Biologically Guided Radiation Therapy (BgRT) and Stereotactic Body Radiation Therapy (SBRT) to Tyrosine Kinase Inhibitor in Oligoprogressive Oncogenic Positive Non-Small Cell Lung Carcinoma

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Age: >= 18 years

• Eastern Cooperative Oncology Group (ECOG) =< 2

• Histologically confirmed advanced non-small cell lung cancer (NSCLC)

• The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR)mutations known to be associated with epidermal growth factor receptor tyrosinekinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or incombination with other epidermal growth factor receptor (EGFR) mutations, which mayinclude T790M.

• Disease progression in the metastatic setting on PET or CT imaging when receivingfirst line standard/approved single agent osimertinib after having had stabledisease (per Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1or PET Response Criteria in Solid Tumors [PERCIST] v 1.0) for more than 6 months

• Disease progression must be in the form of 1-5 extracranial sites (any number ofmetastatic sites at initial diagnosis will qualify). For progression of the primaryand oligoprogressive site(s), the primary should be treated with curative/localcontrol intent. The primary, if progressing is considered as 1 site. Maximum of 3lesions per organ (i.e. patient with 4 oligoprogressive sites in the lung would beexcluded). Each lesion will be considered as 1 "site" so 3 lesions in the lung forexample will be considered 3 sites. Patients with prior metastases that have beentreated with ablative therapies before their current line of systemic therapy areeligible. Patients with brain metastases can be included but brain metastases mustbe treated (asymptomatic and have had no requirement for steroid medication for 1week prior to the first dose of study drug and have completed radiation 2 weeksprior to the first dose of study drug) prior to enrollment (brain metastases [mets]will not be counted as a site of progression)

• Lesion(s) must be amenable to SBRT as determined by the radiation oncologist. If apatient is unable to receive a minimum of 30 Gy in 5 fractions they will not qualify

• At least one lesion must be amenable to BgRT which includes either a lung or bonemetastasis, greater than or equal to 2 cm, which can also receive a minimum of 30 Gyin 5 fractions

• No prior systemic therapy for advanced disease other than osimertinib

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required

• Agreement by females and males of childbearing potential* to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 4 months after the last dose of protocol therapy

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

• Patients must be able to swallow and retain oral medications

• Life expectancy of at least 6 months

Exclusion Criteria:

• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 daysprior to day 1 of protocol therapy (6 weeks for nitrosoureas or mitomycin C).Exceptions to this exclusion are brain radiation (2 weeks) and osimertinib

• Strong CYP3A4 inducers/ inhibitors within 14 days prior to day 1 of protocol therapy

• Patients receiving class 1A or class III antiarrhythmic agents within 14 days priorto day 1 of protocol therapy

• Drugs known to prolong the corrected QT (QTc) interval

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agent

• Clinically significant uncontrolled illness

• Active infection requiring antibiotics bacterial, viral, or fungal infections,requiring systemic therapy

• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis Cinfection

• Prior malignancy other than carcinoma in situ of the cervix, or nonmelanoma skincancer, unless that prior malignancy was diagnosed and definitively treated 5 ormore years prior to study entry with no subsequent evidence of recurrence. Patientswith a history of low grade (Gleason score =< 6 =Gleason group 1) localized prostatecancer will be eligible even if diagnosed less than 5 years prior to study entry.Other malignancies with low probability of recurrence may be allowed with primaryinvestigator (PI) approval

• Females only: Pregnant or breastfeeding

• Any malabsorption condition

• Any other condition that would, in the Investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Diagnosis of congenital long QT syndrome

• New York Heart Association Class III or IV, cardiac disease, myocardial infarctionwithin the past 6 months, unstable arrhythmia, or evidence of ischemia onelectrocardiogram (ECG)

• Clinical evidence of central nervous system (CNS) metastases or leptomeningealcarcinomatosis, except for individuals who have previously-treated CNS metastases,are asymptomatic, and have had no requirement for steroid medication for 1 weekprior to the first dose of study drug and have completed radiation 2 weeks prior tothe first dose of study drug

• Patients with active interstitial lung disease (ILD) / pneumonitis or with a historyof ILD/ pneumonitis requiring steroids

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)