A Randomized, Controlled Phase 2 Study Evaluating LY2875358 plus Erlotinib versus Erlotinib as First-Line Treatment in Metastatic Non-Small Cell Lung Cancer Patients with Activating EGFR Mutations Who Have Disease Control after an 8-Week Lead-In Treatment with Erlotinib

[1] Have a histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC at the time of study entry (American Joint Committee on Cancer Staging Criteria for NSCLC, Seventh Edition; Edge et al. 2009).;[2] Have at least 1 measurable lesion whose presence is assessable using standard techniques by RECIST version 1.1 (Eisenhauer et al. 2009). For patients with prior radiation therapy, measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented at that site since radiation. ;[3] Have molecular evidence of an EGFRmt known to be associated with drug sensitivity (G719X, exon 19 deletion, L858R, L861Q; further activating EGFRmt may be included in the future if supported by scientific evidence after discussion with the sponsor). This determination should be made from a NSCLC tumor sample based on testing with an EGFRmt assay (either a regulatory approved assay or by a local assay validated in a local laboratory according to institutional guidelines and local standard of care).;[4] Availability of adequate tumor-derived material from a biopsy or surgery (tumor blocks or slides) for analysis of MET expression status (needed for stratification) and exploratory biomarkers analysis. ;[5] Have a performance status of =<2 on the Eastern Cooperative Oncology Group (ECOG) scale.;[6] Have not received previous systemic chemotherapy, systemic therapy with biologics, or molecular-targeted therapy for Stage IV NSCLC. Patients who received chemotherapy as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment are eligible. ;[7] Have adequate organ function, as demonstrated by the following
parameters:
• Hematologic: Absolute neutrophil count (ANC) *1.5 × 109/L,
platelets *100 × 109/L, and hemoglobin *8 g/dL
• Hepatic: Bilirubin <=1.5 × upper limits of normal (ULN); albumin >=25
g/L; alkaline phosphatase (ALP), alanine aminotransferase (ALT), and
aspartate aminotransferase (AST) <=2.5 × ULN or <=5 × ULN in patients
with hepatic metastases. NOTE: Patients with bone metastases and
isolated elevation of ALP and patients with a documented Gilbert
syndrome and isolated elevation of bilirubin are eligible.
• Renal: Serum creatinine level <=1.5 × ULN; or calculated serum
creatinine clearance >=50 mL/min according to the method of Cockcroft
and Gault;[8] Patients who require oral anticoagulants (eg, warfarin) are eligible
provided there is increased vigilance with respect to the monitoring of
the patient's international normalized ratio (INR), according to
investigator judgment. If medically appropriate and the treatment is
available, the investigator may also consider switching these patients to
low-molecular-weight heparin or oral factor Xa inhibitors, with which an
interaction with LY2875358 or erlotinib is not expected.;[9] Are men or women at least 18 years of age at the time of screening.;[10] Eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and at least 12 weeks after the last dose of study therapy, or longer if required by local regulations.;Women of child-bearing potential must test negative for pregnancy within 7 days prior to enrollment based on a serum pregnancy test and must also not be breastfeeding.;[11] Are able to swallow tablets.;[12] Have an estimated life expectancy of at least 12 weeks in the judgment of the investigator.;[13] Patients must have given written informed consent prior to any
study-specific procedures and be willing to make themselves available
for the duration of the study and follow study procedures.

[14] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or nonapproved 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.;[15] Have previously completed or withdrawn from this study or any other study investigating LY2875358. (This exclusion criterion does not apply to patients who are rescreened prior to enrollment.);[16] Have a serious concomitant systemic disorder (eg, active infection including human immunodeficiency virus [HIV], or significant cardiac disease (eg, history of New York Heart Association class >=3 disease, unstable angina, or myocardial infarction in 6 months prior to study drug administration) that, in the opinion of the investigator, would compromise the patient*s ability to adhere to the protocol.;[17] Have interstitial pneumonia or interstitial fibrosis of the lung that, in the opinion of the investigator, could compromise the patient or the study treatment with erlotinib.;[18] Have pleural effusion, pericardial fluid, or ascites requiring drainage every other week or more frequently.
NOTE: Patients with a permanently implanted catheter system in place for repeated draining of pleural effusions or ascites (eg, "PleurX" system) are eligible.;[19] Have a history of another malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, other noninvasive cancers that in the judgment of the investigator and sponsor may not affect the interpretation of the study results or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study.;[20] Have any major surgery less than 2 weeks prior to initiation of study treatment. ;[21] Have any condition (eg, psychological, geographical.) that does not permit compliance with study and follow-up procedures or suggests that the patient is, in the investigator*s opinion, not an appropriate candidate for the study. ;[22] Are pregnant or lactating women. ;The following Exclusion Criteria [23]-[24] will be assessed at the end of the 8-week lead-in study period with erlotinib monotherapy: ;[23] Have radiographic or clinical progression of disease (according to RECIST version 1.1) at the end of the 8-week erlotinib lead-in study period. ;[24] Have CNS metastasis (screening not required) except:
Patients with CNS metastases treated with surgery and/or radiation are eligible for randomization if they are, at the end of the 8-week erlotinib lead-in study period, either or both of the following:
• Clinically stable with regard to neurologic function and off corticosteroids after cranial irradiation (ie, whole-brain radiation therapy, focal radiation therapy, or stereotactic radiosurgery) at least 3
weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The patient may have no evidence of Grade >=1 CNS hemorrhage based on pretreatment magnetic resonance imaging (MRI) or IV contrast-enhanced computed tomography (CT) performed within 3 weeks prior to randomization
• asymptomatic with regard to neurologic function and, if taking corticosteroids, must be on a stable dose for >=2 weeks prior to randomization.
Patients with CNS metastases not treated with surgery and/or radiation are eligible for randomization if they are at the end of the 8-week erlotinib lead-in study period asymptomatic and clinically stable with regard to neurologic function and not requiring steroids or anticonvulsants to control CNS metastases-related symptoms.