1. ReferenceStudy Type Risk of Lung Cancer Compared with Nonsmoker MenWomen Risch 1 Case control 9.627.9 Harris 2 Case control 24.541 Zang 3 Case control 11.621.4 Osann 4 Case Control All lung cancer: 19.7All lung cancer: 15.0 Henschke 5 Logistic regression analysis of smokers on screening study 2.7 compared with men 1. Risch HA, et al. Am J Epidemiol. 1993;138:281. 2. Harris RE, et al. Int J Epidemiol. 1993;22:592. 3. Zang EA, et al. J Natl Cancer Inst. 1996;88:183. 4. Osann KE, et al. Int J Cancer. 1993;22:44. 5. Henschke CI, et al. Lung Cancer. 2004;43:1. Women Have Potential Increase in Risk from Smoking

2. Reference Type of Study/ outcome Kreuzer 1 Case control/ lung cancer risk Halpern 2 Cohort/lung cancer mortality Bach3 Cohort/lung cancer risk 1. Kreuzer M, et al. Br J Cancer. 2000;82:227-233. 2. Halpern MT, et al. J Natl Cancer Inst. 1993;85:422-423. 3. Bach PB, et al. J Natl Cancer Inst. 2003;95:470-478. Other Studies Show No Increased Risk for Women Smokers

3. 1. Wei Q, et al. J Natl Cancer Inst. 2000; 92:1764. 2. Spitz MR, et al. Cancer Epidemiol Biomarkers Prev. 2003;12:689. 3. Lord RVN, et al. Clin Cancer Res. 2002;8:2286. DNA Repair Capacity (DRC) Bulky DNA lesions from tobacco repaired by nucleotide excision repair pathway Bulky DNA lesions from tobacco repaired by nucleotide excision repair pathway DRC leads to risk of lung cancer 1,2 DRC leads to risk of lung cancer 1,2 DRC in people <60 years old, women, those with positive family history DRC in people <60 years old, women, those with positive family history However, DRC may improve response to chemotherapy 3 However, DRC may improve response to chemotherapy 3

4. Mollerup S, et al. Cancer Res. 1999;59:3317. CYP1A1 expression significantly correlates with levels of DNA adducts per pack- year smoking history CYP1A1 expression significantly correlates with levels of DNA adducts per pack- year smoking history CYP1A1 0 3006009001200 0 8 16 24 32 40 CYP1A1/10 6 GAPDH DNA-Adducts/10 8 Nucleotides r = 0.50 P =.009

5. WomenMenP-Value Response Rate19%.15 Median survival time9.2 mo 95% CI 8.1–10.4 mo 7.3 mo 95% CI 6.8–8.0 mo.0004 Alive at 1 y38%31% Alive at 2–3 y14%/7%11%/5% Improvement in survival remained even when adjusted for performance status, weight loss, brain metastases, and stage. Wakelee HA, et al. J Thorac Oncol. 2006;1:441. * Patients treated with 1 of 4 platinum doublets. Survival Differences by Gender in E1594*

6. WomenMenP-Value N = 1157431 (37%)726 (63%) Nausea83%70%<.0001 Vomiting65%52%<.0001 Alopecia64%53%.0003 Neurosensory49%42%.02 Neuropsychiatric22%14%.001 Cardiac toxicity grade 3 4.1%7.6%.02 No difference in leukopenia, thrombocytopenia, anemia, coagulation, infection, diarrhea, stomatitis, hepatitic toxicity, hypertension/hypotension. Wakelee HA, et al. J Thorac Oncol. 2006;1:441. * Patients treated with 1 of 4 platinum doublets. E1594 Toxicity*

7. MenWomen OS (HR) 0.69 P =.003 0.96 P =.80 PFS (HR) 0.53 P.0001 0.68 P =.002 RR (%) 23.5 vs 12 P =.006 31.7 vs 7.4 P <.0001 Brahmer J, et al. J Clin Oncol. 2007;24(18S). Abstract 7036. Survival Differences by Gender in E4599* *Patients treated with carboplatin/paclitaxel/bevacizumab vs carboplatin/paclitaxel. OS = overall survival; HR = hazard ratio; PFS = progression-free survival; RR = response rate.

8. Gender Differences in E4599 Higher proportion of women on carboplatin/paclitaxel/ bevacizumab compared with paclitaxel/carboplatin with liver involvement (P =.003) and slightly higher proportion with prior weight loss Higher proportion of women on carboplatin/paclitaxel/ bevacizumab compared with paclitaxel/carboplatin with liver involvement (P =.003) and slightly higher proportion with prior weight loss Higher proportion of women on the carboplatin/paclitaxel/ bevacizumab compared with men on the carboplatin/paclitaxel/ bevacizumab arm had hypertension (P =.02) Higher proportion of women on the carboplatin/paclitaxel/ bevacizumab compared with men on the carboplatin/paclitaxel/ bevacizumab arm had hypertension (P =.02) More grade 5 febrile neutropenia experienced by women than by men on carboplatin/paclitaxel/bevacizumab (P =.03) More grade 5 febrile neutropenia experienced by women than by men on carboplatin/paclitaxel/bevacizumab (P =.03) No differences in % receiving maintenance bevacizumab or 2nd- line treatment No differences in % receiving maintenance bevacizumab or 2nd- line treatment Brahmer J, et al. J Clin Oncol. 2007;24(18S). Abstract 7036.

9. Median Survival Time by Gender and Age 1 Age P-Value <60 years 60 years Women9.0 months n = 274 11.6 months n = 337.03 Men8.3 months n = 390 7.4 months n = 589 NS (0.17) 1. Wakelee HA, et al. J Thorac Oncol. 2007;2(8 suppl 4). Abstract P1-052. 2. Albain K, et al. J Clin Oncol. 2007;25(18S). Abstract 7549. Confirmed similar results by SWOG, presented at ASCO 2007 2 Menopausal Status of Women Affects Survival with Advanced NSCLC Combined Analysis of E1594 and E4599

10. Nelson HH, et al. J Natl Cancer Inst. 1999;91:2032. Positive/TotalPositive (%) Men16/9217.4 Women28/10726.2 K-ras Mutations Promotes cancer growth in response to estrogen and other hormones Promotes cancer growth in response to estrogen and other hormones Significant association between female gender and K-ras mutation after adjustment for carcinogen exposure (OR = 3.3) Significant association between female gender and K-ras mutation after adjustment for carcinogen exposure (OR = 3.3) K-ras mutations in resected lung cancers from female vs male smokers K-ras mutations in resected lung cancers from female vs male smokers