatment setting
    • Combination with chemotherapy rather than monotherapy
  • Lack of survival benefit in 1st-line does not negate responses and symptom improvement in 3rd-line
slide24
“With Genentech’s anti-VEGF announcement recently, SWOG’s evidence of interference by tamoxifen in the efficacy of breast cancer adjuvant therapy, and the IRESSA® results, I think we’re seeing a pattern emerge that is really (paradoxically) quite hopeful.

We’ve said that these new therapies are dramatically unlike chemotherapy but we’ve tried to develop them as if they were.

Now we know they’re not, and IRESSA has to be used following different paradigms.”

Larry Norton, MD

randomized controlled trials in nsclc
Randomized, Controlled Trials in NSCLC

Trial DesignRandomization

3rd line Iressa vs BSC

2nd line Iressa vs Taxotere

Taxotere +/- Iressa

1st line Iressa vs Navelbine

(platinum-ineligible pts)

Protocol final; to start 4Q02

Locally advanced Iressa vs placebo

CT+RT  Taxotere × 3  Randomize

NCI (SWOG / Intergroup) – actively recruiting

Adjuvant Iressa vs placebo

AZ (Japan) - actively recruiting

NCI / NCI-C / EORTC – to start 4Q02

iressa clinical development program26
IRESSA® Clinical Development Program
  • Phase I clinical trials 1998
  • 3rd-line monotherapy 2000(Trials 39 and 16)§
  • 1st-line combination therapy 2000(Trials 14 and 17)§
  • Expanded Access Program (EAP) 2000

§Separate Fast Track designations by FDA

iressa expanded access program
IRESSA® Expanded Access Program
  • Rationale
    • Clinical benefit in Phase I
    • Satisfy patient and physician demand
  • Developed in close collaboration with
    • FDA – NORD
    • Patient advocates – Medical ethicists
  • Eligible population
    • Patients with advanced NSCLC and no other treatment options
iressa expanded access program28
IRESSA® Expanded Access Program
  • Confirmed unmet need in refractory NSCLC

~ 18,000 patients worldwide (2,000 per month)

~ 40% of patients continued IRESSA beyond 6 months

iressa clinical development program29
IRESSA® Clinical Development Program
  • Phase I clinical trials 1998
  • 3rd-line monotherapy 2000(Trials 39 and 16)§
  • 1st-line combination therapy 2000(Trials 14 and 17)§
  • Expanded Access Program (EAP) 2000

§Separate Fast Track designations by FDA

fda questions 1
FDA Questions (1)

The FDA believes the relevance of the symptom improvement data discussed above cannot be adequately evaluated without a randomized, blinded study with an adequate control arm (the two doses of ZD1839 show no difference in efficacy and are thus not adequate). Do you agree?

fda questions 2
FDA Questions (2)

Given the lack of clinical benefit in two large studies of ZD1839 in combination with standard first-line NSCLC chemotherapy, is the Study 0039 response rate of 10% in 139 patients with resistant or refractory NSCLC reasonably likely to predict ZD1839 clinical benefit in NSCLC?

fda questions 3
FDA Questions (3)

More than 12,000 NSCLC patients have received ZD1839 under an Expanded Access Protocol. Please discuss what position FDA should take on ZD1839 expanded access if marketing approval of ZD1839 is not granted at this time.

fda questions 4
FDA Questions (4)

Regardless of whether ZD1839 is granted accelerated approval for treating NSCLC, additional trials may be needed. Please discuss potential study designs to demonstrate that ZD1839 provides clinical benefit to NSCLC patients.

iressa
IRESSA®
  • High unmet need in target population
  • Consistent response rate
  • Correlated symptomatic benefit
  • Well tolerated, easily administered