Genius Study Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Stage IV EGFR Mutation Negative or T790M Single Mutation Who Respond to Pemetrexed/ Platinum as First-line Therapy

An Open Label, Randomized, Multicenter, Phase II Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Advanced (Stage IV) EGFR Mutation Negative or T790M Single Mutation Nonsquamous NSCLC Who Respond to 4 Cycles of Pemetrexed/ Platinum as First-line Therapy

The study aims to randomize 52 patients with advanced (Stage IV) EGFR mutation negative nonsquamous non-small cell lung cancer (NSCLC) who respond (CR/PR/SD) to 4 cycles of pemetrexed / cisplatin or pemetrexed/carboplatin as first-line therapy. In order to achieve that, approximately 144 treatment naïve patients with advanced nonsquamous NSCLC need to be enrolled from around 6 investigational sites in Taiwan that have expertise in lung cancer diagnosis.

The hypothesis tested in this study is that gefitinib / pemetrexed as maintenance therapy in patients with advanced (stage IV) EGFR mutation negative nonsquamous NSCLC who respond to 4 cycles of pemetrexed / cisplatin or pemetrexed/carboplatin as first-line therapy will achieve longer PFS than pemetrexed alone. We assume a median PFS of 4 months for patients receiving pemetrexed alone and the hazard ratio of pemetrexed alone compared to gefitinib/pemetrexed would be 0.42. It also indicates that the median PFS in gefitinib/pemetrexed group will be approximately 9.52 months. This is a 2-arm study in a 1:1 randomisation. Assuming an uniform accrual of 12-month with an addition of 12-month follow-up period, the total evaluable number of patients will be 52 to achieve a power of 80% and one-sided significance level of 0.025 to detect such difference between gefitinib/pemetrexed and pemetrexed alone.

Assuming 60% of patients respond (CR/PR/SD) to 4 cycles of pemetrexed/gefitinib, and among them 60% are EGFR mutation negative, 144 patients need to be enrolled to receive 4 cycles of pemetrexed/cisplatin or pemetrexed/carboplatin as first-line therapy.

Besides, the result of anaplastic lymphoma kinase gene (ALK) mutation will be retrospectively collected if the mutation is available for study patients during the study period.

Inclusion Criteria summary

1. Provision of written informed consent
2. Patients age 20 years or older
3. Histological or cytological confirmed advanced (stageIV) nonsquamous NSCLC
4. NSCLC treatment naïve(except patients who have pre- and post-operative non-platinum based adjuvant chemotherapy greater than 6 months prior to enrolment can be enrolled.)
5. Measurable disease according to RECIST (Version 1.1) criteria
6. World Health Organization (WHO) performance status (PS) of 0 to 1
7. Provision of cancer tissue sample for mutation testing or the result of EGFR mutation test is negative (single T790M mutation positive patients can also be enrolled)

Exclusion Criteria summary

1. Newly diagnosed Central Nervous System (CNS) metastases that have not yet been definitively treated with surgery and/or radiation.
2. Known severe hypersensitivity to gefitinib, pemetrexed, cisplatin and carboplatin or any of the excipients of these products
3. Known severe hypersensitivity to pre-medications required for treatment with pemetrexed / cisplatin or pemetrexed/carboplatin doublet chemotherapy
4. Absolute neutrophil counts (ANC) less than 2.0 x 109/L (2,000/mm3), platelets less than 100 x 109/L (100,000/mm3) or haemoglobin less than 10 g/dl
5. Pre-existing idiopathic pulmonary fibrosis evidence by CT scan at baseline
6. Serum bilirubin is greater than 1.5 times the upper limit of reference range
7. Serum creatinine is greater than 1.5 times the ULRR
8. Unable to tolerate pemetrexed/ cisplatin or pemetrexed/carboplatin doublet chemotherapy, as judged by the investigator.