Molecular Analysis of the IDEAL/INTACT trials: EGFR Mutations and Gene Amplification
Reviewer: S. Jack Wei, MD
University of Pennsylvania School of Medicine
Last Modified: May 15, 2005
Presenter: T.J. Lynch
Presenter's Affiliation: Massachusetts General Hospital Cancer Center
Type of Session: Scientific
- Previous studies have shown that patients with non-small cell lung cancer (NSCLC) who have mutations in the gene for epidermal growth factor receptor (EGFR) have dramatic response and improved survival when treated with gefitinib (Iressa), a small molecular inhibitor of the tyrosine kinase domain of EGFR.
- The demographics of patients who are more likely to have EGFR mutations mirror patients who showed improved survival in phase II and III trials of gefitinib.
- The IDEAL and INTACT trials were large randomized trials examining the role of gefitinib in the treatment stage IIIB and IV NSCLC as first-line and salvage chemotherapy.
- The IDEAL 1 and IDEAL 2 trials randomized patients who had received 1 or 2, or >2 chemotherapy regimens, respectively, to two different doses of gefitinib (250 mg qd vs. 500 mg qd).
- The INTACT 1 and INTACT 2 trials took previously untreated patients who received either gemcitabine (1250mg/m2)/cisplatin (80 mg/m2) or paclitaxel (225mg/m2)/carboplatin (AUC=6), respectively, and randomized them to chemotherapy + gefitinib (500 mg qd), chemotherapy + gefitinib (250 mg qd), or chemotherapy + placebo.
- A retrospective analysis of the patients enrolled in these trials was undertaken to examine whether EGFR overexpression and mutations correlated with improved outcomes.
Materials and Methods
- Paraffin blocks of either the original resection specimen or biopsy were obtained.
- Microdissection of the samples was performed until the samples were >50% tumor cells.
- Bi-directional sequencing of exons 18-21 of EGFR was performed and determination of the EGFR gene copy number was performed using Taqman quantitative real-time PCR.
- Overall, mutations in exon 19 and 21 were the most common mutations seen from these samples, and the mutational analysis focused on mutations in these two exons.
- The mutational status and gene copy number was correlated with response to gefitinib in the IDEAL and INTACT trials.
- 79 evaluable specimens were obtained for mutational analysis from the IDEAL specimens.
- 14 mutations were detected in these samples representing 18% of the evaluable patients.
- 57% of the patients with mutations were women, and adenocarcinoma represented 86% of patients with mutations. There was one patient with squamous cell histology whose tumor exhibited an EGFR mutation.
- 46% of patients with mutations responded to gefitinib compared to 10% of patients with wild-type EGFR (p=0.005).
- Patients with mutations had improved progression-free survival (PFS) (p<0.05).
- Patients with mutations did not show improved overall survival (OS).
- 80 patients were evaluable for EFGR amplification
- 7 patients were found to have amplified EGFR (8% of evaluable patients).
- Amplification was 4 to 90 fold in these patients.
- 29% of patients with gene amplification responded to gefintib compared to 15% of patients with no amplification (p=0.319).
- Patients with gene amplification showed an non-statistically significant improvement in PFS.
- There was no improvement in OS for patients with gene amplification.
- 32 patients with mutations were detected representing 10.2% of the evaluable patients
- 13/18 (72%) of patients with mutations who received gefitinib showed a response compared to 84/152 (55%) of patients with wild-type EGFR.
- Patients with mutations showed a statistically non-significant improvement in PFS compared to patients with wild-type EGFR
- 33 patients with amplification were found representing 7% of evaluable patients.
- Mutational data was available on 14 patients with amplification, and 80% of patients with amplification were found to have wild-type EGFR.
- Patients with EGFR amplification showed a statistically non-significant improvement in PFS compared to patients with no amplification.
- The patients who have mutations are not the same patients as those with overexpression.
- 25.5% of patients non-smokers had mutations compared to 6.3% who had amplifications (p<0.05).
- 17.4% of patients with adenocarcinoma or bronchalveolar carcinoma had mutations compared to 6.9% who had amplifications (p<0.05).
- 18.5% of Asian patients exhibited mutations compared to 5.1% of Asian patients who had amplifications (p<0.05).
- 14.3% of patients less than age 64 exhibited mutations compared to 6.6% of these patients who had amplifications (p<0.05).
- 18.5% of patients over age 64 had gene amplifications compared to 6.8% of these patients who had mutations (p<0.05).
- There was no direct correlation with EGFR gene amplification and overexpression of the EGFR protein.
- EGFR mutation and amplification identify different groups of patients with the population of patients with mutations mirroring those that have been found to have significant benefit from therapy with gefitinib.
- EGFR mutations were associated with improved outcomes.
- EGFR mutations predict for improved response and PFS from gefitinib in the IDEAL trials.
- EGFR amplification may identify another group of patients who benefit from therapy with gefitinib.
- The small number of patient samples in this study limit conclusions regarding impact of mutational status and amplifications on OS.
- Molecular profiling is essential in these patients.
- Future trials should focus on patients with EGFR mutations and examine the role of tyrosine kinase inhibitors such as gefitinib in first-line studies of metastatic disease as well as in adjuvant trials after surgery or radiotherapy.