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