Clinical developmentDiscovery

Typical development timeline

Typically – 8 years Typically 7 years

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

Epidermal growth factor receptor (EGFR)

Epidermal growth factor receptor (EGFR)

• 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

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

ANTI-EGFR (IRESSA) IN SECOND-LINE METASTATIC LUNG CANCER

Myc

Myc

Cyclin D1Cyclin

D1Jun Fos

PPDNA

K

K

Ligand

EGFR

K K

pYpY

pY

MAPK

MEK-1PI3-K

Ras Raf

SOS

Grb-2

PTEN AktSTAT

Proliferation/ maturation

Survival/ apoptosis

Angiogenesis

Metastasis

K

pY

Tyrosine kinasePhosphorylated tyrosine residue

IRESSA

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 K

i-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

Phase II/III trials

• Multicenter Phase II trials: – IRESSA Dose Evaluation in Advanced Lung Cancer (I

DEAL)-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 Thera

py (INTACT)-1 with cisplatin/gemcitabine – INTACT-2 with carboplatin/paclitaxel

Phase II: IDEAL trials

INTACT-1 Patient Characteristics

Tumor Responses

INTACT-1 Progression-free Survival

INTACT-1 Overall Survival

INTACT-2 Design