Inclusion Criteria:

• Patients with a histologically confirmed diagnosis of non-small cell lung cancer (NSCLC) within 5-years of study registration who are being evaluated for palliative whole brain radiotherapy (WBRT) (with or without neurosurgical resection or stereotactic radiosurgery [SRS]) for radiologically or histologically diagnosed brain metastases are eligible for this phase I study
• Life expectance of greater than two months (Graded Prognostic Assessment Score for NSCLC of 1.5 or higher) to allow completion of study treatment and assessment of dose-limiting toxicity
• Patients should have tumor tissue available for molecular marker testing
  • Group 1: patients should have archived tumor tissue available; the archived tumor tissue is not shipped nor are any correlative tests are performed for Group 1 patients in the present study; however, if the present study produces significant results, future protocols to perform correlative studies will be written and samples will be requested at that time
  • Group 2: patients should have archived tumor tissue available or have a fresh sample obtained at baseline and fresh tumor tissue available from the planned craniotomy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 100,000/mcL
• If no known liver metastases: total bilirubin < 1.5 x institutional upper limit of normal (ULN); if known liver metastases, then: total bilirubin < 2.5 x ULN
• If no known liver metastases: aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) < 2 x ULN; if known liver metastases, then: AST/SGOT < 5 x ULN
• Creatinine within normal institutional limits for age OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above ULN
• Negative serum pregnancy test result
  • Note: 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 6 months after completion of VX-970 administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients with 1-3 brain metastases, each < 3 cm by contrast magnetic resonance imaging (MRI), with stable systemic disease and ECOG score of 0-2, who would otherwise be eligible for SRS alone should not be enrolled into this study unless SRS is not feasible due to any medical or logistic limitations as determined by the treating physician; however, patients who develop recurrence post-SRS or surgery alone and are recommended WBRT will be eligible for the protocol
• Presence of leptomeningeal carcinomatosis, > 1 cm mid-line shift, uncial herniation, significant hemorrhage/hydrocephalous or history of seizure
• Patients who have had systemic cytotoxic chemotherapy or other targeted agents or any other investigational agents within 4 half-lives (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment or patients who have not recovered from serious adverse events due to agents administered more than 4 weeks earlier
• Patients must not have received prior WBRT (previous SRS done at least 4 weeks ago is acceptable)
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with VX-970
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to VX-970
• Concomitant administration with strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) should be avoided; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of; ongoing phenytoin should be either discontinued if clinically safe or transitioned to non-enzyme-inducing antiepileptics like Keppra (levetiracetam) with a 8-day washout period (half-life 18-22 hours, time to steady-state 4-8 days) prior to first dose of VX-970 (7-days prior to WBRT)
• Patients needing more than 8 mg dexamethasone per day at the time of start of WBRT will not be eligible to participate in the study; however, patients will be allowed entry into the study if it is medically safe to reduce the daily dose of dexamethasone to 8 mg or less from the day of the start of WBRT; the dexamethasone dose for such patients may be increased beyond 8 mg per day during the course of treatment if medically necessary; this increased need for dose should be communicated to the study's principal investigator, Dr Mohindra at the University of Maryland
• Uncontrolled intercurrent illness that would increase the risk of toxicity or limit compliance with study requirements; this includes but is not limited to, uncontrolled serious infection requiring i.v. antibiotics at the time of registration, symptomatic congestive heart failure, unstable angina pectoris, symptomatic/uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Patients with known diagnoses that are associated with germline DDR defects such as Li Fraumeni syndrome and ataxia telangiectasia are excluded from the study