Changing demographics of smoking and its effects during therapy Egbert F. Smit MD PhD. Dept. Pulmonary Diseases, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands Smoking prevalence adults 1980-2005 1
EU Smoking Rates 1994-2005 Distribution of smoking rates in the EU 2
Smoking prevalence 15-16 years 2007 Time trends in smoking attributable deaths 3
Smoking and Lung Cancer Smoking and Lung Cancer Smoking Small cell lung cancer Squamous cell carcinoma Non-Smoking Adenocarcinoma 4
Smoking and Small Cell Lung Cancer Pleasance et al. Nature 463,184,2010 P53 Mutational Spectra Rudin et al. Clin. Cancer Res. 15,5468,2009 5
Smoking and mol biol of NSCLC Sun et al. Nature Rev. Cancer 7,738,2007 Mutational Spectrum of Adenocarcinoma Ding et al. Nature 455,1069,2008 6
An Evolving View of Adenocarcinoma 1999 2009 KRAS Pending EGFR BRAF PIK3CA FGFR4 HER2 EM L4-ALK Drivers and Passengers 7
EGFR mutation-positive disease: a biologically distinct subtype of NSCLC Survival Proliferation PIP 3 PTEN PIP 2 P PI3K Adaptor GDP-RAS P Adaptor GTP-RAS MEK RAF Preferential AKT heterodimerisation with HER3 MAPK Increased signalling through the AKT and STAT Apoptosis anti-apoptotic pathwaystranscription regulators factors Nucleus Oncogene addiction Sordella, et al. Science 2004 Mutations identified in EGFR gene EGFR transcript Confer sensitivity/resistance to EGFR TKIs Unclear effect on sensitivity to EGFR TKIs Exons 1 16 Exon 17 Exons 18 24 Exons 25 28 G719A/S Deletions D761Y D770_N771 insnpg T790M L858R L861X 18 19 18 20 21 V689M P694X V700D E709X I715S L730F P733L E746K A763V N765A S768I T783A L792P L798F G810S N826S L838V T847I I853T A859T E866K L688P L718P S720X G735S V738F V742A T751I S752Y D761N L833V H835L H850N V851X G863D A864T Riely, et al. Clin Cancer Res 2006 8
Clinical characteristics do not reliably predict EGFR mutation status 100 Spanish Lung Cancer Group trial in advanced NSCLC patients with EGFR mutations (n=350) 80 Female Never smoker Adenocarcinoma Patients (%) 60 40 Significant proportion of EGFR mutation-positive population falls outside typical subgroups 20 0 30% Male 26% Former smoker 9% Gender Smoking status Histology Non-adeno/BAC Rosell, et al. NEJM 2009 MUTATIONS IN EGFR PREDICT FOR RESPONSE TO EGFR-TKI S Lynch TJ et al. New Eng J Med, 2004. 9
Oncogene Addiction Weinberg. Science,2002. Sharma and Settleman, Genes Dev.2007 IPASS: first-line study design Patients Chemo-naïve Age 18 years Adenocarcinoma histology Never or light exsmokers* Life expectancy 12 weeks PS 0-2 Measurable stage IIIB/ IV disease Gefitinib (250 mg/day) 1:1 randomisation Carboplatin (AUC 5 or 6)/ paclitaxel (200 mg/m 2 ) 3 weekly Endpoints Primary PFS (non-inferiority) Secondary ORR OS QoL Disease-related symptoms Safety and tolerability Exploratory Biomarkers EGFR mutation EGFR-gene-copy number EGFR protein expression *Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped ³15 years ago and smoked 10 pack years Maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression; AUC, area under curve Mok et al 2009 10
IPASS: pre-planned analysis of PFS by EGFR mutation status EGFR M+ EGFR M- Probability of PFS 1.0 0.8 0.6 0.4 0.2 N Median (m) Gefitinib 132 9.5 Carboplatin / paclitaxel 129 HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 6.3 Probability of PFS 1.0 0.8 0.6 0.4 0.2 N Median (m) Gefitinib 91 1.5 Carboplatin / paclitaxel 85 HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 5.5 0.0 0 4 8 12 16 20 24 Time from randomisation (months) 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Primary Cox analysis with covariates; intent-to-treat (ITT) population Hazard ratio (HR) <1 implies a lower risk of progression on gefitinib Mok et al 2009 IPASS: pre-planned analysis of ORR by EGFR mutation status ORR (%) 71.2 Gefitinib Carboplatin / paclitaxel EGFR M+ OR (95% CI) 2.75 (1.65, 4.60), p=0.0001 47.3 EGFR M- OR (95% CI ) 0.04 (0.01, 0.27), p=0.0013 23.5 1.1 (n=132) (n=129) (n=91) (n=85) ITT population OR>1 implies greater chance of response on gefitinib OR and p-value from logistic regression with covariate Mok et al 2009 11
NEJ002: study of first-line gefitinib versus carboplatin / paclitaxel in EGFR mutation positive patients: PFS Probability of PFS 1.00 0.75 0.50 N Gefitinib Carboplatin / paclitaxel 96 98 HR (95% CI) = 0.357 (0.25, 0.51) p<0.001 Median PFS (months) 10.4 5.5 0.25 0.00 0 100 200 300 400 500 Time from randomisation (days) Log rank test HR <1 implies a lower risk of progression on gefitinib Kobayashi et al 2009 Saturn PFS in EGFR mut+ tumours* PFS probability 1.0 0.8 0.6 Erlotinib (n=22) Placebo (n=27) HR=0.10 (0.04 0.25) Log-rank p<0.0001 0.4 0.2 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) *60% censored 12
Survival according to type of mutation after first-line EGFR TKI Probability of survival 1.00 0.75 N EGFR+ / KRAS WT 47 RR (%) 68 Median TTP (months) 13.1 Median OS (months) 24.5 EGFR WT / KRAS+ 41 0 3.3 13.0 EGFR WT / KRAS WT 83 5 3.1 11.8 P <0.001 <0.0001 0.002 0.50 0.25 0.0 0 6 12 18 24 30 36 42 48 Time from randomisation (months) RR, response rate; TTP, time-to-progression; OS, overall survival Jackman et al 2009 EML4-Alk Translocation A Novel Driver in NSCLC Horn and Pao. J. Clin. Oncol. 27,4232,2009. 13
Clinical Characteristics of EML4-ALK+ NSCLC Adenocarcinoma Young Never or Light Smokers Resistant to EGFR-TKI s Shaw et al. J. Clin. Oncol. 27,4247,2009 14
Results with Paclitaxel and Trastuzumab in a patient with NSCLC and HER2 mutation (Exon 20 G776L) baseline 2 months 4 months EGFR FISH + HER2 FISH + EGFR Exon 21 A859T HER2 Exon 20 G776L Cappuzzo et al NEJM 2006 However Of all lung cancer 85% is attributable to smoking Most adenocarcinoma of the lung is attributable to smoking If genomic analysis of adenocarcinoma of the lung is unknown, cisplatin doublet is the standard of therapy. 15