![Lung cancer in Never-smokers A clinical entity with increasing clinical relevance in Southern California The role of chemotherapy and updates from ASCO2009 Sai-Hong Ignatius Ou, MD PhD Associate Clinical Professor [email_address] Chao Family Comprehensive Cancer Center Department of Medicine, Division of Hematology-Oncology University of California Irvine Medical Center, Orange, CA 92868 Genetic Epidemiology Research Institute Department of Epidemiology School of Medicine University of California Irvine, Irvine, CA92697](https://image.slidesharecdn.com/lomalindapresentation2009-100118231523-phpapp01/85/Never-smoker-with-lung-cancer-in-Southern-California-1-320.jpg)
![Patient case ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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Never-smoker with lung cancer in Southern California
- 1. Lung cancer in Never-smokers A clinical entity with increasing clinical relevance in Southern California The role of chemotherapy and updates from ASCO2009 Sai-Hong Ignatius Ou, MD PhD Associate Clinical Professor [email_address] Chao Family Comprehensive Cancer Center Department of Medicine, Division of Hematology-Oncology University of California Irvine Medical Center, Orange, CA 92868 Genetic Epidemiology Research Institute Department of Epidemiology School of Medicine University of California Irvine, Irvine, CA92697
- 3. Global Cancer deaths Sun Nature Review cancer 2007; 7 : 778-790
- 4. Global distribution of never-smokers Sun Nature Review cancer 2007; 7 : 778-790
- 5. NSCLC Epidemiology (Orange, San Diego, & Imperial County 1995 to 2003; N=11,969) Variable Number Percent Age 68.3 years +/- 0.1 SE --- Gender Male Female 6470 5497 54.1 45.9 Smoking status Smoker Non-smoker 8762 942 90.3 9.7 Stage Localized Regional Metastatic 2399 3071 5907 21.1 27.0 51.9
- 6. Characteristics of NSCLC according to smoking status
- 7. Characteristics of Asian subgroups Total Ever-smoker Never-smoker P N (%)^ 891 (73.9) 314 (26.1) Median age [years] (95% CI) 68 (47-83) 66 (44-86) .0359* Sex Male Female 671 (75.3) 220 (24.7) 83 (26.4) 231 (73.6) < .0001 Histology Adenocarcinoma BAC Large cell Squamous cell Undifferentiated 361 (40.5) 25 (2.8) 55 (6.2) 183 (20.5) 267 (30.0) 178 (56.7) 23 (7.3) 18 (5.7) 16 (5.1) 79 (25.2) < .0001 AJCC stage Stage 1 Stage 2 Stage 3 Stage 4 Unknown 92 (10.3) 42 (4.7) 203 (22.8) 420 (47.1) 134 (15.0) 31 (9.9) 5 (1.6) 49 (15.6) 190 (60.5) 39 (12.4) .0003
- 8. Proportion of NSCLC patients by gender & smoking status * percentage calculated across the row
- 9. Percentages of Never-smokers in Southern California
- 10. Proportion of NSCLC who were never-smokers 5 major Asian subgroups and period of diagnosis
- 11. Effect of Smoking on overall survival
- 12. Major EGFR signaling pathways
- 13. Expression pattern of EGFR in NSCLC
- 14. EFGR Expression by IHC and Survival Meta-analysis Meert et al, Eur Respir J 2002; 20: 975-981
- 15. Structures of EGFR-TK Inhibitors (Quinazolines) Gefitinib [Iressa ® (ZD1839)] MW=446 CI F N O NH N O O N Erlotinib [Tarceva ™ (OSI-774)] MW=430 O O H 3 C H 3 C O O NH N N NH N O O N
- 16. BR21 OS Shepherd NEJM 2005; 353: 123-132 Erlotinib (N=488) Placebo (N=243) Median Survival 6.7 mo 4.7 mo 1-Year Survival 31.2% 21.5%
- 17. ISEL OS At 7.2 months median follow-up OS: 5.6 months vs 5.1 months 1 yr survival rate: 27% vs 21% HR 0.89, [0.77-1.02]; P = 0.087 At 10.2 months median follow-up HR 0.89, [0.79-1.01]; P = 0.074 Thatcher et al, Lancet 2005; 366: 1527-1537
- 18. ISEL Adenocarcinoma OS At 7.2 months median follow-up OS: 6.3 months vs 5.4 months 1 yr survival rate: 30% vs 18% HR 0.84, [0.68-1.03]; P = 0.089 At 10.2 months median follow-up HR 0.84, [0.70-1.02]; P = 0.072 Thatcher et al, Lancet 2005; 366: 1527-1537
- 19. Overall Survival of ISEL Asian vs. non-Asian Chang JTO 2006; 1: 847-855
- 20. 1. Asians have higher proportion of never-smokers with lung cancer 2. Asian seems to response and have better survival to inhibitors of Epidermal Growth Factor Receptor (EGFR) Why?
- 21. Discovery of activating EGFR mutations in NSCLC
- 22. List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
- 23. Distribution of EGFR mutations Shigematsu Gazdar Int J Cancer 2006; 118: 257-262
- 24. EGFR mutation incidence by cigarette-smoking status Pham et al JCO 2006; 24: 1700-1704 Pham et al JCO 2006; 24: 1700-1704
- 44. Not all mutations are the same!!!
- 45. List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
- 46. Differential response of exon 19 deletions & L858R point mutation to TKIs Riely et al, Clin Cancer Res 2006; 12: 839-844
- 47. Differential response of exon 19 deletions & L858R point mutation to TKIs Jackman et al, Clin Cancer Res 2006; 12: 3908-3914 No K-ras mutation identified RR: gefitinib (78%) vs erlotinib (33%) (P = 0.035) Exon 19 deletion L858R mutation P N 22 10 CR 9% 0% PR 64% 50% ORR 73% 50% 0.25 Median OS 38 mo 17 mo 0.0384 Median TTP 24 mo 10 mo 0.04 Median Duration of Rx for CR/PR 16 mo 13 mo 0.46 Median duration of RX for SD 26 mo 10 mo 0.01
- 53. List of EGFR mutations in NSCLC Sharma Nature Review Cancer 2007; 7: 169-181
- 55. EGFR-TKIs Selectivity IC 50 (nM) EGFR-1 HER-2 Erlotinib (Tarceva) 2 350 Gefitinib (Iressa) 23 3700 BIBW2992 (Tovok) 0.5 14 Lapatinib (GW572016) 11 9
- 56. EGFR-TKIs In vitro EGFR activity IC 50 (nM) Cell line BIBW2992 Gefitinib NCI-H1666 (EGFR WT) 7 100 NCI-H3255 (L858R) 6 50 NCI-H1975 (L858R + T790M) 93 resistant
- 57. 1200.22 Patient 1 46 yo Hispanic Female Never-smoker Exon19 deletion 8/20/2008 9/15/2008
- 58. 1200.22 Patient 1 46 yo Hispanic Female Never-smoker Exon19 deletion 3/2/2009
- 59. 1200.22 Patient 2 63 yo Vietnamese Female Never-smoker Exon19 deletion 12/16/2008 1/9/2009
- 60. 1200.22 Patient 2 63 yo Vietnamese Female Never-smoker Exon19 deletion 2/9/2009 3/9/2009
- 63. Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and ALK Inhibitor PF-02341066 EL Kwak 1 , DR Camidge 2 , J Clark 1 , GI Shapiro 3 , RG Maki 4 , MJ Ratain 5 , B Solomon 6 , Y-J Bang 7 , S-H Ou 8 , R Salgia 5 1. Massachusetts General Hospital 5. University of Chicago Cancer Center 2. University of Colorado Cancer Center 6. Peter MacCallum Cancer Centre 3. Dana-Farber Cancer Institute 7. Seoul National University 4. Memorial Sloan-Kettering Cancer Center 8. University of California at Irvine
- 65. Initial characterization of EML4-ALK fusion in NSCLC Soda Nature 2007; 448:561-566
- 66. Schema of EML4-ALk NSCLC translocations Wong Cancer 2009; 115; 1723-1733
- 67. EML4-ALK NSCLC Adenocarcinoma comparisons (N = 209) Wong Cancer 2009; 115; 1723-1733 EML4-ALK positive EML4-ALK negative Total P Median age 59 (51-61) 64 (55-71) 64 (54.5-71) 0.018 Smoking status Never-smoker Ever-smoker 10 (90.9) 1 (9.1) 117 (59.1) 81 (40.9) 127 (60.8) 82 (39.2) 0.053 EGFR Mutated Wildtype 0 (0) 11 (100) 121 (61.10 77 (38.9) 121 (57.9) 88 (42.1) < 0.001
- 69. EML4-ALK Patients: Waterfall Plot Tumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK Fusions For 2 patients whose best response was PD, patients discontinued prior to first on-study scan 2 16 20 40 8+ 12 4+ 13+ 15+ 8+ 23+ 15+ 2+
- 70. 48 YO Female Non-Smoker with EML4-ALK NSCLC Pre-Treatment After 2 Cycles PF-02341066
- 71. My own pt 51 yo Caucasian Male NSCLC Failed Tarceva, on 6 th line Rx before enrolling in c-met trial Before and After c-met inhibitor Before After 2 months of c-met
- 73. 1 st & 2 nd -line treatment for Never-smoker with NSCLC EGFR Mutation Positive (~60%) EML4-ALK translocation Positive (~5%) EGFR WT EGFR Unknown EGFR not tested (~35%) 06-62 08-01 07-40 A8081007 A8081005 08-49 PF-00299804 1200.32 1200.42
- 74. The End
- 79. Proportion of male NSCLC never-smoker By period of diagnosis and 5 Asian subgroups
- 80. Proportion of female NSCLC never-smoker By period of diagnosis and 5 ethnicities
- 83. Cox models for Never-smokers and Smokers Never-smoker Smoker HR 95% CI P HR 95% CI P Ethnicity* Caucasian Asian African-American Hispanic 1.000 0.866 1.126 0.843 (0.751-0.999) (0.796-1.592) (0.714-0.996) .0483 .8938 .0446 1.000 0.866 0.987 0.981 (0.807-0.928) (0.901-1.081) (0.923-1.043) < .0001 .7800 .5450 Gender Male Female 1.000 0.786 (0.707-0.874) < .0001 1.000 0.841 (0.814-0.868) < .0001 AJCC stage 1 2 3 4 1.00 2.788 2.242 3.033 (2.053-3.785) (1.784-2.818) (2.465-3.731) < .0001 < .0001 < .0001 1.00 1.675 2.009 2.893 (1.537-1.826) (1.885-2.142) (2.729-3.068) < .0001 < .0001 < .0001 Age 1.015 (1.011-1.019) < .0001 1.012 (1.010-1.013) < .0001
- 84. Place of birth-North America Smoker (%)* Never-smoker (%)* Canada All (N=176) Male Female 162 (92.1%) 79 (95.2%) 83 (89.2%) 14 (7.9%) 4 (4.8%) 10 (10.8%) Mexico All (N=647) Male Female 516 (79.8%) 373 (91.6%) 143 (59.6%) 131 (20.3%) 34 (8.4%) 97 (40.4%)
- 85. Interplay between CA repeats and promoter polymorphism in EGFR gene Nomura PLoS Med 2007; 4 (4):e125
- 86. California Cancer Registry http://statecancerprofiles.cancer.gov/
- 87. Birthplace of Asian patients Filipino Vietnamese Chinese Japanese Koreans All Never-smoker Smoker All Never-smoker Smoker All Never-smoker Smoker All Never-smoker Smoker All Never-smoker Smoker N 446 113 333 396 114 282 137 47 90 148 22 126 78 18 60 Native-born Yes (%) No (%) 410 (91.9) 36 (8.1) 107 (94.7) 6 (5.3) 303 (91.0) 30 (9.0) 342 (86.4) 54 (13.6) 101 (88.6) 13 (11.4) 241 (85.5) 41 (14.5) 111 (81.0) 26 (19.0) 36 (76.6) 11 (23.4) 75 (83.3) 15 (16.7) 73 (49.3) 75 (50.7) 14 (63.6) 8 (36.4) 59 (46.8) 67 (53.2) 57 (73.1) 21 (26.9) 12 (66.7) 6 (33.3) 45 (75.0) 15 925.0)
- 88. Proportion of never-smokers by Asian subgroups
- 89. OS according to stage stratified by smoking status
- 90. Pharmodynamic blockade of EGFR pathway
- 91. Positions of Mutations Detected in HER1/EGFR Tyrosine Kinase Domain in NSCLC 747-750 Activation loop L858 G719 Autophosphorylation Tyrosine kinase EGF ligand binding K R H DFG GXGXXG L L Y 718 745 776 835 858 861 869 964 18 19 20 21 22 23 24 757-750 Exon: Paez: Lynch: Pao: Tumor with point mutation (amino acid substitution) Tumor with in-frame deletion EGF = endothelial growth factor; TM = transmembrane. Adapted from: Pao et al. Proc Natl Acad Sci U S A. 2004;101:13306; Lynch et al. N Engl J Med . 2004;350:2129; Paez et al. Science . 2004;304:1497. 719 858 TM K DFG Y Y Y Y
Editor's Notes
- In total, there were 11,969 incident cases of non-small-cell lung cancer during the defined study period detected in our database. Mean age was 68.3 years, and 54% of the group was male. The majority of patients were caucasian (80.4%).
- Structures of EGFR-TK Inhibitors (Quinazolines) IRESSA (gefitinib [ZD1839]) and Tarceva (erlotinib [OSI-774]) are low molecular weight quinazolines that are highly selective and specific inhibitors of EGFR-TK The ATP-mimetic portions of these molecules are highlighted in white
- This is a schematic view of EGFR and its key domains. The extracellular ligand-binding domain The transmembrane domain The tyrosine kinase domain The autophosphorylation domain The tyrosine kinase domain (exons 18 through 24) is expanded, showing the sites of described point mutations at G719, S752, R776, H835, L858, and L861, and in-frame deletions at L747-A750. In the 3-dimensional ribbon structure of the intracellular domain shown on the right of the slide, the positions of 3 of these mutations are shown relative to the activation loop. Pao et al. Proc Natl Acad Sci U S A . 2004;101:13306. Lynch et al. N Engl J Med . 2004;350:2129; Paez et al. Science . 2004;304:1497.