A269
Epidermal Growth Factor (EGFR), K-Ras and B-Raf Mutation Status and Clinical Outcome to Gefitinib (IRESSA) in a Phase III Placebo-controlled Study (ISEL) in Advanced Non-small-cell Lung Cancer (aNSCLC).
Brian Holloway,1 Nick Thatcher,2 Alex Chang,3 Purvish Parikh,4 Jose Rodrigues Pereira,5 Tudor Ciuleanu,6
Joachim von Pawel,7 Angela Flannery,1 Gillian Ellison,1 Emma Donald,1 Lucy Knight,1 Claire Watkins.1 AstraZeneca Pharmaceuticals,1 Macclesfield, England, Christie Hospital,
2 Manchester, England, Johns Hopkins-NUH International Medical Center,3 Singapore, Singapore, Tata Memorial Hospital,4 Mumbai, India, Arnaldo Vieira de Carvalho
Cancer Institute,5 So Paolo, Brazil, Oncology Institute Ion Chiricuta,6 Cluj-Napoca, Romania, Asklepios Fachkliniken,7 Gauting, Germany.
Background:
Gefitinib (IRESSA) is an orally active EGFR tyrosine kinase inhibitor (EGFR-TKI), which in large Phase II studies (IDEAL 1 and 2) led to objective tumor responses in 12-18% of patients with refractory aNSCLC, and symptom improvement
in >40% of patients.
ISEL is a Phase III survival study, which randomized 1692 pretreated patients with aNSCLC to gefitinib 250 mg/day or placebo.
In ISEL, gefitinib showed some improvement in survival compared with placebo, but this did not reach statistical significance in the overall or adenocarcinoma populations: significant improvements in survival were seen in the subgroup of patients of Asian origin, and in never-smokers.1
Activating EGFR mutations have been observed in many
patients with dramatic responses to gefitinib, while mutations in the K-Ras gene have been associated with lack of sensitivity to EGFR-TKIs.
Further evaluation of these parameters may provide additional insight into why certain subgroups derive greater
clinical benefit with gefitinib.
Methods:
Tumor samples were obtained from ISEL
patients.
EGFR mutations were detected by either amplification refractory mutation system (ARMS) or gene sequencing in both forward and reverse direction in ³1 of 3 independent polymerase chain reaction products:
positive results were verified by ARMS or WAVE.
K-Ras and B-Raf mutations were identified by similar methodology:
if codon V599E was detected then the tumor was classed as B-Raf mutation positive,
and if codon 12/13 was detected it was classed as K-Ras mutation positive.
Analysis of the predictivity of mutation status for relative treatment effect on survival is being assessed.
Results:
Tumor samples from 215 patients were evaluable and validated
for exons 18, 19 and 21 of the EGFR-TK domain:
26 patients (12%) were EGFR mutation positive.
K-Ras mutations were identified in 12 of the 152 patients with
samples (8%) available for analysis.
None of the tumor samples analyzed were found
to contain both an EGFR mutation and a K-Ras mutation.
No B-Raf mutations were identified from the 118 patients with samples available for B-Raf mutation analysis.
Analyses of the relationship between mutational status and clinical outcome (overall survival and response) are ongoing and will be presented.
Conclusions: The ISEL study has provided the first opportunity to investigate in a placebo-controlled setting
the relationship between potential molecular markers (including mutations of EGFR, K-Ras, and B-Raf genes) and clinical outcome with gefitinib in NSCLC patients, and
hence to distinguish between predictive and prognostic factors. |
