EGFR-TKIs such as gefitinib, erlotinib or afatinib are recommended as first-line therapy in patients with advanced, recurrent or metastatic nonsquamous NSCLC who have known active EGFR mutation (1). The response rate to gefitinib and erlotinib is up to 75% (2,3). The two most common sensitizing EGFR mutations in NSCLC are in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21. However, patients who achieved response to EGFR TKIs experience disease progression eventually with 10-14 moths of median progression free survival. Platinum-doublets combination chemotherapy remains standard of care for patients with progressive disease. However, patients may derive benefit from EGFR TKIs after RECIST-assessed progression especially for those who experience slow progression. And previous report suggested that premature discontinuation of EGFR TKIs has resulted in rapid progression in symptoms and tumor growth (4). Recently, a prospective phase II single arm study in Asian patients with EGFR mutation-positive NSCLC to determine the continuation of erlotinib beyond progression judged by investigators showed that additional PFS of 3.1 months can be achieved with continuation of erlotinib without serious additional toxicities (5). Until now, no prospective study has been conducted for gefitinib.
In this study the continuation of gefitnib beyond RECIST progression will be investigated to determine the clinical outcomes including the duration of treatment and safety.

Treatment

Patients will be treated 250 mg/day of gefitinib orally (1 cycle for 28 days). Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Gefitinib will be held for 1 week when adverse events equal or greater than grade 3 is appeared. Following resolution of the toxicity to grade 2 the patient may resume treatment with gefitinib.
If a patient required a dose delay > 4 weeks due to a gefitinib related toxicity, then the patient must be discontinued from the study. 
Modification of dose will be according to severity of toxicity. When the toxicities such as diarrhea, rash are not improved even if optimal supportive treatment is applied or patient is intolerable in any reason, dose reduction is done regardless severity of toxicity. Any patient who has had 2 dose reductions and experiences a toxicity that would cause a third dose reduction must be discontinued from study therapy.

Gender

Age

Description

①	Histologically confirmed stage IIIB/IV or recurrent NSCLC with activating EGFR mutation in exon 18 through exon 21 except T790M    
②	Patients who achieved complete/partial response more than 4 months or stable disease more than 6 months with first-line or second line gefitinib, Patients who experience disease progression by RECIST 1.1 criteria 
③	Age ≥ 18years
④	ECOG performance status of 0 to 2
⑤	Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL, CCr ≥ 50mL/min
⑥     Gefitinib baseline adverse event  ≤ Grade 2
⑦	Written informed consent form

①	Prior treatment with EGFR TKI
②	Patients who required dose reduction of gefitinib
③	Surgery undertaken less than 4 weeks before the study
④	Localized radiotherapy unless completed more than 2 weeks before the study
⑤	Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia
⑥	Pregnant or nursing women ( Women of reproductive potential have to agree to use an effective contraceptive method (hormonal or barrier methods))
⑦	Uncontrolled symptomatic brain metastasis
⑧	Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, well-treated thyroid cancer
⑨	Concomitant use of CYP3A4 inducers/inhibitors 
⑩	Prolonged QT interval in ECG (QTc >450 msec)

Time from RECIST progression to second disease progression.(second PFS)

The primary endpoint is Time from RECIST progression to off-gefitinib if gefitinib was extended beyond RECIST (progression free survival)

Overall survival / Safety and toxicity profile

Overall Survival (OS) : OS is measured from the date of start of study to the date of death from any cause. Safety and toxicity profile : Safety and toxicity profile will be measured by the CTCAE scale, version 4.

In patients with EGFR-mutant NSCLC who experience progression, it
is beneficial to maintain gefitinib treatment with local treatment such
as radiotherapy until symptomatic progression. However, in patients
with pleural metastasis or effusion, continuation of gefitinib beyond
progression should be carefully determined.
          .