1. Lung cancer perspectives. Targeted therapy : one for all or a few for one ? Miklos Pless, Winterthur 26.3.2009

2. 2 Standard first line Schiller, NEJM 2002 Any of these Cis- or Carboplatin + “new” agent

3. 3 Second-line Chemotherapy 21 Shepherd et al 2000 0369121518 0.0 0.2 0.4 0.6 0.8 1.0 Months Docetaxel vs BSC

4. 4 Option 2: Pemetrexed (Hanna, JCO 2004)

5. 5 Two types of NSCLC: Adeno carcinoma In stage IV better prognosis Cancer of non-smokers More likely in women More likely to harbor EGFR mutation Squamous cell Worse prognosis in stage IV "Only" in smokers Mostly men Only rarely with EGFR mutation DIFFERENT PROGNOSIS DIFFERENT SENSITIVITIES AND SIDE EFFECTS TO DRUGS DIFFERENT PROGNOSIS DIFFERENT SENSITIVITIES AND SIDE EFFECTS TO DRUGS

6. 6 Study Design: 1º endpoint OS Pre-specified subset analyses: randomization factors plus age, ethnicity, smoking & histology Cisplatin 75 mg/m 2 day 1 plus Gemcitabine 1250 mg/m 2 days 1 & 8 Randomization Factors Stage Performance status Gender Histologic vs cytologic diagnosis History of brain metastases R Cisplatin 75 mg/m 2 day 1 plus Pemetrexed 500 mg/m 2 day 1 Vitamin B 12, folate, and dexamethasone given in both arms Non-inferiority study, OS-difference HR >1.17 excluded Each cycle repeated q3 weeks up to 6 cycles Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.

7. 7 Scagliotti JCO 2008 ?

8. 8 Prognostic Variables* * From separate Cox models, controlling for treatment, disease stage, ECOG PS, gender, and basis of diagnosis SubgroupsHR (95% CI) Superiority P -value Females vs males 0.76 (0.67, 0.86) < 0.001 Ever- vs never-smoker 1.74 (1.44, 2.09) < 0.001 Age (continuous)1.00 (0.99, 1.00) 0.656 Caucasian vs others1.36 (1.18, 1.57) < 0.001 E/SE Asian vs others 0.65 (0.54, 0.78) < 0.001 ECOG PS 0 vs 1 0.65 (0.58, 0.73) < 0.001 Stage IIIB vs IV 0.82 (0.71, 0.93) 0.003 Histo vs Cyto Dx 1.02 (0.91, 1.15) 0.693 Adeno vs others 0.75 (0.67, 0.84) < 0.001 Squamous cell vs others 1.12 (0.98, 1.27) 0.088 Large cell vs others 1.29 (1.07, 1.54) 0.007 Scagliotti JCO 2008

9. 9 Current options EGFR Inhibitors Gefitinib/ErlotinibTKI CetuximabmAB Angiogenesis Inhibitors BevacizumabmAB EGFR Inhibitors Gefitinib/ErlotinibTKI CetuximabmAB Angiogenesis Inhibitors BevacizumabmAB Vessel disrupting agents ASA404SM Angiogenesis Inhibitors Sunitinib/AxitinibTKI IGF1-R Inhibitors manymAB Vessel disrupting agents ASA404SM Angiogenesis Inhibitors Sunitinib/AxitinibTKI IGF1-R Inhibitors manymAB In clincial trials

10. 10 Sandler, NEJM 2006 Bevacizumab median 10.2 vs 12.5 mo 1-and 2-y OS PC 44% and 17% PCB 52% and 22%

11. 11 PFS in AVAiL trial Reck, JCO 2009

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13. 13 1.0 0.8 0.6 0.4 0.2 0  Probability of OS  Time (months)  061218243036  ITT (intent-to-treat) population Placebo + CG Bev 7.5mg/kg + CG Bev 15mg/kg + CG HR0.931.03 p value0.420.76 Median OS (months)13.113.613.4  AVAiL: OS  Manegold ESMO 2008

14. 14 Bevacizumab 2 randomized trials positive ( only one for survival ) Toxicity manageable Platinum/Bevacizumab containing triplet = new Standard for first line treatment of stage IV Adeno-NSCLC? Effect in patients >70 disputed (Ramalingam, JCO 2008) Brain metastases and SCC tumors safe? Under investigation Anticoagulation and central tumors seem safe PROBLEMS : only non-squamous, only with Gemcitabine, many contra-indications

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19. 19 Cetuximab 1 randomized trial positive Toxicity manageable Platinum/Cetuximab containing triplet = the new Standard for first line treatment of stage IV NSCLC? Problems: PFS ! Vinorelbine combination effect marginal

20. 20 Second line targeted Trials EGFR Inhibitor vs BSC Gefitinib: ISELErlotinib: BR.21 Thatcher, Lancet 2005 Shepherd, N Engl J Med 2005 mOS 4.7 vs 6.7 momOS 5.1 vs 5.6 mo

21. 21 Gefitinib! Defies EBM! Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial Edward S Kim et al, Lancet 2008

22. 22 Gefitinib and Erlotinib? From P Jaenne, Clin Cancer Res, 2006

23. 23 Response alone no pedictor for benefit with erlotinib  Patients without objective response to Erlotinib Tarceva (n=367) Placebo (n=204) Median OS (months) HRp value SD/PD8.256.80.820.037 OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file

24. 24 BR.21: overall survival according to gender Survival distribution function 1.00 0.75 0.50 0.25 0 0510152025 Placebo (n=83) Tarceva (n=173) Male RR=6.0% Placebo (n=160) Tarceva (n=315) 051015202530 Shepherd FA, et al. N Engl J Med 2005;353:123–32 1.00 0.75 0.50 0.25 0 Time (months) Female RR=14.4%

25. 25 Shepherd FA, et al. N Engl J Med 2005;353:123–32; Tarceva Summary of Product Characteristics, F. Hoffmann-La Roche, 2007 BR.21: overall survival according to tumour histology Survival distribution function Tarceva (n=246) Adenocarcinoma RR=13.9% Placebo (n=119) Placebo (n=78) Tarceva (n=144) Squamous-cell carcinoma RR=3.8% Adenocarcinoma: HR=0.7; p=0.008* Squamous-cell carcinoma: HR=0.67; p=0.0007* HR *Log-rank test 0.51 Time (months) 1.00 0.75 0.50 0.25 0 0510152025300510152025 1.00 0.75 0.50 0.25 0

26. 26 BR.21: OS in male current/former smokers with squamous-cell carcinoma Survival distribution function 1.00 0.75 0.50 0.25 0 02.55.07.510.012.515.017.520.0 HR=0.66 (95% CI: 0.47– 0.92) Time (months) Clark GM, et al. Clin Lung Cancer 2006;7:389–94 Median OS (months) Tarceva (n=100)5.5 Placebo (n=57)3.4 RR=6.8%

27. 27 SAKK19/03: Erlotinib 1st line in unselected NSCLC patients (D’Addario; Ann Oncol 2008)

28. 28 Mutation in EGFR (Lynch, NEJM 2004) 8/9!

29. 29 L. Sequist, #7504 (iTARGET)

30. 30 Spanish prospective phase II trial (Paz-Ares, ACO 2006) 1047 NSCLC screened 127 (15%) Mutations of EGFR Mutations in 67 (19%) of all Chemonaive patients 40 Patients treated with Erlotinib and evaluated 65% Female 85% PS 0/1 75% Adenocarcinoma 70% Never-smokers

31. 31 Results (Paz-Ares, ACO 2006)  mfu 7 months

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34. 34 Erlotinib 150 mg/d Non-squamous NSCLC stage IIIB/IV Chemonaive EGFR-mutated 4-6 cycles Cis or Carbo- combinations with Gemcitabine or Taxotere Primary endpoint: increase of PFS of 3 months in Erlotinib arm (7 vs 4 months)‏ Secondary endpoints: OS, ORR, QoL n = 147 (screen n= 1500)‏ EURTAC - European Tarceva vs. Chemotherpay, Phase III PD Erlotinib 150 mg/d R 4-6 cycles Cis or Carbo- combinations with Gemcitabine or Taxotere

35. 35 New Drugs:

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43. 43 IF YOU REALLY REALLY CAN NOT PUT THE PATIENT ON A TRIAL: 1st line DDDP/Pemetrexed for Adeno DDDP/Gem/Docetacel (SCC) Consider adding Bevacizumab (Adeno) Consider adding Cetuximab (SCC) Consider EGFR TKI for mutated tumors 1st line DDDP/Pemetrexed for Adeno DDDP/Gem/Docetacel (SCC) Consider adding Bevacizumab (Adeno) Consider adding Cetuximab (SCC) Consider EGFR TKI for mutated tumors 2nd line EGFR TKI or Chemotherapy Start early?! Soon: Better Angiogenesis Inhibitors IGFR-1 Inhibitors VDA 2nd line EGFR TKI or Chemotherapy Start early?! Soon: Better Angiogenesis Inhibitors IGFR-1 Inhibitors VDA

44. 44 Targeted therapy??? Learned a lot about prognostic factors Adeno-, female-, never-smokers, asians Don't know enough about predictive factors Histology? EGFR Mutation? K-ras Mutation? Do we really have targeted treatments??? Do we have the right tools to detect efficacy?

45. 45 Model: randomized trial 2 nd line NSCLC New vs. Docetaxel New targets 25% and “cures” them 710339228139894624700503 0481216202428323640 0.0 0.2 0.4 0.6 0.8 1.0 Months Probability of survival At risk : Docetaxel p 0.05??

46. 46 …all clear?