1. Guidelines on the Treatment of Advanced Non-Small Cell Lung Cancer Rabab Gaafar, MD Prof. Medical Oncology NCI Cairo, Cairo University Board Member EORTC Lung EASO Amman , 2011

5. “ Evidence – Based Medicine” Meta-Analysis of Phase III Trials Randomized Phase III Trial Phase II Clinical Trial (s) Anecdotes In Vitro/Vivo Data Phase I Clinical Trial (s)

8. First Line Therapy

11. G.Giaccone, ESMO 2004 Doubling of RR, Doubling of MST and 4 times more in 1 year survival.

13. Kelly K, et al. J Clin Oncol 2001; 19:3210–3218; Schiller JH, et al. N Engl J Med 2002;346:92–98; Scagliotti GV, et al. J Clin Oncol 2002;20:4285–4291 1 st -line platinum-based CT: Efficacy plateau OS, overall survival Study arm OS (mo) 1 year (%) PCb 8.6 38 CV 8.1 36 Study arm OS (mo) 1 year (%) PC 7.8 31 GC 8.1 36 DC 7.4 31 PCb 8.1 34 Study arm OS (mo) 1 year (%) PCb 9.9 43 GC 9.8 37 CV 9.5 37 Pacli + carbo (PCb) Cis + vin (CV) Overall survival % 100 80 60 40 20 0 0 Months Months Overall survival 30 Pacli + cis (PC) Gem + cis (GC) Doc + cis (DC) Pacli + carbo (PCb) 5 10 15 20 25 Pacli + carbo (PCb) Gem + cis (GC) Cis + vin (CV) Months 0 1.0 0.9 0.6 0.5 0.4 0.3 0.8 0.7 0.2 0.1 0 1.0 0.9 0.6 0.5 0.4 0.3 0.8 0.7 0.2 0.1 0 Overall survival 30 5 10 15 20 25 0 30 5 10 15 20 25

14. Cisplatin/Pemetrexed versus Cisplatin/Gemcitabine Scagliotti G et al. JCO 2008, 26, 3543 Superiority of pemetrexed/cisplatin in non-squamous cell carcinomas p =0.011 p =0.051

15. Incidence of Histological Subtypes in the World Atlas of Cytogenetics in Oncology and Haematology. Available from: http://atlasgeneticsoncology.org/Tumors/LungNonSmallCellID5141.html Accessed January 26, 2011; Bryant A, Cerfolio RJ. Chest 2007;132:185–192 Ginsberg RJ, et al. Cancer: Principles and Practices of Oncology. 5th ed. 1997;858-911.

18. EORTC 08975: Survival (n=480) (Platin-based vs Platin-free CT) (months) 0 3 6 9 12 15 18 21 24 27 30 0 10 20 30 40 50 60 70 80 90 100 v. Meerbeeck et al. ASCO 2001 Pac/Gem 6.9 mo 26.6% Gem/Cis 8.8 mo 32.6% Pac/Cis 8.1 mo 32.1% MS 1-yr-S

28. AVAPERL: PFS from induction a Bev+pem 10.2 months (81 events) Bev 6.6 months (104 events) HR, 0.50 (0.37–0.69); P <.001 Progression -free survival (%) Time (months) 128 126 103 66 25 4 0 125 122 73 38 12 2 0 100 75 50 25 0 0 3 6 9 12 15 18 Pts at risk Bev+pem Bev Bev, bevacizumab; HR, hazard ratio; Pem, pemetrexed; pts, patients. a Randomized pts, Intent-to-treat population Barlesi et al ASCO 2011 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125)

31. Response rate by EGFR expression levels CT CT + cetuximab High EGFR expression (≥200) n=345 (31%) Low EGFR expression (<200) n=776 (69%) Response rate (%) p=0.36 p=0.002 Treatment interaction test p=0.040 CT, chemotherapy 0 50 40 30 20 10 44.4 28.1 0 50 40 30 20 10 29.6 32.6

33. IPASS Phase III Study: First-line Gefitinib vs CP in Advanced NSCLC Untreated Asian patients* with stage IIIb/IV NCSLC and PS 0-2 (N = 1217) Gefitinib 250 mg/day (n = 609) Carboplatin AUC 5-6 + Paclitaxel 200 mg/m 2 3 every wks † (n = 608) Fukuoka M, et al. ASCO 2009. Abstract 8006. Primary endpoint: PFS Secondary endpoints: OS, ORR, QoL, disease-related symptoms, safety, tolerability Biomarker analysis: EGFR mutation, expression, and gene copy number *Never smokers or ex-light smokers. † ≤ 6 cycles. Gefitinib as first line

35. EGFR mutation positive 12 mo prog-free: HR: 0.74; p<0.0001 GEF: 25% PC: 7%

36. 230 patients with EGFR mutated tumors

38. OPTIMAL: confirmed superiority of erlotinib vs chemotherapy in EGFR Act Mut+ NSCLC HR=0.16 (0.10–0.26) Log-rank p<0.0001 13.1 4.6 PFS probability 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 Time (months) Zhou, et al. ESMO 2010 Cut-off date 16 August 2010 8.5 months difference in PFS Gem/carbo (n=72) Erlotinib (n=82)

39. PFS in ITT population (updated analysis 26 Jan 2011) PFS probability Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p<0.0001 Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 Patients at risk Erlotinib 86 63 54 32 21 17 9 7 4 2 2 0 Chemo 87 49 20 8 5 4 3 1 0 0 0 0 Data cut-off: 26 Jan 2011 1.0 0.8 0.6 0.4 0.2 0 9.7 5.2 EURTAC study 4.5 months difference in PFS

40. Overall survival in ITT population (interim analysis 2 Aug 2010) EURTAC study OS probability 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=77; 35% with event) Chemotherapy (n=76; 36% with event) HR=0.80 (0.47–1.37) Log-rank p=0.4170 Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients at risk Erlotinib 77 61 53 41 34 22 14 11 9 2 1 1 1 0 Chemo 76 59 43 35 25 18 14 7 3 2 2 2 0 0 Data cut-off: 2 Aug 2010 N.B. 59 pts in chemotherapy arm had PFS event; 51 of these had second-line treatment, of whom 49 had EGFR TKI

41. Maintenance Therapy

45. Double-blind, Placebo-controlled, Multicenter, Phase III Trial JMEN Overall Survival (Intent-to-treat Population) Belani, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, 2009. MAINTENANCE ALIMTA ® (PEMETREXED) AFTER PRIOR PLATINUM IN STAGE IIIB/IV NSCLC Pemetrexed 13.4 mos Placebo 10.6 mos Survival Probability Time (months) HR=0.79 (95% CI: 0.65–0.95) p=0.012 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

46. Overall Survival by Histology JMEN Pemetrexed 9.9 mos Placebo 10.8 mos Squamous (n=182) HR=1.07 (95% CI: 0.77–1.50) p =0.678 Time (months) Non-squamous Pemetrexed 15.5 mo Placebo 10.3 mo HR=0.70 (95% CI: 0.56-0.88) p=0.002 Survival Probability Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Survival Probability Belani, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, 2009. 5 months difference in Non squamous histology

47. Investigator Assessed PFS (from Maintenance) PARAMOUNT (Continuous Maintenance) Pemetrexed: median =4.1 mos (3.2-4.6) Placebo: median =2.8 mos (2.6-3.1) Log-rank P =0.00006 Unadjusted HR: 0.62 (0.49-0.79) Patients at Risk Pem + BSC N=359 132 57 21 4 0 Placebo + BSC N=180 52 15 5 0 0 Pem + BSC Placebo + BSC

48. Independently Reviewed Tumor Response* (Maintenance) - All randomized patients PARAMOUNT * Response represents a further tumor reduction from the baseline response to induction therapy Pemetrexed (N=316) n (%) Placebo (N=156) n (%) P-value CR 0 0 PR 9 (2.8) 1 (0.6) RR: CR+PR 9 (2.8) 1 (0.6) 0.176 SD 218 (69.0) 92 (59.0) DCR: CR+PR+SD 227 (71.8) 93 (59.6) 0.009 PD 88 (27.8) 61 (39.1) Other / ND 1 (0.3) 2 (1.3)

49. Phase III Studies of EGFR TKI Maintenance 1. Cappuzzo F, et al. ASCO 2009. Abstract 8001. 2. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 3. Miller VA, et al. ASCO 2009. Abstract LBA8002. 4. Kabbinavar FF, et al. ASCO 2010. Abstract 7526. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6 . Gaafar RM, et al. ASCO 2010. Abstract 7518 . Trial Treatment Comparison N PFS OS HR (95% CI) P Value HR (95% CI) P Value SATURN [1,2] Erlotinib vs placebo 1949 0.71 (0.62-0.82) < .0001 0.81 (0.70-0.95) 0.009 ATLAS [3,4] Bev + erlotinib vs bev + placebo 1160 0.72 (0.59-0.88) .0012 0.92 (0.70-1.21) .5604 IFCT-GFPC 0502 [5] Erlotinib vs observation 834 0.82 (0.73-0.93) .002 0.91 (0.80-1.04) NS EORTC 08021 [6 ] Gefitinib vs placebo 173 0.61 (0.45-0.83) .0015 0.83 (0.60-1.15) .2

50. Tarceva maintenance therapy after first-line chemotherapy treatment SATURN Cappuzzo et al. Lancet Oncology 2010 Probability Time (weeks) PFS OS 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) 0 8 16 24 32 40 48 56 64 72 80 88 96 Erlotinib (n=438) Placebo (n=451) Erlotinib (n=437) Placebo (n=447) HR=0.71 (0.62–0.82) Log-rank p<0.0001 HR=0.81 (0.70–0.95) Log-rank p=0.0088 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0

51. PFS WITH MAINTENANCE TARCEVA IN EGFR MUTATION+ and WILD-TYPE SATURN 1.0 0.8 0.6 0.4 0.2 0 Time (weeks) 1.0 0.8 0.6 0.4 0.2 0 Time (weeks) 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Interaction p<0.001 PFS probability Log-rank p<0.0001 HR=0.10 (0.04–0.25) Log-rank p=0.0185 HR=0.78 (0.63–0.96) EGFR mutation+ EGFR wild-type Brugger et al ASCO 2009 abstr 8020 Tarceva (n=199) Placebo (n=189) Tarceva (n=22) Placebo (n=27)

52. OS probability 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 9.6 11.9 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 12.0 12.5 Log-rank p=0.0019 HR=0.72 (0.59–0.89) Log-rank p=0.6181 HR=0.94 (0.74–1.20) SD CR/PR OS is measured from time of randomisation into the maintenance phase Coudert et al. ELCC 2010 OS according to response to 1 st line chemotherapy SATURN Erlotinib (n=252) Placebo (n=235) Erlotinib (n=184) Placebo (n=210)

53. Hazard Ratio(95% CI) = 0.81 (0.59,1.12 ) Median in months (95% CI) Placebo : 9.4 (6.6,13.8) Gefitinib : 10.9 (9.2,13.8) Gaafar RM, et al. ASCO 2010. Abstract 7518 EORTC 08021 A double-blind, randomized, placebo-controlled phase III intergroup study of gefitinib (G) in patients (pts) with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021- ILCP 01/03). Number of patients = 173 Started 2004 Ended 2009 40% reduction in developing PD

55. PFS by EGFR mutation status (unknown) INFORM † Estimated using the Kaplan-Meier method HR <1 implies a lower risk of progression on gefitinib EGFR mutation-unknown Time (weeks) 0 20 40 60 80 100 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS (%) 109 64 36 20 11 8 5 3 2 1 1 1 0 0 0 108 80 62 53 49 44 39 34 31 22 15 12 5 1 0 Placebo Gefitinib No. of patients at risk 27 centers China 296 patients HR (95% CI) = 0.40 (0.29, 0.54) Gefitinib (n=108) Median PFS † , 6.0 months No. events, 90 (83.3%) Placebo (n=109 ) Median PFS † , 2.7 months No. events, 105 (96.3%)

56. Progression-free survival by EGFR mutation status † Estimated using the Kaplan-Meier method HR <1 implies a lower risk of progression on gefitinib 0 20 40 60 80 100 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS (%) Time (weeks) 15 9 5 3 3 2 1 1 1 1 1 1 0 0 0 15 15 14 14 13 11 10 18 7 7 5 3 1 0 0 Placebo Gefitinib No. of patients at risk 0 20 40 60 80 100 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS (%) Time (weeks) 24 9 5 3 2 0 0 0 0 0 0 0 0 0 0 25 14 6 3 3 1 0 0 0 0 0 0 0 0 0 Placebo Gefitinib No. of patients at risk 83% reduction of PD in mutated cases HR (95% CI) = 0.17 (0.07, 0.42) Gefitinib (n=15) Median PFS † , 16.6 months No. events, 9 (60.0%) Placebo (n=15) Median PFS † , 2.8 months No. events, 15 (100.0%) EGFR mutation-positive HR (95% CI) = 0.86 (0.48, 1.51) Gefitinib (n=25) Median PFS † , 2.7 months No. events, 25 (100.0%) Placebo (n=24) Median PFS † , 1.5 months No. events, 24 (100.0%) EGFR mutation-negative

57. Objective response rate and disease control rate (RECIST; ITT population) INFORM ORR (%) (n=148) (n=148) Odds ratio >1 implies a greater chance of response on gefitinib Odds ratio and p-value from logistic regression with covariates ITT, intent-to-treat; RECIST, Response Evaluation Criteria In Solid Tumors Odds ratio (95% CI) = 54.1 (7.17, 408); p= 0.0001 (n=148) (n=148) DCR (%) Odds ratio (95% CI) = 2.69 ( 1.62 , 4.46); p= 0.0001

58. Overall survival (ITT population) INFORM 0 16 40 56 72 96 112 0 10 40 60 80 100 Overall survival (%) 20 30 50 70 90 8 24 32 48 64 80 88 104 120 128 Time (weeks) Placebo Patients at risk: 148 136 97 78 37 0 0 147 115 107 91 66 13 6 0 148 129 102 84 39 0 0 141 114 108 90 75 18 4 0 47 56 127 119 Gefitinib HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608 Gefitinib (n=148) Placebo (n=148) Median OS, months 6-month survival rate, % 12-month OS rate, % No. events, n (%) 18.7 82.2 68.8 79 (53.4) 16.9 84.9 66.0 93 (62.8) HR <1 implies a lower risk of death on gefitinib

59. Second Line Therapy

60. Recommendation 13 Second or third-line therapy should be offered to patients with good PS who present with signs of disease progression (radiological and/or clinical) after first or second-line therapy (I A)

62. Survival (ITT) Pemetrexed (n=283 ) Docetaxel (n=288) Survival Distribution Function Months ITT = intent to treat HR = hazard ratio CI = confidence interval MST = median survival time 0.00 0.25 0.50 0.75 1.00 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 MST 8.3 mos 1-yr OS: 29.7% HR 0.99 95% CI of HR (0.82, 1.20) MST 7.9 mos 1-yr OS: 29.7% Hanna et al, ASCO 2003 Docetaxel vs Pemetrexed in Second line Therapy Equal Efficacy and less Toxicity

63. The Canadian NCIC BR.21 Trial : 731 Patients Significantly improved survival with Tarceva * HR and P -value adjusted for stratification factors at randomization plus HER1/EGFR status. Shepherd et al. N Engl J Med. 2005;353:123-132 HR= 0.70 (95% CI, 0.58-0.85); P < 0.001 21% 31% 1-year Survival 4.7months 6.7 months Median Survival Placebo n= 243 Erlotinib n= 488 45% increase in 1-year survival rate 27% reduction in risk of death with tarceva 42.5% increase in median OS 21% 31% Survival time (months) Survival distribution function 0 5 10 15 20 25 30 1.00 0.75 0.50 0.25 0 Erlotinib Placebo

64. BR.21: Survival by Smoking Status Shepherd et al. J Clin Oncol. 2005;353:123-132; Shepherd et al. Proc Am Soc Clin Oncol. 2004 Never Smokers Erlotinib Placebo Response Rate 24.7% 2.9% Median Survival 12.3 mos 5.6 mos HR= 0.42 (95% CI: 0.28 to 0.64) Survival distribution function 1.00 0.75 0.50 0.25 0 Months 0 5 10 15 20 25 Placebo (n= 42 ) Erlotinib (n= 104) Placebo (n= 187 ) Erlotinib (n= 358) Months 0 5 10 15 20 25 30 1.00 0.75 0.50 0.25 Current/Ex Smokers Erlotinib Placebo Response Rate 3.9% <1% Median Survival 5.5 mos 4.6 mos HR= 0.87 (95% CI: 0.71 to 1.05)

66. HORG : comparable TTP and OS with second-line erlotinib and pemetrexed in NSCLC Probability 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 Time (months) 1-year survival rate (%) 35.7% Erlotinib 38.5% Pemetrexed Time (months) 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=166) Pemetrexed (n=166) p=0.916 Erlotinib (n=163) Pemetrexed (n=161) p=0.299 TTP OS 0 5 10 15 20 25 30 35 40 45 Vamvakas, et al. ASCO 2010 (Abs. 7519)

70. First step : Clinical criteria Third step : Molecular Criteria Second step : Histological criteria Asian Erlotinib Female Light or never smoker Gefitinib Untreated CNS metastasis Uncontrolled hypertension bevacizumab, No hemoptysis Adenocarcinoma = Erlotinib Gefitinib Non squamous = Bevacizumab Pemetrexed EGFR mutated = Gefitinib EML4 ALK = Crizotinib The Change from an Empiric Treatment to Personalized Treatment Occurred in Different Steps

71. NSCLC Guidelines according to NCCN (current and expected approval status considered) 2 nd Line Adapted and simplified from NSCLC NCCN Guidelines (version 3.2011) * For PS 3–4 best supportive care only; ‡ If eligible for bevacizumab § Approval expected in 2011 ¶ Bevacizumab is not licensed for second-line use in NSCLC Maintenance 1 st Line Erlotinib or pemetrexed or docetaxel, based on prior therapy Histologic assessment Erlotinib Platinum doublet* Erlotinib or docetaxel, based on prior therapy Platinum doublet Bevacizumab ‡¶ Post - platinum Start erlotinib or pemetrexed Continuation of bevacizumab EGFR mut- or unknown EGFR TKI (Erlotinib § ) EGFR mut+ Platinum doublet * Bevacizumab ‡ Squamous cell Non-squamous EGFR mutation testing