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Potential Consequences of EGFR Dysregulation EGFR Invasion P PI3K Metastasis Nucleus MAPK Signaling Cascades Gene Activation Cell Cycle Progression Myc M G1 G2 S Fos Jun Survival Angiogenesis P Proliferation Apoptosis 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. ISEL Trial No Survival Benefit with Gefitinib Gefitinib Placebo (n = 1129) (n = 563) Probability of Survival 1.0 Overall median survival (mo) 1-year survival (%) 0.8 5.6 27 5.1 21 HR = 0.89 (95% CI, 0.77–1.02)*; P = .087† 0.6 0.4 Gefitinib Placebo 0.2 0.0 0 2 4 6 8 10 12 Survival Time (Months) *From Cox regression model †From Log-rank test Reprinted from Lancet, 2005;366:1527, with permission from Elsevier. 14 16 Phase III BR.21 Study Design NSCLC • Double-blind • Stratified according to – Center RANDOMIZED – EC0G performance 2:1 status (0/1 vs 2/3) – Best response to prior (Erlotinib) (Placebo) therapy (C or PR vs SD vs PD) – # prior regimens (1 vs 2) – Exposure to prior platinum Rx (Y/N) Shepherd FA, et al. N Engl J Med. 2005;353:123. Erlotinib 150 mg/d Placebo Phase III BR.21 Overall Survival Favors Erlotinib 42.5% Improvement in Median Survival 100 Erlotinib Placebo n = 488 n = 243 Median survival (months) 6.7 4.7 1-y survival (%) 31.2 21.5 Patients (%) 80 60 40 *HR = 0.73, P < .001 20 Erlotinib Placebo 0 0 No. at Risk Placebo 243 Erlotinib 488 6 107 255 12 Months 18 24 30 50 145 9 23 0 4 0 0 *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. BR.21 Survival Across Subgroups Factors Gender Male Female Smoking status Never smoked Current/ex-smoker Ethnicity Caucasian Asian EGFR status EGFR-positive EGFR-negative EGFR unmeasured Performance status 0–1 2–3 Histology Adenocarcinoma Squamous cell carcinoma Other histology Prior regimens 1 >2 N HR 95% CI 475 256 0.76 0.80 0.6–0.9 0.6–1.1 146 545 0.42 0.87 0.3–0.6 0.7–1.0 567 91 0.79 0.61 0.6–1.0 0.4–1.0 185 141 405 0.68 0.61 0.77 0.5–0.9 0.6–1.4 0.6–1.0 486 245 0.73 0.77 0.6–0.9 0.6–1.0 365 222 144 0.71 0.67 1.04 0.6–0.9 0.5–0.9 0.7–1.5 364 367 0.76 0.75 0.6–1.0 0.6–1.0 Adapted from Tarceva® (erlotinib) Product Information. Melville, NY: OSI Pharmaceuticals, Inc, and Genentech, Inc; 2007. Courtesy of Dr. A. Sandler, MD. 0.00 0.50 Decreased risk of death 1.00 1.50 2.00 Increased risk of death EGFR Monoclonal Antibody Cetuximab IgG1 (chimerized antibody) Exclusive for EGFR and its heterodimers Prevents repair and survival of tumor cells damaged by effects of chemotherapy and radiotherapy – Potentiates apoptosis – Inhibits cell-cycle progression – Decreases production of angiogenic factors – Inhibits invasion/metastasis Recent FDA approvals for squamous cell carcinoma of the head and neck and colorectal cancer Cetuximab in Advanced NSCLC Reference Regimen N Overall Response Rate (%) *Lilenbaum ASCO 2005 Cetuximab 66 3.3 8.1 43 Thienelt J Clin Oncol 2005 Carboplatin/paclitaxel/ cetuximab 31 26 11 40 Rosell ASCO 2004 Cisplatin/vinorelbine/ cetuximab Cisplatin/vinorelbine 43 35 8.3 32 43 28 7.0 26 Robert J Clin Oncol 2005 Carboplatin/gemcitabine/ cetuximab 35 29 10.2 46 *Kim ASCO 2003 Docetaxel/cetuximab 47 25 7.5 — Kelly ASCO 2006 Chemotherapy + cetuximab Chemotherapy → cetuximab 106 119 37 25 10 9 49 43 *1 or more prior therapies Median Survival (Mo) 1-Year Survival (%) Other Targeted Agents Mammalian target of rapamycin (mTOR) inhibitors Insulin growth factor receptor antagonists Histone deacetylase inhibitors (HDACs) Bortezomib Next-generation EGFR tyrosine kinase inhibitors – HKI-272 Toll-like receptor (TLR) antagonists Downstream Targets in the Tyrosine Kinase Pathway Receptor Tyrosine Kinase Ras P13K Raf Akt MEK mTOR ERK/MAP kinase P70S6K CDKs Apoptosis Cell Cycle Progression Proliferation 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. Examples of mTOR Inhibitors Under Evaluation for Lung Cancer Temsirolimus (CCI-779): ongoing phase II trial in 1st-line therapy of stage IIIB or IV NSCLC1 – Recent FDA approval for advanced renal cell carcinoma Everolimus (RAD 001): preliminary data from phase I/II studies in combination with EGFR tyrosine kinase inhibitors reported2,3; phase II studies ongoing mTOR = mammalian target of rapamycin. 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.