1. Clinical developmentDiscovery Typical development timeline Typically – 8 yearsTypically 7 years

2. 1990 – compound identified in a screen for PKC inhibitors 1992 – First batch of Gleevec synthesized 1996 – In vivo activity shown in BCR-ABL transformed cells in mice June 1998 – first patient with CML treated June 2000 – Phase III trials initiated Nov 2001 – Approved in Europe and Japan for CML May 2001 – Approved by FDA for CML June 1999 – Phase II trials initiated Feb 2001 – NDA submitted to FDA for CML Feb 2002 – Approved by FDA for GIST Clinical developmentDiscovery Gleevec development timeline

3. Epidermal growth factor receptor (EGFR)

4. Expressed in a variety of solid tumours –Correlates with disease progression, poor survival and response to therapy Upon ligand binding, receptor dimerisation activates tyrosine kinase activity and tyrosine autophosphorylation. Leads to –cell proliferation –increased angiogenesis –invasion and metastasis –decreased apoptosis

5. Example: Gifitinib (Iressa) In preclinical studies of cell lines and human tumor xenografts, gefitinib produced growth inhibition in lung, prostate, breast, colon, and ovarian cancers Gefitinib enhance the antitumor activity of cytotoxic agents, radiation therapy, and hormone therapies Surprisingly, however, the effectiveness of gefitinib as an antitumor agent did not seem to correlate with EGFR expression either in vitro or in vivo

6. ANTI-EGFR (IRESSA) IN SECOND-LINE METASTATIC LUNG CANCER Myc Cyclin D1 JunFos PP DNA K K Ligand EGFR K K pY MAPK MEK-1 PI3-K RasRaf SOS Grb-2 PTEN Akt STAT Proliferation/ maturation Survival/ apoptosis  Angiogenesis Metastasis K pY Tyrosine kinase Phosphorylated tyrosine residue IRESSA     

7. Phase I Studies for Iressa Phase I studies showed antitumor responses in advanced cancers of the lung, head and neck, prostate, ovary, and colon EGFR status of the tumor was not used as a criterion for enrollment of patients into the Phase I studies –At all dose levels, significant decreases in MAPK and Ki-67, significant increases in the cyclin-dependent kinase inhibitor p27KIP1 and in rates of apoptosis –One study found a significant decrease in phosphorylated EGFR pre- and post-treatment

8. Phase II/III trials Multicenter Phase II trials: –IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 global trial with 210 patients –IDEAL-2 US trial with 221 patients Phase III trial first-line therapy for NSCLC, given continuously: –IRESSA NSCLC Trials Assessing Combination Therapy (INTACT)-1 with cisplatin/gemcitabine –INTACT-2 with carboplatin/paclitaxel

9. Phase II: IDEAL trials

10. INTACT-1 Patient Characteristics

11. Tumor Responses

12. INTACT-1 Progression-free Survival

13. INTACT-1 Overall Survival

14. INTACT-2 Design