Pembrolizumab with Chemotherapy for the Treatment of Asymptomatic Brain Metastasis from Non-small Cell Lung Cancer

Inclusion Criteria

• Non-small cell lung cancer (NSCLC) with untreated asymptomatic brain metastases
• Measurable disease as defined by the Response Assessment in Neuro-Oncology (RANO) group criteria. Per RANO, measurable disease is defined as at least one brain lesion that can be accurately measured in at least one dimension with the longest recorded diameter >= 10 mm OR presence of 3 lesions that can be followed* OR presence of one lesion measuring >= 5 mm PLUS a second lesion that can be followed* * RANO criteria considers these "nonmeasurable" lesions
• Presence of fewer than 10 intracranial lesions
• Each lesion measures 3 cm or less
• Absence of known oncogenic driver mutations, i.e., EGFR, ALK, or ROS-1 * NOTE: IF a mutation is discovered after the patient enrolls to this trial, then the patient will be taken off-study and considered "non-evaluable" for analysis
• Absence of new onset neurological symptoms (includes increased intracranial pressure, uncontrolled nausea or vomiting, grade 3 headache, epilepsy, or focal motor deficit attributed to the metastatic lesions)
• Eligible for treatment with immune checkpoint inhibitor. Note that no limit is placed on prior systemic treatment
• Ages 18-85 years
• ECOG performance status =< 2
• Life expectancy of >= 3 months
• Absolute neutrophil count: >= 1,000/mm^3
• Platelets: >= 75,000/mm^3
• Total bilirubin: =< 1.5 x unique learner number (ULN)
• Aspartate aminotransferase (AST) and alanine transaminase (ALT) if no hepatic metastasis: =< 2.5 x ULN
• AST and ALT with hepatic metastasis: =< 5 x ULN
• Creatinine: =< 1.5 x ULN and requires creatinine clearance (CrCl) >= 40 ml/min (per 24-hour [hr] urine collection or calculated via Cockcroft-Gault formula)
• Steroid dose maintenance is allowed, however no more than 10 milligrams (mg) of prednisone or equivalent per day or inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic in agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• The effects of pembrolizumab on the developing human fetus are unknown. The other chemotherapy agents used in this trial are known to be teratogenic. Hence, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 120 days after completion of pembrolizumab administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Presence of known oncogenic driver mutations, such as EGFR, ALK and/or ROS-1, at study pre-screening
• Measurable lesion located within 10mm of the optic chiasm or optic nerve, or within the brainstem
• Known leptomeningeal involvement
• Midline shift
• Pregnant and/or lactating women expecting to conceive or father children within the projected duration of the study, starting with the screening visit and extending through 120 days after the last dose of the trial treatment. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless certain criteria are met
• Active clinically serious infection > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
• Serious non-healing wound, ulcer or bone fracture
• Baseline inability to participate or complete neurocognitive testing, e.g. having developmental disabilities
• Ineligible for immune checkpoint inhibitors based on package insert of the chosen immune checkpoint inhibitor (e.g., uncontrolled immunologic disorders, active hepatitis, active colitis, active pneumonitis, uncontrolled/active hormone gland problems - including thyroid, pituitary, adrenal glands and pancreas)
• Major surgical procedure (including craniotomy and open brain biopsy) or significant traumatic injury within 14 days prior to registration
• Receipt of a non-central nervous system (CNS) minor surgical procedure (e.g. core biopsy or fine needle aspiration) within 3 days prior to registration. There is no waiting period for central line placement
• History of allergic reactions attributed to monoclonal antibodies (mAb), compounds of similar chemical or biologic composition to pembrolizumab. Severe hypersensitivity to pembrolizumab or any of its excipients
• Clinically significant cardiovascular disease, for example cerebrovascular accidents (less than 6 months, cerebrovascular accident [CVA]) /stroke, myocardial infarction (also less than 6 months), unstable angina pectoris, New York Heart Association class 3 or 4 congestive heart failure, or serious cardiac arrhythmia requiring medication
• Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 90mm Hg diastolic despite optimal antihypertensive treatment
• QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment * Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility (i.e., if the average is ≤ 500ms the patient is eligible)
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Patients who received prior radiation (whole brain radiation [WBRT], stereotactic radiosurgery [SRS] or Stereotactic radiotherapy) within the past 3 years at the discretion of the treatment team
• Patients who have a RET or MET driver mutation that can be targeted with an Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor (TKI) that is expected to generate a high response.