Angiogenesis

Signaling Cascades

EGFR

PI3K MAPK

NucleusGene Activation

Cell Cycle Progression

M G1

SG2

Fos

PP

MAPK = mitogen-activated protein kinase; P13K = phosphatidylinositol 3-kinase.

Roskoski R Jr. Biochem Biophys Res Commun. 2004;319:1. Rowinsky EK. Annu Rev Med. 2004;55:433.

Survival

Proliferation

Invasion

Apoptosis

Metastasis

Potential Consequences ofPotential Consequences ofEGFR DysregulationEGFR Dysregulation

Myc

Jun

1.0

0.6

0.8

0.2

0.0

0.4

0 162 144 10 1286

Pro

bab

ilit

y o

f S

urv

ival

Survival Time (Months)

5.6 5.1

27

HR = 0.89 (95% CI, 0.77–1.02)*; P = .087†

21

Gefitinib

Placebo

*From Cox regression model†From Log-rank test

ISEL TrialISEL Trial No No Survival Benefit with GefitinibSurvival Benefit with Gefitinib

Reprinted from Lancet, 2005;366:1527, with permission from Elsevier.

(n = 1129)Placebo(n = 563)

Overall median survival (mo)

1-year survival (%)

Gefitinib

Phase III BR.21 Study DesignPhase III BR.21 Study Design

NSCLC

• Double-blind

• Stratified according to– Center

– EC0G performance status (0/1 vs 2/3)

– Best response to prior therapy (C or PR vs SD vs PD)

– # prior regimens (1 vs 2)– Exposure to prior

platinum Rx (Y/N)

Erlotinib150 mg/d

Placebo

RANDOMIZED 2:1

Shepherd FA, et al. N Engl J Med. 2005;353:123.

(Erlotinib) (Placebo)

*HR and P-value adjusted for stratification factors at randomization and HER1/EGFR status

Adapted from Shepherd FA, et al. N Engl J Med, 353:123-132, Figure 1A. Copyright © 2005 Massachusetts Medical Society. All rights reserved.

Phase III BR.21 Phase III BR.21 Overall Survival Favors ErlotinibOverall Survival Favors Erlotinib

42.5% Improvement in Median Survival

Pat

ien

ts (

%)

*HR = 0.73, P < .001

Erlotinib n = 488

Placebo n = 243

Median survival (months) 6.7 4.7

1-y survival (%) 31.2 21.5

Months

Erlotinib

Placebo

100

80

60

40

20

00 6 12 18 24 30

No. at RiskPlacebo 243 107 50 9 0 0Erlotinib 488 255 145 23 4 0

BR.21BR.21Survival Across SubgroupsSurvival Across Subgroups

Adapted from Tarceva® (erlotinib) Product Information. Melville, NY: OSI Pharmaceuticals, Inc, and Genentech, Inc; 2007.Courtesy of Dr. A. Sandler, MD.

Factors N HR 95% CIGender

Male 475 0.76 0.6–0.9Female 256 0.80 0.6–1.1

Smoking statusNever smoked 146 0.42 0.3–0.6Current/ex-smoker 545 0.87 0.7–1.0

EthnicityCaucasian 567 0.79 0.6–1.0Asian 91 0.61 0.4–1.0

EGFR statusEGFR-positive 185 0.68 0.5–0.9EGFR-negative 141 0.61 0.6–1.4EGFR unmeasured 405 0.77 0.6–1.0

Performance status0–1 486 0.73 0.6–0.92–3 245 0.77 0.6–1.0

HistologyAdenocarcinoma 365 0.71 0.6–0.9Squamous cell carcinoma 222 0.67 0.5–0.9Other histology 144 1.04 0.7–1.5

Prior regimens1 364 0.76 0.6–1.0>2 367 0.75 0.6–1.0

1.000.500.00 1.50 2.00

Decreased risk of death

Increased risk of death

EGFR Monoclonal AntibodyEGFR Monoclonal AntibodyCetuximabCetuximab

IgG1 (chimerized antibody)IgG1 (chimerized antibody)

Exclusive for EGFR and its heterodimersExclusive for EGFR and its heterodimers

Prevents repair and survival of tumor cells damaged Prevents repair and survival of tumor cells damaged by effects of chemotherapy and radiotherapyby effects of chemotherapy and radiotherapy

– Potentiates apoptosisPotentiates apoptosis

– Inhibits cell-cycle progressionInhibits cell-cycle progression

– Decreases production of angiogenic factorsDecreases production of angiogenic factors

– Inhibits invasion/metastasisInhibits invasion/metastasis

Recent FDA approvals for squamous cell carcinoma Recent FDA approvals for squamous cell carcinoma of the head and neck and colorectal cancerof the head and neck and colorectal cancer

Cetuximab in Advanced NSCLCCetuximab in Advanced NSCLC

Reference Regimen N

Overall Response Rate (%)

Median Survival

(Mo)

1-Year Survival

(%)

*LilenbaumASCO 2005

Cetuximab 66 3.3 8.1 43

Thienelt J Clin Oncol 2005

Carboplatin/paclitaxel/cetuximab

31 26 11 40

RosellASCO 2004

Cisplatin/vinorelbine/cetuximab

Cisplatin/vinorelbine

43

43

35

28

8.3

7.0

32

26

Robert J Clin Oncol 2005

Carboplatin/gemcitabine/cetuximab

35 29 10.2 46

*KimASCO 2003

Docetaxel/cetuximab 47 25 7.5 —

KellyASCO 2006

Chemotherapy + cetuximabChemotherapy → cetuximab

106119

3725

109

4943

*1 or more prior therapies

Other Targeted AgentsOther Targeted Agents

Mammalian target of rapamycin (mTOR) Mammalian target of rapamycin (mTOR) inhibitorsinhibitors

Insulin growth factor receptor antagonistsInsulin growth factor receptor antagonists

Histone deacetylase inhibitors (HDACs)Histone deacetylase inhibitors (HDACs)

BortezomibBortezomib

Next-generation EGFR tyrosine kinase inhibitorsNext-generation EGFR tyrosine kinase inhibitors

– HKI-272HKI-272

Toll-like receptor (TLR) antagonistsToll-like receptor (TLR) antagonists

Downstream Targets in the Tyrosine Downstream Targets in the Tyrosine Kinase PathwayKinase Pathway

MAP = mitogen-activated protein; MEK = MAPK kinase; mTOR = mammalian target of rapamycin; P13K = phosphatidylinositol 3-kinase.

Adapted from Cancer Control, 2003;10(2):125, with permission from H. Lee Moffitt Cancer Center and Research Institute, Inc.

Receptor TyrosineKinase

Cell Cycle Progression Proliferation

ApoptosisCDKs

P70S6K

mTOR

Akt

P13K

ERK/MAPkinase

MEK

Raf

Ras

1. CCI-779 protocol available at: http://www.clinicaltrials.gov/ct/show/NCT00079235?order=1. 2. Milton DT, et al. J Clin Oncol. 2005;23(No. 16S):646s. Abstract 7104. 3. Kris MG, et al. J Clin Oncol. 2007;25(No. 18S). Abstract 7575.

mTOR = mammalian target of rapamycin.

Examples of mTOR Inhibitors Under Examples of mTOR Inhibitors Under Evaluation for Lung CancerEvaluation for Lung Cancer

Temsirolimus (CCI-779): ongoing phase II trial in Temsirolimus (CCI-779): ongoing phase II trial in 1st-line therapy of stage IIIB or IV NSCLC1st-line therapy of stage IIIB or IV NSCLC11

– Recent FDA approval for advanced renal cell carcinomaRecent FDA approval for advanced renal cell carcinoma

Everolimus (RAD 001): preliminary data from phase Everolimus (RAD 001): preliminary data from phase I/II studies in combination with EGFR tyrosine kinase I/II studies in combination with EGFR tyrosine kinase inhibitors reportedinhibitors reported2,32,3; phase II studies ongoing; phase II studies ongoing