Trial of Trametinib and Ponatinib in Patients With KRAS Mutant Advanced Non-Small Cell Lung Cancer

Inclusion Criteria:

- Histologically or cytologically proven diagnosis of advanced lung adenocarcinoma

- KRAS mutation

- Radiographic progression following prior treatment with platinum doublet chemotherapy
and prior treatment with a PD-1/L1 inhibitor. Patients who are deemed not eligible for
therapy with a PD-1/L1 inhibitor by their treating physician will also be eligible.

- Able to take oral medications

- Measurable (RECIST 1.1) indicator lesion not previously irradiated

- Karnofsky performance status (KPS) ≥ 70%

- Age >18 years old

- Adequate organ function:

- AST, ALT ≤ 2.5 x ULN - Total bilirubin ≤ 1.5 x ULN -Albumin ≥ 2.5g/dL

- Creatinine < 1.5 x ULN OR calculated creatinine clearance ≥ 50mL/min

- Absolute neutrophil count (ANC) ≥ 1,200 cells/mm^3

- Hemoglobin ≥ 9.0 g/dL

- Platelets ≥ 100,000/mm^3

- Amylase and lipase within normal limits (amylase ≤ 100, lipase ≤ 51)

- Female patients who:

- Are postmenopausal for at least 1 year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
through 30 days after the last dose of study drug, or agree to completely abstain
from heterosexual intercourse

- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 30 days after the last dose of study drug, or

- Agree to completely abstain from heterosexual intercourse

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

- History of acute pancreatitis within 1 year of study entry or history of chronic
pancreatitis

- History of or ongoing alcohol abuse that, in the opinion of the Investigator, would
compromise compliance or impart excess risks associated with study participation.

- Pregnant or lactating women

- Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of
starting treatment on protocol

- Patients who have received prior treatment with MEK inhibitor

- A history of clinically significant interstitial lung disease or pneumonitis

- Significant uncontrolled or active cardiovascular disease, specifically including, but
not restricted to: History of clinically significant (as determined by the treating
physician) atrial arrhythmia; or any ventricular arrhythmia, History of congenital
long QT syndrome., Abnormal QTc (≥ 450 msec in males and ≥ 470 msec in females),
Ejection fraction ≤ 50% as assessed by echocardiogram.

- History of arterial thrombotic disease, specifically including, but not restricted to:
Myocardial infarction or unstable angina, cerebrovascular event (CVA) or transient
ischemic attack (TIA), Peripheral vascular disease or claudication within the past 6
months. Note: Participants enrolled after this window must be on appropriate
anti-platelet therapy

- Uncontrolled hypertension (Diastolic blood pressure > 100 mmHg; Systolic blood
pressure > 150 mmHg).

- History of venous thromboembolism (e.g. deep venous thrombosis or pulmonary embolism)
within 6 months of study entry. Note: Participants enrolled after this window must be
on appropriate therapeutic anticoagulation.

- History of central serous retinopathy or retinal vein occlusion

- Patients with baseline risk factors for central serous retinopathy or retinal vein
occlusion such as evidence of new optic disc cupping, evidence of new visual field
defects, and intraocular pressure >21 mmHg are excluded from the trial

- History of prior malignancy within 2 years that requires treatment. Patients who are
considered NED from a malignancy may be considered on a case by case basis.

- Any other condition that, in the opinion of the investigator, may compromise the
safety, compliance of the patient, or would preclude the patient from successful
completion of the study