Innovazioni Terapeutiche In Oncologia Dott. Massimo Ghiani A USL N 8 Ospedale A. Businco Oncologia Medica III. Tarceva TM

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2 Innovazioni Terapeutiche In Oncologia Dott. Massimo Ghiani A USL N 8 Ospedale A. Businco Oncologia Medica III Tarceva TM

3 Tarceva TM (erlotinib HCl) High-affinity, reversible inhibitor of HER1/EGFR Tyrosine kinase (TK) inhibits HER1/EGFR TK at ATP binding site Prevents signalling by HER1/EGFR homodimers and heterodimers HN O O N.HCl O O N ATP = adenosine triphosphate Moyer JD, et al. Cancer Res 1997;57:

4 Tarceva TM (erlotinib HCl) (cont d) HER1/EGFR extracellular ligandbinding domain HER1/EGFR TK TarcevaTM Small-molecule inhibitor of HER1/EGFR TK Chemical class: quinazoline Previously known as CP-385,774 and OSI-774 A joint global development program with Roche, OSI Pharmaceuticals Inc. and Genentech Inc.

5 Tarceva TM : mode of antitumor activity Tarceva TM Proliferation Invasion Metastasis Angiogenesis Adhesion Apoptosis Sensitivity to chemotherapy

6 Tarceva preclinical profile Orally available, competitive, reversible and selective inhibitor of TK ATP Inhibits purified HER1/EGFR TK with an IC 50 of 2nM Highly selective for HER1/EGFR over other receptors Induces tumour-cell apoptosis and inhibits EGFmediated mitogenesis Additive effects with chemotherapy and biologic agents Enhances response to radiation

7 Results of Tarceva phase I daily-dosing monotherapy studies Dose-limiting toxicity: diarrhoea at 200mg/day p.o. Diarrhoea manageable with loperamide, if needed, at oral doses of up to 150mg/day p.o. Skin rash observed at all doses, but never worse than moderate in severity at 150mg/day p.o. At 150mg/day, plasma concentration was above 500ng/mL; the level necessary for antitumour activity in vivo Progression to phase II/III trials justified using a dose of 150mg/day p.o. for monotherapy Hidalgo M, et al. J Clin Oncol 2001;19:

8 Tarceva: activity in other indications

9 Tarceva: first improvement in survival in pancreatic cancer for over 8 years Positive FU Phase III trial results Negative Gemcitabine BAY Exatecan +/- gemcitabine 5-FU + gemcitabine Tipifarnib + gemcitabine Marimastat + gemcitabine Irinotecan + gemcitabine Oxaliplatin + gemcitabine 2004 Tarceva + gemcitabine Pemetrexed + gemcitabine

10 Tarceva: first improvement in survival in pancreatic cancer for over 8 years Fase III trial of NCIC-CTG GEM 1000 mg\ m w > 3out of 4 w +/- Erlotinib 100 mg Accrual Nov 2001-Jannuary pt GEM GEM + E OS 17% 24% TCR 49% 57% CR+PR 8% 9% Improve quality of life

11 Tarceva: first improvement in survival in pancreatic cancer for over 8 years Fase I trial MSKCC GEM + RT + E GEM 40 mg\ m 2 biw RT 50.4 Gy in 28 day Escalation dose of E ( mg) GEM 1000 mg\ m 2 + E 100 mg daily x 4 cycles 9 pts enrolled MTD E =100 mg 7 SD 1 PD 1 resectable Ongoing study more 10 pts enrolled

12 Promising activity in glioma M. Prados et all. University of California San Francisco Fase I trial E +/- TMZ Pts With SD or Recurrent MG, also treated with TMZ 4 cohorts of PT: E +/- TMZ in PT with or without enzymeinducing antiepiletic drugs (gruop B ; group A) E Starting dose 100 mg Increase 50 mg until DLT occurred TMZ 150 mg\ m 2 x 5 days 1 cycle then 200 mg 66 pts enrolled ( 39 with E ;27 with E + TMZ) DLT = Group A : E mg E + TMZ 250 mg Group B : E mg E + TMZ 350 mg oxicityisacceptable K data decreased exposure of E and metabolites in group B

13 Promising activity in glioma (GBM) A. Young et all. MD A Cancer Center, UCLA, Genetech. University of California Fase II Trial in First relapsed GBM : 48 pts enzyme- inducing antiepiletic drugs group : 21 pts E 300 mg Tritration from mg Non enzyme- inducing antiepiletic drugs group : 27 pts E 150 mg Tritration from mg 3 PR 8.4% 1 Cr 18 SD 37.5 % PFS 6 m 17 % MS 10 m

14 Promising activity in glioma Efficacy conclusions from trials in patients with various types of glioma (alone or with chemotherapy) Tarceva Encouraging objective response rate 16% (relapsed; n=49) 1 Encouraging response/sd rate (50%), possible lack of durability (recurrent; n=16) 2 Suggest activity response/sd rate 45% (first relapse; n=45) 3 Ongoing studies Tarceva + RT 1 Prados M, et al. Eur J Cancer 2003;1:S14 (Abs. 33); 2 Vogelbaum M, et al. Proc ASCO 2004;23:121 (Abs. 1558); 3 Yung A, et al. Proc ASCO 2004;23:120 (Abs. 1555); 4 Raizer JJ, et al.

15 Promising activity in Head And Neck Cancer Phase II Study of E, in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck ; Manuel Hidalgo et all 115 PTS 40 % E 150 mg daily 6 % E escalation >200 mg 46 % E reduction 100 mg OR 4.3% SD 38.3% PFS 9.6 w OS 6 m E well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization; hence, further evaluation of itsrolein thistumortypeiswarranted.

16 Promising activity in Head And Neck Cancer : VOKES et all : metastatic and recurrent HNC Erlotinib 150 mg d + Bevacizumab 15 mg / kg q 3 w 51 pts = 2 CR 3 PR 31 SD 11 PD PFS 127 days OS 226

17 Promising activity in Head And Neck Cancer Ongoin studies : Fase I/II RT+ CDDP+ E ( Ist NAtionale de cancer, Brasil; University of Washinghton, no G IV tossicity 4/7 CpR Fase II study : MD Anderson Cancer ctr Docetaxel + CDDP+ E 19 Pts (metastatic/ recurrent) 16 PR No severe tox

18 Phase II study of XELOX plus erlotinib (Tarceva) in previously treated pts with mcrc JA Meyerhardt, ASCO 2004 # 3580 o Tarceva is an orally active, selective inhibitor of the HER1/EGFR tyrosine kinase o 1 prior systemic regimen for mcrc or PD within 12 mths of adjuvant therapy o XELOX (X at 750 mg/m2, O at 130 mg/m2 on day 1, and erlotinib 150 mg QD) Results Comments N 22 73% had prior CPT-11 Objective Response 20% 0 CR; 4 PR Stable Disease 64%

19 Summary Tarceva is the only HER1/EGFR-targeted agent to improve survival as second- or third-line therapy for advanced NSCLC Encouraging activity in pancreatic cancer and other indications (glioma; head & neck; ovarian; breast; colorectal cancer)