Non-Small-Cell Lung Cancer

• Leading cause of cancer-related mortality in the US

• Current Therapies: – “Despite great efforts, only minor gains”

Traynor et al. 2004 – Combination of Chemo/Surgery/Radiotherapy:

Platinum Doublets favored, in combo with other chemo reagent.

• Future Therapies: 166 ongoing clinical trials– EGFR over expressed in 40 to 80 % of cancers

Peptide Vaccine

• Phase I Study of EGFRvIII Peptide Vaccine With Sargramostim (GM-CSF) Versus Keyhole Limpet Hemocyanin as Adjuvant in Patients With EGFRvIII-Expressing Cancer

Epidermal Growth Factor Receptor VIII Peptide Vaccination Is Efficacious against

Established Intracerebral TumorsHeimberger et al. 2003

Vaccine Based Immunotherapy to L523S

– Phase I: Safety and Immunogenicity of Recombinant DNA and Adenovirus Expressing L523S Protein in Early Stage Non-Small Cell Lung Cancer The purpose of this trial is to examine the safety and immunogenicity of a therapeutic vaccine regimen with recombinant DNA and adenovirus expressing L523S protein in patients with early stage non-small cell lung cancer. The vaccine regimen will consist of two fixed doses of recombinant DNA (pVAX/L523S) followed by two doses of recombinant adenovirus (Ad/L523S). The trial will evaluate the dose escalation of Ad/L523S through three cohorts of patients.

EGFR Schematic

Sordella et al. 2004

Gefitinib:

• Targeting the proliferative signals in cancer cells --> EGFR– 1) In-Vitro Proof of Concept

• ZD1839 Synthesized/Screened --1994-2001

– 2) Animal Models– Mouse Xenografts: Success Not Dependant on Level of Expression of

EGFR ---2002

– 3) Initial Clinical Trials: 2001-2• Limited Tox• Response in only 10-19% of chemo-refractory advanced NSCL cancers• R Bailey et al. 2003 --> EGFR Expression not an effective predictor of

response to gefitinib

– 4) Molecular explanation???

• Factors that favor Gefitinib sensitivity:– Woman– Non-Smoker– Japenese– Adenocarcinoma

» Paez et al. 2004

A highly significant effect in sensitive patients

So What are the Mutations?

• Extract DNA

• Amplify Gene of Interest (28 exons)

• PCR

• Sequence (Sense + Antisense)

What do these mutations tell us?

• 1) Hypothesis: Improved stability for binding of ATP and Gefitinib– Modified ATP binding pocket.

• 2) Hypothesis: Mutation plays a key role in the development of this cancer.– Somatic– Heterozygous ---> Dominance– Sequenced 95 primary tumors, 108 cancer-derived cell

lines. No EGFR mutants

What does this all mean?

• Marker for the success of gefitinib?– Is this a good clinical test?– If there is no toxicity, can you add drug on top of standard

therapy despite low probability of success?

• Why the insensitivity with W.T. gefitinib?– 1) Kinetics: Bioavailability poor, (KD too high)

• Find a better way to knock out Kinase

– 2) The Mutant Kinase is more important to the cancer, than the wild type.

• Overexpression does not mean functionality is key. In-vitro models have to be interpreted carefully.

Science, August 20th 2004.