CE-1 IRESSA ® Clinical Efficacy Ronald B. Natale, MD Director Cedars Sinai Comprehensive Cancer Center Ronald B. Natale, MD Director Cedars Sinai Comprehensive Cancer Center

CE-2 Outline  Pivotal data from Trial 39  Supportive data from Trial 16  Association between response, disease- related symptoms, and other clinical signs  Conclusions  Pivotal data from Trial 39  Supportive data from Trial 16  Association between response, disease- related symptoms, and other clinical signs  Conclusions

CE-3 IRESSA ® 3rd-Line Program Rationale  No effective treatment following 2nd-line therapy  Disease progression inevitable  Symptom worsening likely  No effective treatment following 2nd-line therapy  Disease progression inevitable  Symptom worsening likely

CE-4 Study Aims Determine for each dose  Objective response rate §  Symptom improvement rate §  Safety profile Randomization  250 mg versus 500 mg daily oral doses Determine for each dose  Objective response rate §  Symptom improvement rate §  Safety profile Randomization  250 mg versus 500 mg daily oral doses Trial 39 §Hypothesis: > 5% response and symptom improvement rate.

CE-5 Rationale for Dose Selection  250 mg –Above the lowest dose at which clinical response seen  500 mg –Highest dose level that is well tolerated chronically by most patients  250 mg –Above the lowest dose at which clinical response seen  500 mg –Highest dose level that is well tolerated chronically by most patients

CE-6 Prior Therapy Inclusion Criteria  Received prior treatment with at least 2 chemotherapy regimens that contained platinum and docetaxel, given concurrently or as separate regimens  Prior regimens must have failed the patient because of disease progression on therapy or unacceptable toxicity  Patients who entered trial due to disease progression on therapy had to have documentation that their most recent dose of chemotherapy was within 90 days prior to this progression  Received prior treatment with at least 2 chemotherapy regimens that contained platinum and docetaxel, given concurrently or as separate regimens  Prior regimens must have failed the patient because of disease progression on therapy or unacceptable toxicity  Patients who entered trial due to disease progression on therapy had to have documentation that their most recent dose of chemotherapy was within 90 days prior to this progression Trial 39

CE-7 3rd-Line NSCLC Patient Eligibility  96% of patients satisfied the inclusion criteria  “Refractory/Resistant” versus “Sensitive” –Not relevant to NSCLC –No precedence in NSCLC  96% of patients satisfied the inclusion criteria  “Refractory/Resistant” versus “Sensitive” –Not relevant to NSCLC –No precedence in NSCLC

CE-8  Investigator assessed  SWOG modified UICC/WHO criteria –Standard, well established –Response categories (CR, PR, SD) required confirmation ≥ 28 days  Tumor assessed: day 28, 56, every 2 months  Investigator assessed  SWOG modified UICC/WHO criteria –Standard, well established –Response categories (CR, PR, SD) required confirmation ≥ 28 days  Tumor assessed: day 28, 56, every 2 months Trial 39 Objective Response Assessment

CE-9 Symptom Improvement Criteria  Lung Cancer Subscale (LCS), a component of FACT-L  Validated, sensitive, reliable  7 scored symptoms –Pulmonary Shortness of breath Cough Tightness in the chest Ease of breathing –Advanced cancer Weight loss Appetite Thinking clearly Trial 39 §Cella et al. J Clin Epid. 2002;55:

CE-10 Symptom Improvement Criteria  Lung Cancer Subscale (LCS), a component of FACT-L  Validated, sensitive, reliable §Cella et al. J Clin Epid. 2002; 55:  Minimum 2-point improvement in patient’s total score required to be considered as improvement  Minimum 2-point improvement in patient’s total score required to be considered as improvement  Minimum group score change known to have statistically significant association with NSCLC patient outcomes including objective response, TTP, PS and body weight § Trial 39

CE-11 Symptom Improvement Criteria  Minimum duration of 4 weeks with no interval worsening of ≥ 2 points from baseline  Clinically significant if expected median survival ≤ 6 months  Reduces likelihood of possible placebo effect  Weekly assessment  Precedes tumor response assessment  Markedly enlarge data base  Minimize impact missing data point(s)  Precedes tumor response assessment  Markedly enlarge data base  Minimize impact missing data point(s) Trial 39 §Cella et al. J Clin Epid. 2002;55:

CE-12 Results of Trial 39

CE-13 Summary of Demographic Characteristics 250 mg N = mg N = 114 Median age, years6162 M:F, %59:4155:45 WHO PS = 2, %1920 Adenocarcinoma, %6964 Metastatic disease, %8592 ≥ 2 sites5970 Median time from diagnosis to entry, months 2417 Trial 39

CE-14 Prior Treatment Summary Patients, n (%) Treatment history 250 mg N = mg N = 114 ≥ 2 prior regimens100 (98)114(100) Prior platinum and docetaxel101 (99)113(99) Most recent therapy Progressive disease ≤ 90 days82 (80)88(77) Unacceptable toxicity15 (15)23(20) Trial 39

CE-15 Highly Symptomatic Patient Population Patients, % Asymptomatic Most severe symptoms Study entry: percent patients at each LCS score Median: 16.0 Range: 2 to 26 Median Eligibility criterion Trial 39

CE-16 Objective Tumor Response Rate by Dose 500 mg250 mg Vertical bars represent 95% CI. Trial 39

CE-17 The 22 IRESSA ® Responders  22 PRs –13 with tumor area 10 to 60 cm 2 –5 with tumor area < 10 cm 2 –4 with nonmeasurable disease  16 achieved PR status by Week 4  All PR achieved by 16 weeks  16 achieved PR status by Week 4  All PR achieved by 16 weeks  Median duration (updated December 2001) –7.4 months at 250 mg –5.8 months at 500 mg  Median duration (updated December 2001) –7.4 months at 250 mg –5.8 months at 500 mg  Responses observed regardless of prior regimens, performance status, age, gender Size Quality Duration Rapidity Trial 39

CE-18 Symptom Improvement Rate LCS data collection: the average weekly compliance was 84% (range, ) N = 102N = 104 Vertical bars represent 95% CI. Trial 39  2-point increase  28 days

CE-19 Mean LCS Change by Week All Patients 16 Vertical bars represent 95% CI. LCS score change Weeks from randomization Trial 39

CE-20 The 84 IRESSA ® Symptom Improvers  Mean change on study 4.5 points on LCS  Greatest improvement: shortness of breath, coughing, ease of breathing, tightness in chest  86% onset of improvement within 4 weeks  75% response at 3 months  65% response at 6 months  Median not reached  75% response at 3 months  65% response at 6 months  Median not reached  Symptom improvement observed regardless of prior regimens, performance status, age, gender  40% had 6 to 7 symptoms improve  1 point  32% received new supportive medications (vs 46% of those without symptom improvement)  Symptom improvement observed regardless of prior regimens, performance status, age, gender  40% had 6 to 7 symptoms improve  1 point  32% received new supportive medications (vs 46% of those without symptom improvement) Size Quality Duration Rapidity Trial 39

CE-21 Summary of Antitumor Effects and Symptom Benefit of IRESSA ®  IRESSA response rate of 10% was achieved in heavily pretreated NSCLC patients  IRESSA symptom improvement rate of 40% was achieved in 3rd-line NSCLC patients  Responses and symptom improvements –Rapid –Durable –Similar for both doses  IRESSA response rate of 10% was achieved in heavily pretreated NSCLC patients  IRESSA symptom improvement rate of 40% was achieved in 3rd-line NSCLC patients  Responses and symptom improvements –Rapid –Durable –Similar for both doses Trial 39

CE-22 IRESSA ® Supportive Trial 16

CE-23 Supportive Trial 16  Same design and methods as Trial 39  Eligibility difference –Maximum 2 prior regimens Prior platinum required Prior docetaxel not required –Progression within 90 days not required –Symptoms not required at entry  Same design and methods as Trial 39  Eligibility difference –Maximum 2 prior regimens Prior platinum required Prior docetaxel not required –Progression within 90 days not required –Symptoms not required at entry Trial 16

CE-24 Results of Trial 16

CE-25 Summary of Patient Characteristics 250 mg N = mg N = 106 Median age, years6160 M:F, %75:2566:34 WHO PS = 2, %13 Adenocarcinoma, %6264 Metastatic disease, %7881 Median time from diagnosis to entry, months Symptom evaluable at entry, % prior regimens, %4443 Trial 16

CE-26 Objective Tumor Response Rate by Dose Vertical bars represent 95% CI. Trial 16

CE-27 The 39 IRESSA ® Responders  39 responders –1 CR –38 PRs 26 with tumor area 10 to 85 cm 2 11 with tumor area < 10 cm 2 1 nonmeasurable  31 achieved PR status by Week 4  39 achieved PR status by Week 16  31 achieved PR status by Week 4  39 achieved PR status by Week 16  Median not reached (1 to 6+, 90% ongoing with followup time 4 to 8 months)  Responses observed regardless of 1 or 2 prior regimens, performance status, age, gender Size Quality Duration Rapidity Trial 16

CE-28 Symptom Improvement Rate by Dose N = 67 N = Vertical bars represent 95% CI. Trial 16

CE-29 Summary of Antitumor Effects and Symptom Benefit  Overall objective response rate 19 % in 2nd- and 3rd-line NSCLC  Overall symptom improvement rate 39%  Results supportive of Trial 39 results  Overall objective response rate 19 % in 2nd- and 3rd-line NSCLC  Overall symptom improvement rate 39%  Results supportive of Trial 39 results Trial 16

CE-30 Tumor Response and Symptom Improvement Association Trial 39

CE-31 Association of Tumor and Symptom Response Partial responseStable diseaseProgressive disease Symptom improvement rate, % 250 mg* 500 mg* 100 n = *P <.0001 Trial 39

CE-32 LCS Mean Change by Week All Patients 16 Trial 39 LCS score change Weeks from randomization –2 –4 –6 –8 –10

CE-33 LCS Mean Change by Week by Objective Response Trial 39 LCS score change Weeks from randomization –2 –4 –6 –8 10 6

CE-34 LCS Mean Change by Week Patients with a Partial Response Baseline17.6 Mean change % CI P-value<.001 Trial 39 Vertical bars represent 95% CI. LCS score change Weeks from randomization –2 –4 –6 –8 10 6

12 months1 month Pre-IRESSA ® Baseline 46-year-old female, Stage IV NSCLC, CNS metastases Carbo/paclitaxel, carbo/docetaxel, gemcitabine, vinorelbine CE-35 Patient 0037 Trial 39

CE-36 Patient 0037 Aggressive, Bulky Disease Weeks from randomization LCS score (–85%) PR 6.3 (–89%) PR 4.8 (–92%) PR 3.3 (–95%) PR 3.3 (–95%) PR Lung, liver: 60 cm 2 CNS: nonevaluable 60 (0) Craniotomy Most improved Cough Appetite Chest tightness –2 Trial 39

CE-37 Patient 0166: PS 2 “Non-Bulky” Disease Weeks from randomization LCS score (–56%) PR 2.0 (–67%) PRNM nodes 1.0 (–84%) PR Pneumonia Liver: 6.1 cm 2 Nodes, bone, lung: nonmeasurable PS 1 Most improved Breathing Cough Appetite 6.1 (0) –2 PS 2 Trial 39

CE-38 Association of Tumor Response and PS Improvement Trial 39

CE-39 Summary of Association Between Tumor Response and Symptom Improvement  Responders derive clinical benefit  Significant symptom improvement  Rapid and durable symptom improvement  Responders derive clinical benefit  Significant symptom improvement  Rapid and durable symptom improvement

CE-40 Overall Efficacy Conclusions  IRESSA ® provides a meaningful 10% tumor response rate in 3rd-line NSCLC  IRESSA provides 40% symptom improvement rate in 3rd-line NSCLC  IRESSA efficacy findings are consistent in 2 separate but similar trials  Responders derive clinical benefit  Comparable efficacy with 250-mg and 500-mg daily dose  IRESSA ® provides a meaningful 10% tumor response rate in 3rd-line NSCLC  IRESSA provides 40% symptom improvement rate in 3rd-line NSCLC  IRESSA efficacy findings are consistent in 2 separate but similar trials  Responders derive clinical benefit  Comparable efficacy with 250-mg and 500-mg daily dose