Strategies in the therapy of advanced NSCLC SAMO Winter-Conference 2008 on Chest tumors Miklos Pless Medical Oncology Kantonsspital Winterthur
2 Setting the stage.
1995: Chemotherapy works! Meta-Analysis 1995 BMJ 3
4 Good news: QoL besser
1997: Die New ones : Vinorelbine, Gemcitabine, Taxanes In combination with Platin: median OS 2 months p 0.004 1 year OS 20% 40% 2 year OS 10% 20% QoL better! Sandler, JCO 2000 5
6 And the elderly patients (>70 y).
What is the standard doublet? Any of these Cis- or Carboplatin + new agent Schiller, NEJM 2002 7
Time! We knew that! 8
9 Cis- vs. Carbo!
10 Ardizzoni et al., JNCI 2007
RR Ardizzoni et al., JNCI 2007 11
OS Ardizzoni et al., JNCI 2007 12
mos: 9.1 vs. 8.4 mo 1-y OS: 37% vs. 34% 13 Ardizzoni et al., JNCI 2007
Subgroups 14 Ardizzoni et al., JNCI 2007
15 Targeted Cisplatin? OS and DFS Soria, NEJM 2006
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 2006 16 Lilenbaum (CALGB 9730), JCO 2006
How long??? 3 cycles? 4 6 until progression? until best response + 2? 17
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
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 2006 19
20 Avail Study, Manegold, ASCO 2007
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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
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
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
Grade 3 & 4 Drug-related Toxicities* Toxicities Cis/Pem N=839 Cis/Gem N=830 P-value Neutropenia 127 (15.1%) 222 (26.7%) < 0.001 Anemia 47(5.6%) 82 (9.9%) 0.001 Thrombocytopenia 34 (4.1%) 105 (12.7%) < 0.001 Leukocytes 40 (4.8%) 63 (7.6%) 0.019 Febrile neutropenia 11 (1.3%) 31 (3.7%) 0.002 Alopecia (any grade) 100 (11.9%) 178 (21.4%) < 0.001 Nausea 60 (7.2%) 32 (3.9%) 0.004 Vomiting 51 (6.1%) 51 (6.1%) 1.000 Fatigue 56 (6.7%) 41 (4.9%) 0.143 Dehydration (any grade) 30 (3.6%) 17 (2.0%) 0.075 Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 26
Probability without Event 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Patients at Risk CP 862 295 CG 863 312 Progression-Free Survival (months) 54 68 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 (0.94-1.15) 14 18 4 7 Probability without Event 0 0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 Patients at Risk CP 862 598 CG863 590 Survival Time (months) 341 327 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 (0.84-1.05) 146 139 45 34 0 0 Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 27
Adenocarcinoma or Large Cell Probability without Event 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 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 (0.79-1.02) 0 6 12 18 24 30 Patients at Risk CP 512 194 CG488 174 PFS (months) in Non-Squamous Patients PFS 38 34 11 7 Probability without Event 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 2 3 Survival Time (months) in Non-Squamous Patients Patients at Risk CP 512 369 235 109 36 Scagliotti GV et al, Presented at 12 th World Conference on CG Lung 488 Cancer: Sept 334 5, 2007; Seoul, 188 Korea. 80 21 28 0 0 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 (0.70-0.94) 0 6 12 18 24 30 0 0
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) 0.94 0.97 0.88 0.84 0.98 0.93 0.88 1.34 0.93 1.00 0.91 0.95 0.92 0.99 0.89 0.95 0.84 0.67 1.23 1.08 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 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
Prognostic Variables* Subgroups HR (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 others 1.36 (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 *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
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
Second-line Chemotherapy 1.0 0.8 Docetaxel vs BSC 0.6 0.4 0.2 0.0 0 3 6 9 12 15 18 Months Shepherd et al 2000 21 32
33 Option 2: Pemetrexed (Hanna, JCO 2004)
34 Option 3: Erlotinib Shepherd, NEJM 2005
Option 4: weekly Docetaxel Camps, Ann Oncol 2006 RR und OS little difference Less toxicity with weekly 35
Its getting crowded: how to choose? 36
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 2004 37 From Jänne, J Clin Oncol 2005
PS: Smoking is bad? Hamilton, Clin Cancer Res, 2006 38
How to choose? Erlotinib for Adenocarcinoma Females Never Smokers From Asia Same group as: Bevacizumab/Pemetrexed!!! 39
40 Is this the waiting room in your clinic?
41..or this?
Mutation in EGFR (Lynch, NEJM 2004) 8/9! 42
43?
44 Predictors of Erlotinib Effect (Tsao, NEJM 2005)
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
What is the significance of the mutations? From P Jaenne, Clin Cancer Res, 2006 46
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
Results (Paz-Ares, ACO 2006) mfu 7 months 48
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Sequist 98 34 Gefitinib 58% 11.8 mos 52
53 L. Sequist, #7504 (itarget)
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 Thank you!
57
Response Rates Cis/Pem N=762 CR 2 (0.3%) Cis/Gem N=755 3 (0.4%) P-value 0.647 PR 231 (30.3%) 210 (27.8%) 0.284 SD 314 (41.2%) 346 (45.8%) 0.070 PD 174 (22.8%) 155 (20.5%) 0.276 ORR (95% CI) 233 (30.6%) (27.3, 33.9%) 213 (28.2%) (25.0, 31.4%) 0.312 Duration of response 4.5 months (4.27, 5.32) 5.1 months (4.57, 5.52) 0.198 Scagliotti GV et al, Presented at 12 th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea. 58
Gefitinib and Erlotinib? From P Jaenne, Clin Cancer Res, 2006 59
Case Report mit Meningeosis: Gefitinib-Response nach Erlotinib-Resistenz (Choong, Nat Clin Pract Oncol 2006) 60
SAKK19/03: Erlotinib 1st line in unselected NSCLC patients (D Addario; Ann Oncol 2008) 61
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 8.25 6.8 0.82 0.037 OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file 62
BR.21: overall survival according to gender Survival distribution function 1.00 0.75 0.50 0.25 Placebo (n=83) Female RR=14.4% Tarceva (n=173) 0 0 5 10 15 20 25 Time (months) 1.00 0.75 0.50 0.25 Male RR=6.0% Tarceva (n=315) Placebo (n=160) 0 0 5 10 15 20 Time (months) 25 30 63 Shepherd FA, et al. N Engl J Med 2005;353:123 32
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 1.00 0.75 0.50 0.25 Adenocarcinoma RR=13.9% Tarceva (n=246) 1.00 0.75 0.50 0.25 Squamous-cell carcinoma RR=3.8% Tarceva (n=144) Placebo (n=119) Placebo (n=78) 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 64 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
BR.21: OS in male current/former smokers with squamous-cell carcinoma Survival distribution function 1.00 0.75 0.50 0.25 Median OS (months) Tarceva (n=100) 5.5 Placebo (n=57) 3.4 HR=0.66 (95% CI: 0.47 0.92) RR=6.8% 0 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Time (months) 65 Clark GM, et al. Clin Lung Cancer 2006;7:389 94
Basel results before and after 1997 1.0.8 1 year 2 year < 97 19 + 9% 5 + 5% 97 40 + 8% 23 + 7%.6 OS.4 1997, n=150, mos 36 weeks.2 p=0.0001 <1997, n=80, mos 27 weeks 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 66 months (F. Waechter, Chest 2005)