Study of Chemotherapy Sequenced by or Combined With EGFR-TKIs for NSCLC Patients Failed to EGFR-TKIs Therapy

Responses to EGFR-TKIs are quiet dramatic and durable, especially in patients with EGFR gene classic mutations, such as 19 deletion or 21 leucine 858 arginine(L858R). However, most patients with NSCLC who respond to EGFR-TKIs eventually experience progression of disease after approximately 12 months. The lack of an established therapeutic option for NSCLC patients who have progressive disease after EGFR-TKIs failure poses a great challenge to physicians in terms of how best to manage this growing group of lung cancer patients.

In clinical practice some of the initially EGFR-TKI sensitive tumors which progressed evidence a striking increase in tumor volume within several weeks, after being taken off EGFR-TKI. This response is called "rebound phenomenon". Most experts still believe that these tumors continue to be "oncogene-addicted" to EGFR. So it is rational that EGFR-TKI combined with another chemotherapy regimen can be used to treat NSCLC after the failure of EGFR-TKI therapy.

However in some phase Ⅱclinical trials involved a few NSCLC patients who failed to EGFR-TKI therapy, another treatment mode, that is to say, at least one cytotoxic chemotherapy was used firstly then switched to EGFR-TKI therapy until progression of disease, was used and called reintroduction or retreatment of EGFR-TKI. Using this treatment mode, some investigators reported the partial remission (PR) and disease control rate (DCR) were observed in 21.7%-36% and 65.2%-86% NSCLC patients.

• combined group (Drug), also known as Docetaxel (Taxotere), Pemetrexed (Alimta), Gefitinib (Iressa): chemotherapy with docetaxel 75mg/m2 d1 or pemetrexed 500mg/m2 d1, every 3 weeks,at least 2 cycles and the maximal cycle is 6 depending on disease evaluation and patient's physical condition combined with gefitinib 250mg once per day from the start day of chemotherapy until disease progression or intolerable side effects.
• Sequenced group (Drug), also known as Docetaxel (Taxotere), Pemetrexed (Alimta), Gefitinib (Iressa): sequenced group chemotherapy with docetaxel 75mg/m2 d1 or pemetrexed 500mg/m2 d1, every 3 weeks,at least 2 cycles and the maximal cycles is 6 depending on disease evaluation or patient's physical condition sequenced by gefitinib 250mg once per day until disease progression or intolerable side effects.

Primary outcomes

• progression free survival [up to 52 weeks (about one year)]: 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.

Secondary outcomes

• overall survival [up to 100 weeks]: From date of randomization until the date of death from any cause, assessed up to 100 weeks.
• objective response rate [up to 9 weeks]: The objective response rate includes the complete remission and partial remission rate.
• the score of functional assessment of cancer treatment-lung(FACT-L) [up to 100weeks]: FACL-L is assessed at different time points.(Date of randomization,1 week after chemotherapy,every cycle of chemotherapy,every month of EGFR-TKI maintain treatment,up to 100 weeks)
• Number of participants with adverse events [Participants will be followed for the duration of treatment, an expected average of 52 weeks.]: The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria(version3.0) (NCI-CTC).

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* age ≥ 18 years
* histologically and cytologically proven non-small cell bronchogenic carcinoma (sputum cytology alone was not acceptable)
* clinical stages ⅢB or Ⅳ
* recurrent or refractory disease following previous first-line chemotherapy regimens containing platinum and second-line EGFR-TKIs therapy
* partial remission (PR) or stable disease (SD) at least for 6 months during previous EGFR-TKI treatment
* at least one bidimensionally measurable or radiographically assessable lesion
* Eastern cooperative oncology group performance status (ECOG PS) ≤ 2
* life expectancy ≥ 12 weeks
* adequate hematological, renal, and hepatic functions

Exclusion Criteria:

* 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 or surgery
* pregnancy or breast feeding phase

• Results publication: Oh IJ, Ban HJ, Kim KS, Kim YC. Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib: a single-arm, open-label, phase II study. Lung Cancer. 2012 Jul;77(1):121-7. doi: 10.1016/j.lungcan.2012.01.012. Epub 2012 Feb 12. PMID 22333554
• Results publication: Li J, Hao X, Wang Y, Zhang X, Shi Y. [Clinical response to gefitinib retreatment of lung adenocarcinoma patients who benefited from an initial gefitinib therapy: a retrospective analysis]. Zhongguo Fei Ai Za Zhi. 2012 Jan;15(1):44-8. doi: 10.3779/j.issn.1009-3419.2012.01.09. Chinese. PMID 22237124
• Results publication: Watanabe S, Tanaka J, Ota T, Kondo R, Tanaka H, Kagamu H, Ichikawa K, Koshio J, Baba J, Miyabayashi T, Narita I, Yoshizawa H. Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis. BMC Cancer. 2011 Jan 1;11:1. doi: 10.1186/1471-2407-11-1. PMID 21194487
• Results publication: Becker A, Crombag L, Heideman DA, Thunnissen FB, van Wijk AW, Postmus PE, Smit EF. Retreatment with erlotinib: Regain of TKI sensitivity following a drug holiday for patients with NSCLC who initially responded to EGFR-TKI treatment. Eur J Cancer. 2011 Nov;47(17):2603-6. doi: 10.1016/j.ejca.2011.06.046. Epub 2011 Jul 23. PMID 21784628

• Mengzhao Wang, MD, Principal investigator, Peking Union Medical College Hospital