Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised Phase 2 Trial of Pemetrexed and Gefitinib Versus Gefitinib as First Line Treatment for Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations
Brief Summary: The purpose of this study is to compare the combination of pemetrexed and gefitinib versus gefitinib alone, in terms of progression-free survival. This study is in participants who have stage IV non squamous NSCLC with activating epidermal growth factor mutations and who have not had any previous chemotherapy for stage IV disease.


Options:
A: Inclusion Criteria:

* Locally advanced Stage IIIB not amenable to local therapy or Stage IV (metastatic) NSCLC with adenocarcinoma histology.
* Never smokers or light ex-smokers.(ceased smoking at least 15 years before Day 1 of study treatment and 10 pack-years or fewer)

Exclusion Criteria:

* Had prior chemotherapy, biological (including targeted therapies such as EGFR and vascular epidermal growth factor (VEGF) inhibitors) or immunological therapy.
* Pre-existing idiopathic pulmonary fibrosis evidence by CT scan at baseline.
B: Inclusion Criteria:

* Histological diagnosis of NSCLC with locally advanced or metastatic disease that is of non-squamous histology.
* Participants must be "light ex-smokers" or "never-smokers".

  * "Light ex-smokers" defined as having ceased smoking for greater than or equal to 5 years and not to have exceeded 10 pack-years.
  * "Never-smokers" are defined as having smoked \<100 cigarettes or equivalent during his/her lifetime.
* Participants must be of East Asian ethnicity.
* No prior systemic therapy for lung cancer.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion Criteria:

* Presence of clinically significant (by physical exam) third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry.
* Any evidence of clinically active interstitial lung disease. Asymptomatic participants with chronic, stable, radiographic changes are eligible.
* Participants whose Epidermal Growth Factor Receptor (EGFR) mutation status is known prior to study entry will be excluded. Participants in which EGFR mutation testing has not been performed, or whose EGFR mutation status is unknown or inconclusive at study entry are eligible.
C: Inclusion Criteria:

* Histologically or cytologically confirmed advanced (Stage IV) or recurrent non-squamous NSCLC
* Eligible participants of reproductive potential must agree to use adequate contraceptive methods during the study period and for at least 6 months after the last dose of study therapy
* Negative pregnancy test for women of childbearing potential
* Males or females, aged 18 years or above
* Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
* The participant's primary NSCLC tumor has an activating Epidermal Growth Factor Receptor (EGFR) mutation, as determined by any validated method
* The participant consents to provide a tissue sample for prestudy EGFR mutation testing and the tumor tissue sample is available for detection of EGFR expression and other markers for centralized testing by Lilly
* The participant has measurable disease at the time of study entry, documented by computed tomography (CT) scan or magnetic resonance imaging (MRI), as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
* The participant has not had any prior systemic chemotherapy, immunotherapy, or biological therapy (for example, targeted therapy, such as erlotinib or gefitinib) for Stage IV or recurrent non-squamous NSCLC
* The participant has adequate organ function, defined as:

  * White blood cell count ≥3 x 10\^9/liter (L); absolute neutrophil count (segmented and bands) ≥1.5 x 10\^9/L; platelet count ≥100 x 10\^9/L; hemoglobin ≥9.0 gram per deciliter (g/dL)
  * Total bilirubin ≤1.5 times the upper limit of the normal (ULN) range; and alkaline phosphatase (AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times ULN (or ≤5 times ULN if the liver has tumor involvement)
  * Calculated creatinine clearance ≥45 milliliter per minute (mL/min)
* The participant is able to take folic acid, vitamin B12, and dexamethasone, according to the protocol's requirements
* Life expectancy of at least 3 months
* Provision of informed consent
* Prior radiation therapy is allowed to \<25% of the bone marrow; however, prior radiation to the whole pelvis not allowed. Prior radiation therapy must be completed at least 2 weeks prior to first study-drug administration. Participants must have recovered from the acute toxic effects prior to first study-drug administration.

Exclusion Criteria:

* The participant has received prior chemotherapy for advanced and/or metastatic disease, or adjuvant/neoadjuvant treatment with pemetrexed or an EGFR-tyrosine Kinase inhibitor (TKI)
* The participant's tumor contains predominantly small cell lung cancer or squamous NSCLC
* The participant is receiving concurrent treatment with any other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, biological or targeted therapy, or radiotherapy (palliative irradiation of bone lesions is allowed)
* The participant has untreated central nervous system (CNS) metastases Participants with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, stereotactic radiosurgery) ending at least 2 weeks before enrollment, or after surgical resection performed at least 28 days before enrollment. No evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or Intravenous (IV) contrast CT scan (performed within 21 days before randomization).
* The participant has undergone radiotherapy within 28 days before enrollment (localized radiotherapy for pain relief allowed, provided 25% or less of their total bone marrow had been irradiated)
* The participant has clinically relevant congestive heart failure (New York Heart Association \[NYHA\] II-IV) or symptomatic or poorly controlled cardiac arrhythmia
* The participant has a serious illness or medical condition that would compromise their safety or impair their ability to comply with the protocol's requirements, including, but not limited to, the following:

  * Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness
  * Active or uncontrolled clinically serious infection
  * Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study
  * Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain
  * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the participant ineligible for entry into this study
  * The participant has significant third space fluid retention, and is not amenable for required repeated drainage
  * Known allergy or hypersensitivity reaction to any of the treatment components
* Are unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 grams per day, for at least 2 days (5 days for long-acting agents \[for example, piroxicam\]) before, during, and for at least 2 days after administration of pemetrexed
* Concomitant use of cytochrome P450 (CYP)3A4 inducers or CYP3A4 inhibitors
* Participants under therapy with warfarin or coumarin derivatives who are unable to switch to low molecular weight heparin, unless regular monitoring of changes in prothrombin time (PT) (PT/international normalized ratio \[INR\]) will be applicable
* Any known significant ophthalmologic abnormalities of the surface of the eye. The use of contact lenses is not recommended during the study
* Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Participants participating in surveys or observational studies are eligible to participate in this study
* The participant has previously received treatment with gefitinib, erlotinib or pemetrexed
* Any evidence of clinically active interstitial lung disease. Asymptomatic participants with chronic, stable, radiographic changes are eligible.
* Have preexisting idiopathic pulmonary fibrosis as evidenced by computed tomography (CT) scan/x-ray at baseline; have or had any disease of acute lung injury, idiopathic pulmonary fibrosis, pulmonary pneumonia, or pneumoconiosis evident on an x-ray; have or had any disease of radiation pneumonia or drug-induced pneumonia, which requires treatment with corticosteroids.
* The participant is pregnant or breastfeeding
D: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed non-small cell lung cancer meeting 1 of the following stage criteria:

  * Stage IIIB

    * Pleural fluid and/or supraclavicular nodes allowed provided patient is not eligible for consolidation radiotherapy
  * Stage IV disease
* No disease progression after 2-6 courses of prior platinum-containing first-line palliative induction chemotherapy
* Brain metastases allowed provided patients are asymptomatic after cranial irradiation completed at least 4 weeks ago

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* WHO 0-2

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* Not specified

Renal

* Not specified

Pulmonary

* No history, signs, or symptoms of clinically active interstitial lung disease

  * Patients with chronic, stable, asymptomatic radiographic changes are eligible

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up
* No other malignant disease within the past 5 years except basal cell skin cancer or adequately treated superficial carcinoma of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No concurrent immunotherapy

Chemotherapy

* See Disease Characteristics
* Recovered from prior chemotherapy (alopecia allowed)
* No concurrent chemotherapy

Endocrine therapy

* Not specified

Radiotherapy

* See Disease Characteristics

Surgery

* Not specified

Other

* No prior epidermal growth factor receptor inhibitors
* No concurrent administration of any of the following drugs:

  * Phenytoin
  * Carbamazepine
  * Rifampin
  * Phenobarbital
  * Hypericum perforatum (St. John's wort)
* No other concurrent anticancer therapy
* No other concurrent experimental drugs

Answer: C