LUNG CANCER MOLECULAR THERAPY Prof. Dr. Can ÖZTÜRK

1. LUNG CANCER MOLECULAR THERAPY Prof. Dr. Can ÖZTÜRK Gazi University School of Medicine Department of Pulmonology

2. Turkey - Male (All ages) Crude Rate* ASR (World) *per 100.000

3. Turkey - Female (All Ages) Crude Rate*ASR (World) *per 100.000

4. UNTREATED NSCLC- PROGNOSIS

5. UNTREATED SCLC- PROGNOSIS

6. Treatment- Prognosis Status of treatment is dismal Five year survival approx. 15% 61% for Colon 86% for Breast 96% for Prostate

7. NSCLC – Survival based on stages Greene et al, eds. AJCC Cancer Staging Manual. 6th ed. 2002.

8. NSCLC CURRENT TARGET STAGE % % IA 70-85 85-95 IB 60-70 70-85 IIA 35-45 45-60 IIB 25-35 35-45 IIIA 5-20 20-30 IIIB 3-7 10-20 IV <1 2-5 SCLC CURRENT TARGET STAGE % % LTD 15-25 25-30 EXT <1 2-5 5 year survival - TARGETS Langer CJ, Fox Chase Cancer Center-2006

9. NSCLC- Systemic Therapy • Uptodate standart therapies • Epidermal Growth Factor Receptor (EGFR) Inhibitors • Gefitinib (Iressa) • Erlotinib (Tarceva) • Anti-EGFR Monoclonal antibodies • Cetuximab (Erbitux) • Anti-Vascular Endothelial Growth Factor (VEGF) Monoclonal antibody • Bevacizumab (Avastin-Altuzan)

10. 2-drug platinum-based combinations Systemic Therapy – First Line 2 drug platinum based regimens • Schiller JH. NEJM 2002; 346:92-98

11. Results- First Line Survival Medan survival 8 months Response rate %19 TTP MedianTTP 3.7 months Schiller JH. NEJM 2002; 346:92-98

12. Second Line Therapies • Docetaxel is superior than best supportive care • Response rate %7 • Median survival 7.0 vs 4.6 months* • Median TTP 10.6 vs. 6.7 weeks* • Pemetrexed (Alimta) is effective as docetaxel, but less toxicity profile Shepherd et al. JCO 2000;18:2095-2103 Hanna et al. JCO 2004; 22:1589-97

13. Targeted Therapies in Lung Cancer

14. Targeted Therapies • EGFR Inhibitors • Gefitinib (Iressa) • Erlotinib (Tarceva) • Anti-EGFR Monoclonal antibody • Cetuximab (Erbitux) • Anti-VEGF Monoclonal antibody • Bevacizumab (Avastin-Altuzan)

15. Epidermal Growth Factor Receptor (EGFR) & Human Cancer • EGFR critically regulates tumor cell division, proliferation, repair • EGFR may play a critical role in metastasis, angiogenesis, invasion • Binding of specific ligands to EGFR (eg, EGF, TGF-a) activates the receptor and triggers signal transduction cascades that affect cell proliferation • EGFR is expressed in a significant percentage of human tumors and is correlated with poor prognosis, decreased survival, and/or increased metastasis • Inhibition of EGFR on tumor cells may inhibit the growth or progression of EGFR-expressing tumors

16. EGFR structure TK Extracellular area Transmembranous area Intracellular area

20. NSCLC 40-80% Prostate 40-80% Gastric 33-74% Breast 14-91% Colorectal 25-77% Pancreatic 30-50% Ovarian 35-70% Invasion Metastasis Late-stage disease Chemotherapy resistance Hormone-therapy resistance Poor outcome EGFR expression in human tumors Tumors showing high EGFR expression High expression generallyassociated with

21. NSCLC- EGFR & HER2 Lung Cancer- EGFR expression F. Hirsch et al. Semin Oncol, 2002

22. Relationship of HER1 & HER2 to Survival in NSCLC NSCLC- EGFR & HER2Survival J. Brabender et al. Clin Cancer Res, 2001

23. EGFR Targeted Therapies • Inhibition of EGFR signalling with either the monoclonal Ab or the tyrosine kinase inhibitors(TKI) reduces proliferation in a variety of epithelial tumor cells and blocks cell cycle progression in the G1 phase • Inhibition of cell cycle progression is an effective mechanism for modulating the growth of tumors • EGFR inhibition, using TKI; induce apoptosis (in human tumor cells and vascular endothelial cells) • Ongoing trials are evaluating the clinical utility of EGFR inhibitors for the treatment of EGFR-expressing cancers

24. Acquired spesifications of Cancer Cells Spesifications Autocrine growth signalYes Yes Insensitivity to anti-growth signals Yes Yes Awareness of cell death Yes Yes Uncontrolled proliferation Yes Yes Continious angiogenesis Yes Yes Tissue invasion and MetastasisYes Yes Increase by EGFR activation Decrease by EGFR Inhibition Hanahan ve Weinberg, Cell, 2000

25. TKI-Small molecules: mechanism of action TKI ¯ Proliferation ­ Apoptosis ¯ Invasion ­ Sensitivity to chemotherapy ¯ Metastasis ¯ Adhesion ¯ Angiogenesis Etessami A, et al. Drugs Fut 2000;25:895–9 Moyer J, et al. Cancer Res 1997;57:4838–48Harari PM, et al. Semin Radiat Oncol 2002;12(Suppl. 2):21–6

26. + GeneTranscription S Growth Factor Priming G1 G0 G2 Cell Cycle M Growth Factors & Cell Cycle Receptors

27. Targeted Therapies • EGFR Inhibitors • Gefitinib (Iressa) • Erlotinib (Tarceva) • Anti-EGFR Monoclonal antibody • Cetuximab (Erbitux) • Anti-VEGF Monoclonal antibody • Bevacizumab (Avastin-Altuzan)

28. Gefitinib- with ChemotherapyFirst Line-Phase III INTACT 1 & 2 Untreated advanced NSCLC* Stratification: Weight loss in last 6 months(%5 vs >%5) PS: 0-1 vs 2 Chemo†x 6 cycles + 250 mg gefitinib Gefitinib / Placebo until progression Chemo†x 6 cycles Randomise + 500 mg gefitinib Chemoi†x 6 cycles + Placebo *Evre IIIB/IV KHDAK†INTACT = IRESSA NSCLC Trial Assessing Combination Therapy; INTACT 1 (N=1093) gemcitabin (1250 mg/m2)/cisplatin (80 mg/m2); INTACT 2 (N=1037) paclitaxel (225 mg/m2)/carboplatin (AUC=6).

29. Gefitinib- with ChemotherapyFirst Line-Phase III Med. survival ~10 months ~10 months

30. Gefitinib – Second & Third Line-Phase II (250mg vs. 500mg) • 250mg ve 500mg doses- no difference in efficacy • Adverse effects- acceptable (rash and diarrhea) – more frequent in 500 mg group IDEAL-1: M. Fukuoka et al. JCO 2003; 21:2237-2246 IDEAL-2: MG Kris et al. JAMA 2003; 2149-2158

31. Gefitinib – Second & Third Line-Phase III ISEL: Iressa Survival Evaluation in Lung Cancer R A N D O M İ Z E Gefitinib 250 mg/gün • Inclusion Criteria • StageIIIB veya IV NSCLC • Treated with platinum based CT( 1 or 2 times) • PS 0-3 N=1692 Placebo Thatcher et al. Lancet 2005

32. Gefitinib – Second & Third Line-Phase III ISEL - Survival Gefitinib Placebo (n=1129) (n=563) 1.0 Median survival (mts) 5.6 5.1 0.8 1-year survival (%) 27 22 0.6 HR=0.89 (95% CI, 0.78-1.03)* P<0.11* Probability 0.4 Gefitinib 0.2 Placebo 0.0 0 2 4 6 8 10 12 14 16 Months Thatcher et al. Lancet 2005

33. Targeted Therapies • EGFR Inhibitors • Gefitinib (Iressa) • Erlotinib (Tarceva) • Anti-EGFR Monoclonal antibody • Cetuximab (Erbitux) • Anti-VEGF Monoclonal antibody • Bevacizumab (Avastin-Altuzan)

34. Erlotinib-With Chemotherapy-First Line - Phase III • TALENT study - Cisplatin/gemcitabine + (tarceva or placebo) • 1172 pts, chemo-naive Gatzemeier U. ASCO 2004 Abstract

35. Erlotinib-with chemotherapy-First Line-Phase III • TRIBUTE study - Carboplatin/paclitaxel + (tarceva or placebo) • 1059 pts, chemo-naive Herbst R. J Clin Oncol 2005

36. Erlotinib-with chemotherapy-First Line-Phase III • TRIBUTE study – Subgroup analysis: Nonsmokers tarceva vs placebo: Median survival = 23 mts vs. 10 mts Miller VA et al. ASCO 2004 Abstract

37. Why are TALENT and TRIBUTE negative studies? Possible explanations • Concurrent use may be antagonistic • in vitro evidence of antagonism with combination chemotherapy regimens • Remarkable benefit in the non-smoker subset: • smoking potentially reduces exposure to Tarceva via induction of metabolising enzymes1 • Triplets are redundant doublets; Tarceva kills the same tumour cell population? 1Hamilton M, et al. Proc Am Assoc Cancer Res 2005;43 (Abs. 6165)

38. Erlotinib – Second or Third Line BR.21 Phase III

39. R A N D O M I S E Erlotinib: 150 mg/day • Stratification • Center • PS: 0-1 vs. 2-3 • Previous response: PR vs. SD vs. PD • Previous CT: 1 vs. 2 • Previous cisplatin: Yes or No 2 1 Placebo: “150 mg”/day Erlotinib – Second or Third LineBR.21 Phase III

40. Erlotinib – Second or Third LineBR.21 Phase III En sık yan etki: kızarıklık, diyare Shepherd FA et al. NEJM 2005

41. BR.21 Study-Survival 100 Median Survival (mts) 1-year Survival (%) 80 Erlotinib Placebo 6.7 31.2 4.7 21.5 60 % Survival HR=0.73, P<0.001* 40 20 0 0 5 10 15 20 25 30 Months

42. BR.21: Toxicity Tarceva (erlotinib) PI.

43. BR.21 Summary • Erlotinib has confered a survival advantage in previously treated and relapsed NSCLC patients • Erlotinib is effective in both subgroups • Therapy is well tolerated • Most frequent toxicity is rash and diarrhea • Pulmonary toxicity is rare, but 30% fetal

45. Response to TKI- Important factors Fukuoka JCO 2003;21:2237-46. Kris JAMA 2003;290:2149-58. Miller JCO 2004;22:1103-09.

46. 0 5 10 15 20 25 30 Months Erlotinib - Faz II Survival & Grade of Rash 1.00 Grade 2/3 (n=17) 0.75 Survival 0.50 Grade 1 (n=26) Yok (n=14) 0.25 0.00 Perez-Soler R, et al. Am Soc Clin Oncol Mol Ther Symp. 2002

47. NSCLC & EGFR Mutations

48. Gefitinib-EGFR mutation and amplification EGFR EGFR amplification mutation + - + - %33 %67 %17 %83 Obj. response(%)36 3 (<.001) 53 5 (<.001) Med. Survival (ay) 18.7 7.0 (.03) 20.8 8.4 (.09) 1 year survival (%) 57 33 (.03) 57 38 (.22) Cappuzzo JNCI 97:643,2005

49. Targeted Therapies • EGFR Inhibitors • Gefitinib (Iressa) • Erlotinib (Tarceva) • Anti-EGFR Monoclonal antibody • Cetuximab (Erbitux) • Anti-VEGF Monoclonal antibody • Bevacizumab (Avastin-Altuzan)

50. Single agent Cetuximab Phase II study (n=60, ≥1 chemo): Response rate: % 3.3 Median TTP: 2.3 ay Median survival: 8.1 mo. • Well tolerated(Most frequent adverse effect: rash) Lilenbaum ASCO 2005