Gefitinib or Docetaxel as Second Line Therapy for Wild-type Epidermal Growth Factor Receptor (EGFR) NSCLC

Study Overview
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Brief Summary
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Gefitinib, the first EGFR-tyrosine kinase inhibitor (TKI) in the world was examined as monotherapy in two phase Ⅱ studies called IDEAL trials. Response rate with doses of 250mg and 500mg/day were similar, ranging from 10% to 18%. Posterior analysis demonstrated that patients with EGFR mutation had an improved response rate (RR) to gefitinib compared to wild-type patients (46% versus 10%). The early trials that evaluated EGFR-TKIs for the second- and third-line settings of advanced NSCLC did not select patients on the basis of any EGFR marker. The IEESSA Survival Evaluation in Lung Cancer (ISEL) trial evaluated the role of second-line gefitinib 250mg/day in 1692 patients with advanced NSCLC. Patients with EGFR mutations had higher RR than patients without (37.5% versus 2.6%). From the above results, the response rate in patients without EGFR gene mutation was obviously different (10% versus 2.6%). The methods used for detecting EGFR gene mutation was different, which might contribute to the difference of response rates. In IDEAL trial, EGFR gene mutation was detected by sequencing. But in ISEL trial, EGFR gene mutation was detected by ARMS. As we know, ARMS was more sensitive than sequencing in detecting EGFR gene mutation. That is to say, in IDEAL trials some EGFR mutant patients were misdiagnosed as wild-type patients, so the response rate was higher. Recently, Wu Yi-Long et al reported that relative abundance of EGFR mutations predicted benefit form gefitinib treatment for advanced non small cell lung cancer. The study cohort was all Chinese. In this study, the objective response rate in patients without EGFR mutation detected by ARMS was 16.1%, which was significantly higher than the response rate of docetaxel. But in 2012 American society of clinical oncology (ASCO) annual meeting, the Tailor study in which Italian NSCLC patients were enrolled demonstrated a clear superiority of docetaxel over erlotinib as second line treatment for patients without EGFR mutations in exons 19 or 21. So we wonder if the racial difference is the determinant factor. So the purpose of this trial is to compare the efficacy and safety of gefitinib with docetaxel as second-line therapy for advanced or metastatic Chinese NSCLC patients with wild-type EGFR.

Detailed Description
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The adoption of docetaxel as a standard second line therapy was based on data from two phase Ⅲ trials. In the first trail, docetaxel (75mg/m2, every 3 weeks) significantly prolonged median and 1-year survival duration compared with best supportive care (median survival, 7.5 months versus 4.6 months; P=0.010; 1-year survival, 37% versus 12%), although the response rate was low (5.5%). In the second study the 6-months and median survival rates were similar for docetaxel and vinorelbine or ifosfamide. However, the 1-year survival rate was significantly greater with docetaxel than ifosfamide or vinorelbine (32% versus 19%, P=0.025). In both studies docetaxel significantly improved some parameters of quality of life. Since these two pivotal studies, new potential second-line drugs were compared with the docetaxel standard of care. With regards to the therapeutic results of the docetaxel arm of these studies, it must be emphasized that response rates and survival data were highly and significantly reproducible.

Official Title
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A Phase Ⅱ Randomized Controlled Trial to Compare Gefitinib With Docetaxel as Second-line Therapy for Advanced or Metastatic Non-squamous NSCLC Patients With Wild-type EGFR

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Gefitinib
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age more than 18 years old Life expectancy more than 12 weeks histologically or cytologically confirmed inoperable non-squamous NSCLC (stage ⅢB/Ⅳ) ineligible for curative radiotherapy no prior radiotherapy for the target lesions Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 previous treatment include first-line platinum doublet chemotherapy no EGFR gene mutation detected by Scorpions-ARMS at least one bidimensionally measurable or radiographically assessable lesion adequate bone marrow reserve adequate hepatic and renal function Exclusion Criteria: prior treatments including any of the following drugs: gefitinib and docetaxel additional malignancies uncontrolled systemic disease any evidence of clinically active interstitial lung disease newly diagnosed central nervous system (CNS)metastasis and not treated by radiotherapy of surgery pregnancy or breast feeding phase

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefitinib<br>Gefitinib (Iressa) 250mg once per day until progression disease or intolerant side effects | Drug: Gefitinib<br>* Gefitinib 250mg once per day until the progression disease or intolerant side effects<br>* Other names: Iressa;|
| Active Comparator: Docetaxel<br>Docetaxel 75mg/m2,d1,every 3 weeks, at least 2-6 cycles depending on the progression disease or the patient's physical condition | Drug: Docetaxel<br>* Docetaxel 75mg/m2 iv, d1,every 3 weeks, at least 2-6 cycles depending on the progression disease or the patient's physical condition<br>* Other names: Taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 52 weeks. | up to 52 weeks (about one year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | From the date of randomization until the date of death from any cause, assessed up to 100 weeks. | Up to 100 weeks | 
| Objective response rate | The objective response rate includes the complete remission and partial remission rate. | up to 9 weeks | 
| the score of functional assessment of cancer treatment-lung (FACT-L) | FACT-L is assessed at different time points.(Date of randomization, 1 week after chemotherapy/EGFR-TKI, every cycle of chemotherapy/EGFR-TKI, every month of EGFR-TKI treatment/observation, up to 100 weeks) | up to 100 weeks | 
| Number of participants with adverse events | The adverse events are assessed by National Cancer Institute-Common Toxcity Criteria (Version 3.0)(NCI-CTC). | Up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-small cell lung cancer, wild-type EGFR, gefitinib, docetaxel, second-line therapy