De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors

Pilot Study to Identify the Mechanism of De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) in NSCLC With EGFR Mutation.

This study is based on the following hypothesis "De novo resistance to EGFR-TKI in EGFR mutation positive patients is related with mutations in EGFR downstream genes".

Investigators will prospectively collect genomic DNA and clinical data regarding treatment outcomes to EGFR-TKI in NSCLC patients with activating EGFR mutations. Investigators will sequence candidate mutations of EGFR downstream genes and analyze c-met gene amplification and protein expression in PTEN, HGF, and IGFR. To identify genetic mutations, amplification, and protein over expression as predictive markers of treatment outcomes, investigators analyzed the association of treatment outcomes with the presence of genetic alteration or protein over expression. Investigators will attempt to identify biomarkers that are able to predict de novo resistance to EGFR-TKI in EGFR mutated NSCLC.

Study Overview

• Status: Unknown
• Conditions: NSCLC

Detailed Description

Investigators will prospectively enroll patients who match the following criteria: pathologically proven unresectable NSCLC, planning to treat with EGFR-TKI, patients with activating EGFR mutations, and available tissue sample for DNA extraction.

• Study Type: Observational
• Enrollment (Anticipated): 155

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

NSCLC patient with EGFR mutation

Description

Inclusion Criteria:

1. Pathologically proven unresectable NSCLC
2. 20 years of age or older
3. Planned treatment with Iressa®
4. Patients with activating EGFR mutation (del 19, L858R)
5. Available detailed smoking history
6. Available tissue samples (archival tissue) for mutational or molecular analysis (representative paraffin block or unstained sections from tumor diagnostic specimen are mandatory)
7. Available blood sample
8. At least one lesion that is measurable according to the RECIST 1.1 criteria by CT or MRI
9. Written informed consent

Exclusion Criteria:

1. More than 3rd line treatment
2. Previously treated with other EGFR-TKI
3. Life expectancy of less than 12 weeks
4. Pregnant or lactating female
5. Any unresolved toxicity greater than CTC grade 2 (version 4.0) from previous anti cancer treatment.
6. Unsuitable patient in this treatment as determined by doctor.

Study Plan

How is the study designed?

Design Details

• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Iressa; Lung cancer patients with EGFR mutation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hazard rates of PFS	The primary objective is to compare hazard rates of PFS in patients treated with Iressa between with and without any molecular aberrancy in EGFR-downstream genes/proteins.	1year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Overall survival (OS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Disease control rate (DCR) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Progression-free survival (PFS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification)	2years

Collaborators and Investigators

• Sponsor: Severance Hospital
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Joo Hang Kim, MD, PhD, Severance Hospital

Publications and helpful links

General Publications

• Lim SM, Kim HR, Cho EK, Min YJ, Ahn JS, Ahn MJ, Park K, Cho BC, Lee JH, Jeong HC, Kim EK, Kim JH. Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium). Oncotarget. 2016 Jun 14;7(24):36311-36320. doi: 10.18632/oncotarget.8904.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Anticipated): September 1, 2014
• Study Completion (Anticipated): September 1, 2014

Study Registration Dates

• First Submitted: September 12, 2012
• First Submitted That Met QC Criteria: September 26, 2012
• First Posted (Estimate): October 2, 2012

Study Record Updates

• Last Update Posted (Estimate): October 2, 2012
• Last Update Submitted That Met QC Criteria: September 26, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: lung cancer; Iressa; EGFR mutation; De Novo Resistance
• Other Study ID Numbers: ISSIRES0067