Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib (G) versus carboplatin/paclitaxel (C/P) in clinically selected patients (pts) with advanced non- small cell lung cancer (NSCLC) in Asia (IPASS). Authors:M. Fukuoka, Y. Wu, S. Thongprasert, C. Yang, D. Chu, N. Saijo, C. Watkins, E. Duffield, A. Armour, T. Mok Reviewed By: Dr. Charles Butts Date Posted: June 2009

BACKGROUND IPASS was a study in Asian countries comparing first line gefitinib to carbo/paclitaxel. Patients selected for clinical factors predicting for EGFR mutation positive status. Preliminary results suggest possible benefit of gefitinib in some patients.

R Treatment A: Gefitinib 250 mg po daily Treatment B: Carboplatin/Paclitaxel q3w x 6 Chemo-naïve Never or ex-light smoker adenoca Primary EP: PFS Secondary EP: OS, ORR, QoL Exploratory EP: Biomarkers

BIOMARKERS EGFR mutation EGFR gene copy number EGFR protein expression Significant attrition –1217 patients enrolled –1038 consent for biomarkers –633 samples 437 for mutations 406 for gene copy number 365 for protein expression

RESULTS Patients in biomarker studies representative of overall population in study. EGFR mutation correlated best with PFS –Mutation positive patients gefitinib significantly better (HR.48, p<0.0001) in terms of PFS –Mutation negative gefitinib significantly worse (HR2.86, p<0,0001) in terms of PFS ORR data consistent with PFS findings.

STUDY COMMENTARY OS not significantly different but trend in favor of gefitinib in mutation positive patients. Gene copy number possibly predictive but results driven by mutation positive patients. Protein expression not predictive.

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS Caution should be exercised in recommending first line EGFR TKI therapy for patients based on clinical selection only! The patients in this study were highly selected for EGFR mutation (Asian, adeno, never or light ex-smoker) Those who were EGFR negative did significantly worse with initial TKI therapy. This is further evidence to support having EGFR mutation status available for selecting therapy for patients. Difficult to know if this applies in the “western” population. The TORCH trial may sort this out.