1. FIRST-LINE THERAPY FOR ADVANCED NSCLC Rogerio C. Lilenbaum, MD Clinical Associate Professor of Medicine University of Miami School of Medicine Director, Thoracic Oncology Program The Mount Sinai Comprehensive Cancer Center Miami Beach, FL

2. QUESTIONS FOR DISCUSSION What are the options for 1 st line therapy? What is the optimal management of the elderly and the PS 2 patients? What is the role of the non-platinum regimens? What is the role of the molecular targeted agents in 1 st line therapy?

3. Cis/Vin and Cis/Gem vs. Cisplatin : Overall Survival 100% 80% 60% 40% 20% 0% 01224364860 J Clin Oncol 2000, 18:122-30. P=.004 Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 05101520 25 Gem/Cis 260 9.0 39% 15% Cis 262 7.6 28% 8% N MS 1YS 2YS Vin/Cis 206 8 36% 12% Cis 209 6 21% 7% Cis/Vin vs Cisplatin J Clin Oncol 1998, 16:2459-64. Cis/Gem vs Cisplatin

4. Median Survival Survival NDeaths(Months)1-Year2-Year 1 CBDCA+Pac208159838%15% CDDP+Vin202156836%16% 0612182430 Months 100% 80% 60% 40% 20% 0% Cis-Vinorelbine vs Carbo-Paclitaxel SWOG 9509 1 J Clin Oncol. 2001;19:3210-3218.

5. A Phase III Four-Arm Trial in Advanced NSCLC Paclitaxel 135 mg/m 2 over 24 hours, day 1 Cisplatin 75 mg/m 2, day 2 Gemcitabine 1000 mg/m 2 days 1, 8, and 15 Cisplatin 100 mg/m 2 day 1 Docetaxel 75 mg/m 2 day 1 Cisplatin 75 md/m 2 day 1 Paclitaxel 225 mg/m 2 over 3 hours, day 1 Carboplatin AUC=6 day 1 RANDOMIZEDRANDOMIZED Stratification PS 0-2 WT Loss Stage - IIIB, IV Brain mets (+/-) Schiller, NEJM 2002:92-98

6. A Phase III Four-Arm Trial in Advanced NSCLC RegimenRR (%) MST (mo.) TTP (mo.) 1-yr Survival (%) Cis/Paclitaxel21.37.83.531 Cis/Gemcitabine21.08.14.5*36 Cis/Docetaxel17.37.43.631 Carbo/Paclitaxel15.38.23.335 *P =.002 by log rank test

7. A Phase III Four-Arm Trial in Advanced NSCLC CIS-PACCIS-GEMCIS-DOCCARBO- PAC N = 282N = 273N = 278N = 272 GR 4 ANC55374942 Gr 4 thrombocytopenia226*12 Gr 3 nausea2536238* Gr 3 neuropathy4858 Gr 3-4 febrile neutropenia164*103* Gr 3-5 renal39*31 Worst Gr 4-589708657* *P < 0.05 vs. Arm A

8. Tax 326: Randomized Phase III Trial for Advanced NSCLC RANDOMIZERANDOMIZE Stratification Factors: Stage of Disease IIIB vs. IV Region US/Canada Latin America Europe/Lebanon Israel South Africa/Australia New Zealand Response assessment every 2 cycles Docetaxel 75mg/m 2 IV Carboplatin AUC 6 IV Q 3 wks Vinorelbine 25mg/m 2 IV D 1, 8, 15 & 22 Cisplatin 100mg/m 2 IV D 1Q 4 wks Docetaxel 75mg/m 2 IV Cisplatin 75mg/m 2 IV Q 3 wks vs.

9. 406396401 10.910.09.1 464138 211416 Tax 326: Randomized Phase III Trial for Advanced NSCLC Docetaxel /Navelbine/ Docetaxel / CisplatinCisplatinCarboplatin N Median survival (mo) 1-Yr survival (%) 2-Yr survival (%) Belani et al. 2001 P=.044, Adjusted Log-Rank 2y Survival 21 vs 14%, p =.035 P=.66, Adjusted Log-Rank 2 y Survival 18 vs 14% Cis/Tax vs. Cis/NavCarbo/Tax vs Cis/Nav

10. ASCO 2002 Clinical Trials of 2-Drugs vs 1 StudyTherapyMST1-Yr Surv CALGB 1 Paclitaxel P + Carbo 6.7 m 8.8 m 33% 37% SLUSG 2 Gemcitabine G + Carbo 9.0 m 11.0 m 32% 44% GCGLC 3 Docetaxel D + Cispl 8.0 m 10.1 m 42% 48% 1 Proc ASCO 21:1a (A #2), 2002; 2 Proc ASCO 21:291a (A #1162), 2002; 3 Proc ASCO 21:291a (A #1163), 2002

11. CALGB 9730 - DESIGN RANDOMIZERANDOMIZE Paclitaxel 225 mg/m 2 over 3 hours on day 1 Paclitaxel 225 mg/m 2 + Carboplatin to AUC 6 Every 3 weeks for up to 6 cycles IIIB/IV PS 0-1/2 Age  /  70 Lilenbaum, ASCO 2002

12. CALGB 9730 – SURVIVAL P = 277CP = 284 FFS (mo) (95% CI) 2.5 (2.3, 2.8) 4.6 (4.1, 5.3) MST (mo) (95% CI) 6.7 (5.8, 7.9) 8.8 (8.8, 9.9) 1-Y SURV (95% CI) 33% (28%, 39%) 37% (32%, 43%) Median follow-up was 19.7 months

13. CALGB 9730 – OVERALL SURVIVAL Log-rank = 0.2022 Wilcoxon = 0.0125

14. Gemcitabine/Carboplatin versus MIC Gemcitabine 1200 mg/m 2 d 1, 8 Carboplatin AUC = 5 d 1 q.21 days Mitomycin 6 mg/m 2 Ifosfamide 3 g/m 2 Cisplatin 50 mg/m 2 Day1 q.21 days Stage IIIb/IV NSCLC PS 0-3 Rudd, ASCO 2002:A1164

15. LLCG: GC vs MIP in Advanced NSCLC Survival GC MIP Proportion Surviving Pts. Med 1-Y GC 10.2m 38% MIP 6.9m 28% Months

16. What are the options for 1 st line therapy? Patients with advanced NSCLC and good PS should be treated with a platinum-based doublet. Platinum-based doublets are better than an old single agent (Cis) and a new single agent (Paclit) All platinum-based doublets have comparable efficacy, but vary in cost and toxicity Three-drug regimens are more toxic and no better than doublets The preferred platinum analog remains controversial CISPLATIN CARBOPLATIN PACLITAXEL DOCETAXEL VINORELBINE GEMCITABINE +

17. QUESTIONS FOR DISCUSSION What are the options for 1 st line therapy? What is the optimal management of the elderly and the PS 2 patients? What is the role of the non-platinum regimens? What is the role of the molecular targeted agents in 1 st line therapy?

18. Non-Platinum Regimens Deliver comparable survival with less toxicity better therapeutic index Represent alternative regimens to patients who are not optimal candidates for platinum-based therapy

19. Non-Platinum, Taxane-Based Doublets Paclitaxel + gemcitabine Docetaxel + gemcitabine Paclitaxel + vinorelbine Docetaxel + vinorelbine Non-Platinum, Non-Taxane Doublets Vinorelbine + Gemcitabine Gemcitabine + Irinotecan Vinorelbine + Ifosfamide

20. A EORTC Randomized Phase III Trial of Three Chemotherapy Regimens In Advanced Non-Small Cell Lung Cancer NSCLC PS 0-2 Stage IIIB or IV Paclitaxel 175 mg/m 2 d 1 Cisplatin 80 mg/m 2 d 1 every 21 days Gemcitabine 1250 mg/m 2 d 1, 8 Cisplatin 80 mg/m 2 d 1 every 21 days Gemcitabine 1250 mg/m 2 d 1, 8 Paclitaxel 175 mg/m 2 d 1 every 21 days Van Meerbeeck et al, Proc Am Soc Clin Oncol, 20: #1228, 2001 RANDOMIZEDRANDOMIZED

21. Van Meerbeeck - Efficacy Cis/PacCis/GemPac/Gem Response Rate 31%36%27% PFS4.4 mo5.6 mo3.9 mo Median Survival 8.1 mo8.8 mo6.9 mo 1-year Survival 35.5%32.6%26.5%

22. Van Meerbeeck - Toxicity Toxicity (% of pts)Cis/PacCis/GemPac/Gem Gr. 3/4 ANC334330 Neutropenic Fever132 Gr. 3/4 Thrombocytopenia1366 Gr. 3/4 Bleeding101 Gr. 3/4 Anemia3114 Gr. 3/4 Nausea8136 Gr. 3/4 Vomiting8135 Gr. 3/4 Sensory Neurotoxicity 321 Gr. 3/4 Motor Neuropathy313 Gr. 3/4 Lethargy911 Gr. 3/4 Dyspnea81012 Toxic deaths314

23. GEMVIN – Study design RANDOM Cisplatin 80 mg/ /m², d 1 Vinorelbine 30 mg/m², d 1&8 or (at random) Cisplatin 80 mg/ /m², d 1 Gemcitabine 1200 mg/m², d 1&8 Gemcitabine 1000 mg/m², d 1&8 Vinorelbine 25 mg/m², dd 1&8 Every 3 weeks, for a maximum of 6 cycles Gridelli, ASCO 2002

24. GEMVIN – Progression-free survival CDDP-based (n=250) GemVin (n=251) # events (%)212 (85)222 (88) Median PFS (95% CI) (wks) 23 (18-27)17 (14-20) 6 – month PFS probability 0.440.26 1 – year PFS probability0.130.09 GemVin vs CDDP-based1.29 (1.10-1.52)*p=0.004

25. GEMVIN – Overall survival CDDP-bsed (n=250) GemVin (n=251) # events (%)175 (70)180 (72) Median OAS (95% CI) (wks) 38 (35-45)32 (30-39) 6 – month OAS probability0.660.62 1 – year OAS probability0.370.31 GemVin vs CDDP-based1.15 (0.96-1.37)*p=0.08

26. Phase II Study of Vinorelbine-Gemcitabine vs Paclitaxel-Carboplatin Stratification Stage IIIB/IV PS 0−1/2 R A N D O M IZ A T I O N Vinorelbine 25 mg/m 2 days 1, 8 Gemcitabine 1,000 mg/m 2 days 1, 8 Paclitaxel 200 mg/m 2 day1 Carboplatin (AUC=6) day 1 Every 3 weeks, for a maximum of 6 Cycles Primary endpoint: QoL analysis (LCSS)

27. What is the role of the non-platinum regimens? Taxane-based regimens appear to offer comparable efficacy to platinum-based combinations Toxicity, however, is not significantly reduced and ca be substantial, especially in patients with less than optimal performance status The non-platinum, non-taxane based regimens are less toxic, but questions about equivalent efficacy remain. They are a viable option for patients unable to tolerate platinum-based therapy

28. QUESTIONS FOR DISCUSSION What are the options for 1 st line therapy? What is the optimal management of the elderly and the PS 2 patients? What is the role of the non-platinum regimens? What is the role of the molecular targeted agents in 1 st line therapy?

29. Biological Agents for Solid Tumors Signal Transduction/Cell-Cycle Inhibitors –Farnesyl transferase –Flavopiridol –Retinoids –UCN-101 Gene Therapy –GM-CSF –Wild-type p53 –Antisense –c-myc –PKC Vaccines –Tumor cells –Peptides –Dendritic cells –Viral vaccines Angiogenesis Inhibitors –SU5416/SU6668 –Anti-VEGF antibodies –Interferon-  /  –Marimastat –ZD6474 –LY317615 –TNP-470 –Endostatin/angiostatin Receptor-Targeted Therapy –Trastuzumab –Anti-EGFR –ZD1839 –C225 –OSI-774

30. Stage III/IV NSCLC N=1029/Trial * Gemcitabine/cisplatin (trial 14) * Paclitaxel/carboplatin (trial 17) Randomize Chemotherapy * x6 cycles + 250 mg ZD1839 Chemotherapy * x6 cycles + 500 mg ZD1839 Chemotherapy * x6 cycles + Placebo Continue ZD1839 or placebo until disease progression Primary endpoint: Survival ZD1839 Randomized Trials With Chemotherapy in Advanced NSCLC

32. Bevacizumab (rhuMAb-VEGF) in NSCLC: ECOG4599 Schema RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Eligibility: No prior Rx Stage IIIB or IV Non-SqCCa ECOG PS 0-1 Eligibility: No prior Rx Stage IIIB or IV Non-SqCCa ECOG PS 0-1 CBDCA: AUC = 6 Paclitaxel: 200 mg/m 2 CBDCA: AUC = 6 Paclitaxel: 200 mg/m 2 CBDCA: AUC = 6 Paclitaxel: 200 mg/m 2 rhuMAb-VEGF: 15 mg/kg CBDCA: AUC = 6 Paclitaxel: 200 mg/m 2 rhuMAb-VEGF: 15 mg/kg Upon PD crosssover to Anti-VEGF NOT ALLOWED

33. The Affinitac Phase III Trial Eligible patients randomized to: Restaging for response every 2 cycles Treatment continues up to 6 cycles (more if patient is benefiting) Treatment continues up to 6 cycles (more if patient is benefiting) Post-Treatment follow-up Survival Tumor progression Post-Treatment follow-up Survival Tumor progression Day 0: Paclitaxel 175 mg/m 2 Carboplatin AUC 6 21-day cycle Day 0: Paclitaxel 175 mg/m 2 Carboplatin AUC 6 21-day cycle ARM A ARM B Days 0-14: ISIS 3521, CIV Day 3: Paclitaxel 175mg/m 2 Carboplatin AUC 6 Days 15-21: Rest Days 0-14: ISIS 3521, CIV Day 3: Paclitaxel 175mg/m 2 Carboplatin AUC 6 Days 15-21: Rest Stratified for: Stage History of CNS Disease Stratified for: Stage History of CNS Disease Sample size = 600

34. What is the role of the molecular targeted agents in 1 st line therapy?