Strategies in the therapy of advanced NSCLC SAMO Winter-Conference 2008 on Chest tumors

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1 Strategies in the therapy of advanced NSCLC SAMO Winter-Conference 2008 on Chest tumors Miklos Pless Medical Oncology Kantonsspital Winterthur

2 2 Setting the stage.

3 1995: Chemotherapy works! Meta-Analysis 1995 BMJ 3

4 4 Good news: QoL besser

5 1997: Die New ones : Vinorelbine, Gemcitabine, Taxanes In combination with Platin: median OS 2 months p year OS 20% 40% 2 year OS 10% 20% QoL better! Sandler, JCO

6 6 And the elderly patients (>70 y).

7 What is the standard doublet? Any of these Cis- or Carboplatin + new agent Schiller, NEJM

8 Time! We knew that! 8

9 9 Cis- vs. Carbo!

10 10 Ardizzoni et al., JNCI 2007

11 RR Ardizzoni et al., JNCI

12 OS Ardizzoni et al., JNCI

13 mos: 9.1 vs. 8.4 mo 1-y OS: 37% vs. 34% 13 Ardizzoni et al., JNCI 2007

14 Subgroups 14 Ardizzoni et al., JNCI 2007

15 15 Targeted Cisplatin? OS and DFS Soria, NEJM 2006

16 Whom not to treat? PS 2? Vinorelbine Mono (or other monotherapy?) Combination-chemotherapy? Erlotinib not as effective as P/C chemotherapy in PS 2 Lilenbaum, ASCO Lilenbaum (CALGB 9730), JCO 2006

17 How long??? 3 cycles? 4 6 until progression? until best response + 2? 17

18 How long??? more cycles: Carbo/Vinorelbine 3 vs. 6 cycles (von Plessen, Br J Cancer 2006) MiViP 3 vs. 6 cycles (Smith, JCO 2001) longer treatment: Carbo/Taxol 4 vs. until PD (Socinski, JCO 2002) better TTP, more toxicity, no OS benefit maintenance/change: MIC 6 cycles +/- Vinorelbine maintenance (Westeel, JNCI 2005) GIC 3 cycles, then GIC vs Taxol 3 Zyklen (Sculier, Ann Oncol 2007) 18

19 Bevacizumab The new kid on the block. median 10.2 vs 12.5 mo 1-and 2-y OS PC 44% and 17% PCB 52% and 22% Sandler, NEJM

20 20 Avail Study, Manegold, ASCO 2007

21 21

22 22

23 Bevacizumab 2 randomized trials positive (only one for survival) Toxicity manageable Platinum/Bevacizumab containing triplet = new Standard for first line treatment of stage IV NSCLC? Effect in patients >70 disputed (#7535, ASCO 2007) Brain metastases and SCC tumors safe? Under investigation Anticoagulation and central tumors seem safe 23

24 A Randomized Phase III Trial of Cisplatin + Pemetrexed vs. Cisplatin + Gemcitabine in Locally Advanced or Metastatic NSCLC Data Presented at: 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Simms L, Sugarman K, Obasaju C & Blatter J and 14 th European Congress of Clinical Oncology: Sept 27, 2007; Barcelona, Spain. Manegold C, Digumarti R, Zukin M, de Marinis F, Mellemgaard A, Gandara D, Simms L, Kaiser C, Blatter J, Gatzemeier U On behalf of the JMDB investigators

25 Study Design: 1º endpoint OS Pre-specified subset analyses: randomization factors plus age, ethnicity, smoking & histology 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 Each cycle repeated q3 weeks up to 6 cycles Cisplatin 75 mg/m 2 day 1 plus Gemcitabine 1250 mg/m 2 days 1 & 8 Vitamin B 12, folate, and dexamethasone given in both arms Non-inferiority study, OS-difference HR >1.17 excluded Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 25

26 Grade 3 & 4 Drug-related Toxicities* Toxicities Cis/Pem N=839 Cis/Gem N=830 P-value Neutropenia 127 (15.1%) 222 (26.7%) < Anemia 47(5.6%) 82 (9.9%) Thrombocytopenia 34 (4.1%) 105 (12.7%) < Leukocytes 40 (4.8%) 63 (7.6%) Febrile neutropenia 11 (1.3%) 31 (3.7%) Alopecia (any grade) 100 (11.9%) 178 (21.4%) < Nausea 60 (7.2%) 32 (3.9%) Vomiting 51 (6.1%) 51 (6.1%) Fatigue 56 (6.7%) 41 (4.9%) Dehydration (any grade) 30 (3.6%) 17 (2.0%) Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 26

27 Probability without Event Patients at Risk CP CG Progression-Free Survival (months) PFS Median (95% CI) CP 4.8 (4.6, 5.3) CG 5.1 (4.6, 5.5) CP vs CG Adjusted HR (95% CI) 1.04 ( ) Probability without Event Patients at Risk CP CG Survival Time (months) OS Median (95% CI) CP 10.3 (9.8, 11.2) CG 10.3 (9.6, 10.9) CP vs CG Adjusted HR (95% CI) 0.94 ( ) Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 27

28 Adenocarcinoma or Large Cell Probability without Event Median (95% CI) CP 5.3 (4.8, 5.7) CG 4.7 (4.4, 5.4) CP vs CG Adjusted HR (95% CI) 0.90 ( ) Patients at Risk CP CG PFS (months) in Non-Squamous Patients PFS Probability without Event Survival Time (months) in Non-Squamous Patients Patients at Risk CP Scagliotti GV et al, Presented at 12 th World Conference on CG Lung 488 Cancer: Sept 334 5, 2007; Seoul, 188 Korea OS Median (95% CI) CP 11.8 (10.4, 13.2) CG 10.4 (9.6, 11.2) CP vs CG Adjusted HR (95% CI) 0.81 ( )

29 Cis/Pem vs Cis/Gem in First-line NSCLC Subgroup Analyses Forest Plot All Patients (N=1722) Age < 65 (n=1116) Age >=65 (n=606) Female (n=514) Male (n=1208) Caucasian (n=1346) East/Southeast Asian (n=220) Other Origin (n=156) Ever-smoker (n=1265) Never-smoker (n=250) ECOG PS 0 (n=612) ECOG PS 1 (n=1110) Histological Diagnosis (n=1145) Cytological Diagnosis (n=577) Stage IIIB (n=414) Stage IV (n=1308) Adenocarcinoma (n=846) Large Cell Carcinoma (n=153) Squamous Cell Carcinoma (n=473) Other Histologic Diagnosis (n=250) Hazard Ratio (95% CI) Favors CP Favors CG Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 29

30 Prognostic Variables* Subgroups HR (95% CI) Superiority P-value Females vs males 0.76 (0.67, 0.86) < Ever- vs never-smoker 1.74 (1.44, 2.09) < Age (continuous) 1.00 (0.99, 1.00) Caucasian vs others 1.36 (1.18, 1.57) < E/SE Asian vs others 0.65 (0.54, 0.78) < ECOG PS 0 vs (0.58, 0.73) < Stage IIIB vs IV 0.82 (0.71, 0.93) Histo vs Cyto Dx 1.02 (0.91, 1.15) Adeno vs others 0.75 (0.67, 0.84) < Squamous cell vs others 1.12 (0.98, 1.27) Large cell vs others 1.29 (1.07, 1.54) *From separate Cox models, controlling for treatment, disease stage, ECOG PS, gender, and basis of diagnosis Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 30

31 Cis/Pem vs Cis/Gem in First-line NSCLC Conclusions Cisplatin/Pemetrexed is not inferior to Cisplatin/Gemcitabine (HR=0.94) Cisplatin/Pemetrexed less RBC & platelet transfusions, ESAs, and G/GM-CSFs A pre-planned subset analysis showed: In adenocarcinoma and large cell histology, Cisplatin/ Pemetrexed had statistically superior overall survival time (P=0.03) In squamous histology, Cisplatin/Gemcitabine had marginally superior overall survival time (P=0.05) Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 31

32 Second-line Chemotherapy Docetaxel vs BSC Months Shepherd et al

33 33 Option 2: Pemetrexed (Hanna, JCO 2004)

34 34 Option 3: Erlotinib Shepherd, NEJM 2005

35 Option 4: weekly Docetaxel Camps, Ann Oncol 2006 RR und OS little difference Less toxicity with weekly 35

36 Its getting crowded: how to choose? 36

37 Clinical experience: retrospective studies, cohorts, phase II Best Results for RR (and OS?) with EGFR TKI for: Kris JAMA 2003 Fukuoka JCO 2003 Kris JAMA 2003 Miller JCO From Jänne, J Clin Oncol 2005

38 PS: Smoking is bad? Hamilton, Clin Cancer Res,

39 How to choose? Erlotinib for Adenocarcinoma Females Never Smokers From Asia Same group as: Bevacizumab/Pemetrexed!!! 39

40 40 Is this the waiting room in your clinic?

41 41..or this?

42 Mutation in EGFR (Lynch, NEJM 2004) 8/9! 42

43 43?

44 44 Predictors of Erlotinib Effect (Tsao, NEJM 2005)

45 Why are EGFR-mutations irrelevant? Too little n? n= 21 vs. 19? Bad sequencing? 20/40 were new mutations, no duplicates at PCR (Marchetti, NEJM 2006 letter) 45

46 What is the significance of the mutations? From P Jaenne, Clin Cancer Res,

47 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 47

48 Results (Paz-Ares, ACO 2006) mfu 7 months 48

49 49

50 50

51 51

52 Sequist Gefitinib 58% 11.8 mos 52

53 53 L. Sequist, #7504 (itarget)

54 Proposal PS 0-1 (any age): And now????? How I do it.. Platinum containing doublet in first line Use Cisplatin if response is needed Consider Bevacizumab in selected cases Consider Pemetrexed in Adenocarcinoma? Consider Gemcitabine (Docetaxel?) in SCC Use Erlotinib in 2 nd line in patients with promising clinical profile Erlotinib as 3 rd line in others Consider Erlotinib in 1st line in patients with exon 19/21 mutations PS 2: use single agent Vinorelbine or Gemcitabine 54

55 55 Thank you!

56

57 57

58 Response Rates Cis/Pem N=762 CR 2 (0.3%) Cis/Gem N=755 3 (0.4%) P-value PR 231 (30.3%) 210 (27.8%) SD 314 (41.2%) 346 (45.8%) PD 174 (22.8%) 155 (20.5%) ORR (95% CI) 233 (30.6%) (27.3, 33.9%) 213 (28.2%) (25.0, 31.4%) Duration of response 4.5 months (4.27, 5.32) 5.1 months (4.57, 5.52) Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 58

59 Gefitinib and Erlotinib? From P Jaenne, Clin Cancer Res,

60 Case Report mit Meningeosis: Gefitinib-Response nach Erlotinib-Resistenz (Choong, Nat Clin Pract Oncol 2006) 60

61 SAKK19/03: Erlotinib 1st line in unselected NSCLC patients (D Addario; Ann Oncol 2008) 61

62 Response alone no predictor for benefit with erlotinib Patients without objective response to Erlotinib Tarceva (n=367) Placebo (n=204) Median OS (months) Median OS (months) HR p value SD/PD OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file 62

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

64 BR.21: overall survival according to tumour histology Adenocarcinoma: HR=0.7; p=0.008* Squamous-cell carcinoma: HR=0.67; p=0.0007* *Log-rank test 0.5 HR 1 Survival distribution function Adenocarcinoma RR=13.9% Tarceva (n=246) Squamous-cell carcinoma RR=3.8% Tarceva (n=144) Placebo (n=119) Placebo (n=78) Time (months) Time (months) Shepherd FA, et al. N Engl J Med 2005;353:123 32; Tarceva Summary of Product Characteristics, F. Hoffmann-La Roche, 2007

65 BR.21: OS in male current/former smokers with squamous-cell carcinoma Survival distribution function Median OS (months) Tarceva (n=100) 5.5 Placebo (n=57) 3.4 HR=0.66 (95% CI: ) RR=6.8% Time (months) 65 Clark GM, et al. Clin Lung Cancer 2006;7:389 94

66 Basel results before and after year 2 year < % 5 + 5% % %.6 OS , n=150, mos 36 weeks.2 p= <1997, n=80, mos 27 weeks months (F. Waechter, Chest 2005)