A Phase 1/2 Trial of Trametinib and Erlotinib in Patients With EGFR-Mutant Lung Adenocarcinomas and Acquired Resistance to Erlotinib

Inclusion Criteria:

- Pathologic evidence of advanced stage IV or recurrent lung adenocarcinoma reviewed at
MSKCC

- Somatic activating mutation in EGFR Radiographic progression during treatment with
erlotinib.

- Any number of prior chemotherapy regimens is permitted.

- Measurable (RECIST 1.1) indicator lesion not previously irradiated

- KPS >/= 70%

- Age >18 years old

- Must have undergone biopsy after development of acquired resistance to erlotinib with
available archived tissue (equivalent of > 10 unstained slides)

- Left ventricular Ejection Fraction >/= the lower limit of normal by ECHO or MUGA

- Adequate organ function:

- AST, ALT
- Total bilirubin
- Albumin>/=2.6g/dL - Creatinine < 1.5 x ULN OR calculated creatinine clearance
>/=50mL/min

- Absolute neutrophil count (ANC) >/= 1,200 cells/mm3

- Hemoglobin>/=9.0 g/dL

- Platelets >/=100,000/mm3

Exclusion Criteria:

- Patients with symptomatic brain metastasis requiring escalating doses of steroids

- Patients with grade 2 or greater diarrhea prior to study initiation despite maximal
medical management due to medications or a medical condition such as Crohn's disease
or malabsorption

- Pregnant or lactating women

- Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of
starting treatment on protocol except for a EGFR TKI

- Patients who have received prior treatment with a MEK inhibitor

- Any major surgery or extensive radiotherapy within 21 days of starting treatment on
protocol.

- A history of clinically significant interstitial lung disease or pneumonitis

- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within 6 months from Day 1 of study administration, New York Heart
Association Class III or IV congestive heart failure, or symptomatic uncontrolled
Arrythmias, prolonged corrected QT interval >480msec, treatment refractory
hypertension, presence of a cardiac defibrillator

- History of central serous retinopathy or retinal vein occlusion