Gerard A. Silvestri, MD, FCCP; and M. Patricia Rivera, MD, FCCP NSCLC EGFR NSCLC EGFR EGFR NSCLC. (epidermal growth factor receptor);

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1 CHEST Gerard A. Silvestri, MD, FCCP; and M. Patricia Rivera, MD, FCCP (NSCLC) NSCLC (EGFR) EGFR EGFR NSCLC EGFR (gefitinib) (erlotinib) EGFR NSCLC EGFR cetuximab NSCLC NSCLC (epidermal growth factor receptor); (lung cancer); (targeted therapy); (tyrosine kinase inhibitor) EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; FDA = Food and Drug Administration; IDEAL = IRESSA Dose Evaluation in Advanced Lung Cancer; ILD = interstitial lung disease; NSCLC = non-small cell lung cancer; PS = performance status; TGF = transforming growth factor; TK = tyrosine kinase; TKI = tyrosine kinase inhibitor [1] 1/3 [1] 314

2 % [2] [3] [2] (pemetrexed) [3] [10] NSCLC ( y 15%) [4] [10] (FDA) NSCLC (NSCLC) 85% [4] NSCLC NSCLC [1] NSCLC (EGFR) ( 1) [11 13] EGFR EGFR NSCLC [11] NSCLC ( ) (TK) 3 (paclitaxel) TK [14] (gemcitabine) (vinorelbine) (EGF) (irinotecan) (TGF) -α EGFR (docetaxel) [5] [6, 7] [8, 9] 1y NSCLC NSCLC From the Divisions of Pulmonary and Critical Care Medicine (Dr. Silverstri), Medical University of South Carolina, Charleston, SC; and the University of North Carolina at Chapel Hill (Dr. Rivera), Chapel Hill, NC. Correspondence to: Gerard A. Silvestri, MD, FCCP, Medical University of South Carolina, Room 812 CSB, 171 Ashley Ave, Charleston, SC 29425; silvestri@musc.edu. 1 [11, 12, 14] EGFR Akt PI3K 3 PKC C Grb2 2 Sos SOS MAPK CHEST

3 EGFR IgG cetuximab TK ( 1) Panitumumab ( IgG 2 ) EDM ( IgG 1 ) 1 [12, 13] [20] EGFR [12] TK NSCLC EGFR-TK 40% 80% NSCLC EGFR (84%) [13] (68%) (65%) [14, 15] [11, 12, 14, 16, 17] EGFR ( 70 Gy) cetuximab ( 400 mg / m 2 ) cetuximab (cetuximab EGFR NSCLC 3y 54 mo 28 mo 57% 44% P = 0.02) cetuximab EGFR EGFR cetuximab [21] cetuximab ( ) [22] NSCLC EGFR EGFR cetuximab (20% 31.7%) cetuximab NSCLC / TK EGFR EGFR NSCLC Cetuximab NSCLC [20] [21] [21] 424 cetuximab / / 43 / 43 [22] Kim [23] cetuximab 3mo EGFR NSCLC 47 NSCLC EGFR 13 8 EGFR [23] TGFα EGF EGFR cetuximab NSCLC [18] TK cetuximab NSCLC FDA [19] 316

4 1 (1) EGFR-TKI, IDEAL-1, IDEAL-2 (210 ) (216 ) (57 ) 250 mg / d 500 mg / d 250 mg / d 500 mg / d 150 mg / d / % ( )/% /mo ND 1y / % ND / % ND (1) [25, 26, 36] IDEAL ND TK [25, 26] (TKI) TK NSCLC IDEAL mg/d [24] (ATP) EGFR IDEAL NSCLC TKI (Gefitinib) FDA NSCLC EGFR- TKI IDEAL-1 [25, 26] (compassionate-use) NSCLC 1y 30% (Functional Assessment of Cancer [27] (erlotinib) Therapy-Lung study quality-of-life questionnaire) TKI NSCLC [29] NSCLC [28] 1 IDEAL-1 IDEAL-2 NSCLC [25, 26] 250 mg / d FDA IDEAL-1 IDEAL-2 18% 12% NSCLC 500 mg / d 250 mg / d [25, 26] [25] IDEAL-1 68% EGFR-TKI NSCLC IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) IDEAL [25, 26] 2 IDEAL-2 (lung cancer subscale) 1mo IDEAL mg / d 500 mg / d 7 6 mo CHEST

5 NSCLC EGFR 37% 43% [34, 35] [36] 35% ( ) IDEAL-1 IDEAL-2 TK EGF [34] TK EGFR EGF EGFR 15 min 3h [34] TK [25, 26] IDEAL [34] 40% 250 mg 500 mg (performance status, PS) EGFR 10 [34] Lynch [34] ( 9 8 EGFR ) 7 EGFR (P IDEAL ) 9 >18mo [25, 26] Lynch [34] NSCLC NSCLC EGFR NSCLC EGFR IDEAL-2 250mg/d 500 mg / d 43% 35% ( 2) IDEAL-1 [25] [37] IDEAL-2 NSCLC 57 56% 1wk 1 ( 1) 75% 3wk ( 3) EGFR 96% [26, 30, 31] 2 BR.21 (1) ( 4) IDEAL-2 13 mo 5mo (488 ) (243 ) P < /mo [32, 33] 1y EGFR (1) EGFR EGFR-TK / mo < / % NA Shepherd [28] NA 318

6 3 85% 75% [38] 56% EGFR [39] cetuximab 4 0 1wk 2wk 3wk cetuximab IDEAL-2 [40] ( ) ( ) [25, 26] [41] 150mg/d 13% 51% 2 (47 250mg/d ) 13% 500mg/d (taxane) (40 ) 10% [37] (BR.21 ) [28] : 1 150mg/ [31] d EGFR TKI (427 ) 9% (211 ) <1% 35% NSCLC IDEAL- 27% 2 (6.7 mo P = 0.001) (2.2 mo P < 0.001) ( 2) [28] ( 0.8 [28] ) NSCLC 0.4 IDEAL-2 IDEAL-1 EGFR-TK [25, 26, 28, 30, 31] EGFR EGFR-TKI / / mo mo EGFR [26, 30, 31] 4 IDEAL CHEST

7 ( 70 ) 10 [48] 50% [42] (ILD) PS2 3 [46, 49] ILD <1% EGFR 0.3% [27] [43, 44] ILD [28] BR.21 ILD <1% 1% ILD NSCLC 250mg/d 700 mg / d IDEAL ILD [25, 26] 250 mg / d EGFR-TKI 500mg/d ( ) 150mg/d NSCLC 50% EGFR-TKI [5] ( ) ( ) NSCLC EGFR-TKI PS NSCLC EGFR-TKI PS / EGFR-TKI [45] PS NSCLC EGFR CI-1033 pan-erbb TKI erbb [50] TK 4 CI-1033 erbb1 (EGFR) erbb2 erbb3 EGFR erbb4 cetuximab EGFR-TKI EGFR panitumumab EMD [46] bevacizumab [47] (EGF 1 TGF-α) 320

8 EGFR [51] DAB389-EGF NSCLC [53] ( ) EGFR EGFR-TKI ( ) Society, 2004 NSCLC 2 Greenlee RT, et al. CA Cancer J Clin 2000;50: Jemal A, et al. CA Cancer J Clin 2003;53: Landis SH, et al. CA Cancer J Clin 1999;49: Pfister DG, et al. J Clin Oncol 2004;22: EGFR 8 Schiller JH, et al. N Engl J Med 2002;346: : Hanna N, et al. J Clin Oncol 2004;22: Arteaga C. Semin Oncol 2003;30:3 14 NSCLC 12 Raymond E, et al. Drugs 2000;60(Suppl 1): Veale D, et al. Br J Cancer 1993;68: (American Society of Clinical Oncology) 15 Cerny T, et al. Br J Cancer 1986;54: (National Comprehensive Cancer Network) 16 Tateishi M, et al. Cancer Res 1990;50: [5, 52] NSCLC / 1 Cancer Facts & Figures Atlanta, GA: American Cancer 6 Shepherd FA, et al. J Clin Oncol 2000;18: Fossella FV, et al. Lung Cancer 2002;38(Suppl):S5 S12 9 Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 13 Salomon DS, et al. Crit Rev Oncol Hematol 1995;19: Rusch V, et al. Clin Cancer Res 1997;3: Baselga J. Signal 2000;1: Herbst RS, et al. Expert Opin Biol Ther 2001;1: Baselga J, et al. J Clin Oncol 2000;18: Bonner JA, et al. Am Soc Clin Oncol Available at: / org/ac/1,1003,_ _ _ , 00. asp. Accessed July 2004 NSCLC 22 Rosell R, et al. Proc Am Soc Clin Oncol 2004;23: Kim ES, et al. Proc Am Soc Clin Oncol 2003;22: Mendelsohn J. Endocr Relat Cancer 2001;8:3 9 CHEST

9 25 Fukuoka M, et al. J Clin Oncol 2003;21: Kris MG, et al. JAMA 2003;290: Ochs J, et al. Proc Am Soc Clin Oncol 2004;23: Shepherd FA, et al. N Engl J Med 2005;353: Cella D, et al. J Clin Epidemiol 2002;55: Douillard J-Y, et al. Proc Am Soc Clin Oncol 2002;21(pt 1): 299a 31 Natale RB, et al. Proc Am Soc Clin Oncol 2002;21(pt 1):292a 32 Bailey R, et al. Proc Am Assoc Cancer Res 2003;44 (2nd ed): Bailey LR, et al. Proc Am Soc Clin Oncol 2004;23: Lynch TJ, et al. N Engl J Med 2004;350: Paez JG, et al. Science 2004;304: Pao W, et al. Proc Natl Acad Sci U S A 2004;101: Perez-Soler R, et al. Lung Cancer 2003;41(Suppl 2):S Busam KJ, et al. Br J Dermatol 2001;144: Rowinski EK, et al. J Clin Oncol 2004;22: Saltz LB, et al. Proc Am Soc Clin Oncol 2003;22: Herbst RS, et al. Clin Lung Cancer 2003;4: Inoue A, et al. Lancet 2003;361: Giaccone G, et al. J Clin Oncol 2004;22: Johnson DH, et al. Ann Oncol 2002;13(Suppl 5): Govindan R. Curr Treat Options Oncol 2003;4: Gridelli C, et al. Br J Cancer 2003;89: Williams CC, et al. Proc Am Soc Clin Oncol 2004;23: Dickson NR, et al. Proc Am Soc Clin Oncol 2004;23: Zinner R, et al. Proc Am Soc Clin Oncol 2004;23: Slichenmyer WJ, et al. Semin Oncol 2001;5(Suppl 16): Shaw JP, et al. J Biol Chem; 1991;266: National Comprehensive Cancer Network. Clinical practice guidelines in oncology: non-small cell lung cancer; version Available at: license_agreement.asp. Accessed June 18, Schroen AT, et al. Chest 2000;118: CHEST 2005;128:

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