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 </= 2.5 x ULN
• Total bilirubin </= 1.5 x ULN
• 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