Gene Expression Analysis for targeted Chemotherapy in Lung Cancer Patients PF-00299804 Robert J McKenna Jr. MD Robert J McKenna Jr. MD Head, Thoracic.

Gene Expression Analysis for targeted Chemotherapy in

Lung Cancer PatientsPF-00299804

Gene Expression Analysis for targeted Chemotherapy in

Lung Cancer PatientsPF-00299804

Robert J McKenna Jr. MDRobert J McKenna Jr. MD

Head, Thoracic SurgeryHead, Thoracic Surgery

Cedars Sinai Medical CenterCedars Sinai Medical Center

Stage of Lung Cancer at Diagnosis- SEER Data

18%18%

39%25%

1

23

4

Adjuvant Chemotherapy

• No clear supportive data in Stage 1

• Benefit seen in tumors greater than 4 cm

• Statistically significant benefit in Stage II and Stage IIIA

• Benefit all with cis-platin based chemo.

Schiller JH. NEJM 2002; 346:92-98

Chemotherapy Doublets for Lung Cancer Treatment

Lung Cancer Chemotherapy

• Overall, any doublets have about a 40% response rate– That means 60% chemo given has no clinical

response

• Adjuvant treatment increases survival 5-10%– That means 90% given with no change in

survival

Lung Cancer Chemotherapy

• Future of lung cancer chemotherapy– Get better drugs

• There is some benefit from current drugs– Individualize treatment for patients

EGFR Inhibition• The epidermal growth factor receptor is

on the surface of cells. It transmits signals to the cell, including to grow and divide.

• Erlotinib has shown benefit in NSCLC.

• Overall magnitude of the benefit is small.

• Magnitude of benefit in responders is high.

Primary Tumor Work

• Tissue is obtained

• RNA is evaluated in the laboratory to ensure samples are of high quality

• Microarray analysis is performed using the Agilent system

• Molecular data is correlated with clinical data and patient outcome

Cy3

Cy5

22,000 spots each containing a 60mer representing a known gene.The two probes hybridize to the spots in proportion to concentrationof the specific RNA in each probe.

mRNAs

AGILENT MICROARRAY PLATFORM1. Pre treatment core vs tumor reference2. Pre- vs post3. Post-vs pre-

Fluor reversal

RNA extraction of Lung Tumors

S-06-38515 RIN 9.3

S-06-39372 RIN 9.0

S-06-38568 RIN 9.4

S-07-00211 RIN N/A

Lung Tumors: Cluster All Probes22,000 Genes Significantly Changed

337

Tumors

Normals

Keratin Expression in 337 Lung Tumors

337Tumors

Keratins

Krt5/6, 14/16 Positive Lung Tumors

37 tumors(11%)

Squamous Lung Tumors on Cluster

337

Tumors Agilent 44K Chip

Neuroendocrine Tumors on Cluster

337

Tumors Agilent 44K Chip

Conclusions from primary samples

• High quality RNA has been obtained from nearly all of the samples

• Clear molecular subtypes can be found

• Data correlating gene expression with patient outcome will be available soon

Cell Line Collaboration

• We are evaluating novel compounds in a panel of 60 NSCLC cell lines

• Correlate cell line data with the data from primary tissue

• For a pre-surgical study, we selected the irreversible pan-HER inhibitor PF-299804

Clinical Trial

• A presurgical study to evaluate molecular changes that occur in human non-small cell lung cancer tissue after short term exposure to PF-00299804

Lung Mass

Diagnostic Biopsy

Surgery

Appropriate Additional Therapy

Appropriate Follow-Up

Assess Response to any Further

Therapy

5-11 days of drug

Clinical Trial

• Evaluate molecular changes with chemo

• Evaluate changes in cell metabolism with chemo

Future of Lung Cancer Chemo

• Individualize treatment based upon a patient’s tumor markers or gene analysis