Phase III Prospective Randomized Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Chemoradiation for Locally-Advanced Non-Small Cell Lung Cancer
Trial ID: NCT05624996
Status: RECRUITING
Study type: INTERVENTIONAL
Phase: PHASE3
Start date: 2023-07-12
Completion date: 2031-10-15
Sponsor: NRG Oncology
Conditions: Locally Advanced Lung Non-Small Cell Carcinoma; Stage IIB Lung Cancer AJCC v8; Stage III Lung Cancer AJCC v8
Interventions: Carboplatin; Cisplatin; Computed Tomography; Durvalumab; Etoposide; Image Guided Radiation Therapy; Nab-paclitaxel; Osimertinib; Paclitaxel; Pemetrexed; Positron Emission Tomography; Questionnaire Administration; Stereotactic Body Radiation Therapy
Locations: University of Alabama at Birmingham Cancer Center; The Kirklin Clinic at Acton Road; Gulf Health Hospitals Inc/Infirmary Cancer Care - Malbis; Thomas Hospital; Mobile Infirmary Medical Center; Gulf Health Hospitals Inc/Infirmary Cancer Care - Saraland; Kingman Regional Medical Center; Cancer Center at Saint Joseph's; Mayo Clinic Hospital in Arizona; Banner University Medical Center - Tucson; University of Arizona Cancer Center-North Campus; NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro; University of Arkansas for Medical Sciences; AIS Cancer Center at San Joaquin Community Hospital; Mills-Peninsula Medical Center; Palo Alto Medical Foundation-Fremont; Los Angeles General Medical Center; USC / Norris Comprehensive Cancer Center; Fremont - Rideout Cancer Center; Memorial Medical Center; Palo Alto Medical Foundation-Camino Division; Palo Alto Medical Foundation Health Care; Sutter Cancer Centers Radiation Oncology Services-Roseville; Sutter Roseville Medical Center; Sutter Medical Center Sacramento; California Pacific Medical Center-Pacific Campus; Mills Health Center; Sutter Pacific Medical Foundation; Palo Alto Medical Foundation-Sunnyvale; Sutter Solano Medical Center/Cancer Center; UCHealth University of Colorado Hospital; Rocky Mountain Cancer Centers-Penrose; UCHealth Memorial Hospital Central; Memorial Hospital North; UCHealth - Cherry Creek; Poudre Valley Hospital; Cancer Care and Hematology-Fort Collins; UCHealth Greeley Hospital; UCHealth Highlands Ranch Hospital; UCHealth Lone Tree Health Center; Medical Center of the Rockies; Beebe Medical Center; Beebe South Coastal Health Campus; Helen F Graham Cancer Center; Medical Oncology Hematology Consultants PA; Christiana Care Health System-Christiana Hospital; Beebe Health Campus; Christiana Care Health System-Wilmington Hospital; Bay Pines VA Healthcare System; Morton Plant Hospital; Halifax Health Medical Center-Centers for Oncology; Memorial Regional Hospital/Joe DiMaggio Children's Hospital; Mayo Clinic in Florida; Jupiter Medical Center; Orlando Health Cancer Institute; Memorial Hospital West; Saint Joseph's Hospital/Children's Hospital-Tampa; Winter Haven Hospital; Grady Health System; Emory Proton Therapy Center; Emory University Hospital Midtown; Emory University Hospital/Winship Cancer Institute; Emory Saint Joseph's Hospital; Augusta University Medical Center; WellStar Cobb Hospital; Hamilton Medical Center - Peeples Cancer Institute; Wellstar Kennestone Hospital; CTCA at Southeastern Regional Medical Center; Lewis Cancer and Research Pavilion at Saint Joseph's/Candler; Hawaii Cancer Care Inc - Waterfront Plaza; Queen's Cancer Cenrer - POB I; Queen's Medical Center; Straub Clinic and Hospital; University of Hawaii Cancer Center; Kuakini Medical Center; Queen's Cancer Center - Kuakini; The Cancer Center of Hawaii-Liliha; Hawaii Cancer Care - Westridge; Pali Momi Medical Center; Alton Memorial Hospital; Rush-Copley Medical Center; Advocate Outpatient Center - Aurora; Advocate Good Shepherd Hospital; OSF Saint Joseph Medical Center; Illinois CancerCare-Bloomington; Illinois CancerCare-Canton; Illinois CancerCare-Carthage; Centralia Oncology Clinic; Northwestern University; Advocate Illinois Masonic Medical Center; AMG Crystal Lake - Oncology; Carle at The Riverfront; Cancer Care Specialists of Illinois - Decatur; Decatur Memorial Hospital; Northwestern Medicine Cancer Center Kishwaukee; Advocate Good Samaritan Hospital; Carle Physician Group-Effingham; Crossroads Cancer Center; Advocate Sherman Hospital; Illinois CancerCare-Eureka; Illinois CancerCare-Galesburg; Northwestern Medicine Cancer Center Delnor; Advocate South Suburban Hospital; Illinois CancerCare-Kewanee Clinic; AMG Libertyville - Oncology; Condell Memorial Hospital; Illinois CancerCare-Macomb; Carle Physician Group-Mattoon/Charleston; Cancer Care Center of O'Fallon; HSHS Saint Elizabeth's Hospital; Advocate Christ Medical Center; Illinois CancerCare-Ottawa Clinic; Advocate High Tech Medical Park; Advocate Lutheran General Hospital; Illinois CancerCare-Pekin; Illinois CancerCare-Peoria; OSF Saint Francis Radiation Oncology at Peoria Cancer Center; Methodist Medical Center of Illinois; OSF Saint Francis Medical Center; Illinois CancerCare-Peru; Illinois CancerCare-Princeton; UW Health Carbone Cancer Center Rockford; Memorial Hospital East; Southern Illinois University School of Medicine; Springfield Clinic; Springfield Memorial Hospital; Carle Cancer Center; Northwestern Medicine Cancer Center Warrenville; Illinois CancerCare - Washington; Midwestern Regional Medical Center; Northwest Cancer Center - Main Campus; Northwest Oncology LLC; Northwest Cancer Center - Hobart; Saint Mary Medical Center; The Community Hospital; Women's Diagnostic Center - Munster; Northwest Cancer Center - Valparaiso; Mary Greeley Medical Center; McFarland Clinic - Ames; UI Health Care Mission Cancer and Blood - Ankeny Clinic; Saint Luke's Hospital; Mercy Cancer Center-West Lakes; UI Health Care Mission Cancer and Blood - West Des Moines Clinic; Heartland Oncology and Hematology LLP; Methodist Jennie Edmundson Hospital; Greater Regional Medical Center; Iowa Methodist Medical Center; UI Health Care Mission Cancer and Blood - Des Moines Clinic; Mercy Medical Center - Des Moines; UI Health Care Mission Cancer and Blood - Laurel Clinic; UI Health Care Mission Cancer and Blood - Waukee Clinic; Mercy Medical Center-West Lakes; University of Kansas Cancer Center; Lawrence Memorial Hospital; The University of Kansas Cancer Center - Olathe; University of Kansas Cancer Center-Overland Park; Salina Regional Health Center; University of Kansas Health System Saint Francis Campus; University of Kansas Hospital-Westwood Cancer Center; Ascension Via Christi Hospitals Wichita; University of Kentucky/Markey Cancer Center; Louisiana State University Health Science Center; University Medical Center New Orleans; Touro Infirmary; MaineHealth Maine Medical Center - Portland; MaineHealth Cancer Care Center of York County; MaineHealth Maine Medical Center- Scarborough; MaineHealth Cancer Care and IV Therapy - South Portland; Luminis Health Anne Arundel Medical Center; Greater Baltimore Medical Center; Sinai Hospital of Baltimore; TidalHealth Richard A Henson Cancer Institute; TidalHealth Peninsula Regional; William E Kahlert Regional Cancer Center/Sinai Hospital; UMass Memorial Medical Center - University Campus; Trinity Health Saint Joseph Mercy Hospital Ann Arbor; McLaren Cancer Institute-Bay City; Trinity Health IHA Medical Group Hematology Oncology - Brighton; Trinity Health Medical Center - Brighton; Henry Ford Cancer Institute-Downriver; Chelsea Hospital; Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital; McLaren Cancer Institute-Clarkston; Michigan Healthcare Professionals Clarkston; Henry Ford Macomb Hospital-Clinton Township; Henry Ford Medical Center-Fairlane; Wayne State University/Karmanos Cancer Institute; Henry Ford Hospital; Michigan Healthcare Professionals Farmington; Weisberg Cancer Treatment Center; Corewell Health Farmington Hills Hospital; McLaren Cancer Institute-Flint; Trinity Health Grand Rapids Hospital; Allegiance Health; Bronson Methodist Hospital; West Michigan Cancer Center; Beacon Kalamazoo; Karmanos Cancer Institute at McLaren Greater Lansing; University of Michigan Health - Sparrow Lansing; McLaren Cancer Institute-Lapeer Region; Trinity Health Saint Mary Mercy Livonia Hospital; Michigan Healthcare Professionals Macomb; Michigan Healthcare Professionals Madison Heights; McLaren Cancer Institute-Macomb; McLaren Cancer Institute-Central Michigan; Henry Ford Medical Center-Columbus; McLaren Cancer Institute-Northern Michigan; Michigan Healthcare Professionals Pontiac; Trinity Health Saint Joseph Mercy Oakland Hospital; McLaren-Port Huron; Corewell Health William Beaumont University Hospital; Munson Medical Center; Corewell Health Beaumont Troy Hospital; Michigan Healthcare Professionals Troy; Henry Ford Health Warren Hospital; Henry Ford West Bloomfield Hospital; University of Michigan Health - West; Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus; Sanford Joe Lueken Cancer Center; Essentia Health Saint Joseph's Medical Center; Essentia Health - Deer River Clinic; Essentia Health Cancer Center; Essentia Health Saint Mary's Medical Center; Miller-Dwan Hospital; Essentia Health Hibbing Clinic; Mayo Clinic in Rochester; Coborn Cancer Center at Saint Cloud Hospital; Essentia Health Sandstone; Essentia Health Virginia Clinic; Baptist Memorial Hospital and Cancer Center-Desoto; Saint Francis Medical Center; Siteman Cancer Center at Saint Peters Hospital; MU Health - University Hospital/Ellis Fischel Cancer Center; Siteman Cancer Center at West County Hospital; Parkland Health Center - Farmington; Freeman Health System; University of Kansas Cancer Center - Briarcliff; University of Kansas Cancer Center - North; University of Kansas Cancer Center - Lee's Summit; Sainte Genevieve County Memorial Hospital; Mercy Hospital Springfield; Washington University School of Medicine; Mercy Hospital South; Siteman Cancer Center-South County; Missouri Baptist Medical Center; Siteman Cancer Center at Christian Hospital; Mercy Hospital Saint Louis; Missouri Baptist Sullivan Hospital; BJC Outpatient Center at Sunset Hills; Billings Clinic Cancer Center; Bozeman Health Deaconess Hospital; Benefis Sletten Cancer Institute; Nebraska Cancer Specialists/Oncology Hematology West PC - MECC; Nebraska Methodist Hospital; Oncology Associates PC; Renown Regional Medical Center; Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center; Memorial Sloan Kettering Basking Ridge; Cooper Hospital University Medical Center; Jefferson Cherry Hill Hospital; The Cancer Institute of New Jersey Hamilton; Jersey City Medical Center; Monmouth Medical Center Southern Campus; Saint Barnabas Medical Center; Monmouth Medical Center; Memorial Sloan Kettering Monmouth; Memorial Sloan Kettering Bergen; Rutgers Cancer Institute of New Jersey; Rutgers New Jersey Medical School; Sidney Kimmel Cancer Center Washington Township; Robert Wood Johnson University Hospital Somerset; Community Medical Center; University of New Mexico Cancer Center; Presbyterian Kaseman Hospital; Memorial Medical Center-Las Cruces; Presbyterian Rust Medical Center/Jorgensen Cancer Center; Wilmot Cancer Center at Batavia; Northwell Health Imbert Cancer Center; Sands Cancer Center; Memorial Sloan Kettering Commack; Memorial Sloan Kettering Westchester; Glens Falls Hospital; Northwell Health Cancer Institute at Huntington; Northwell Health/Center for Advanced Medicine; New York Proton Center; Manhattan Eye Ear and Throat Hospital; Memorial Sloan Kettering Cancer Center; Lenox Hill Hospital; Wilmot Cancer Institute Radiation Oncology at Greece; Highland Hospital; University of Rochester; Staten Island University Hospital; Stony Brook University Medical Center; State University of New York Upstate Medical University; Montefiore Medical Center-Einstein Campus; Montefiore Medical Center-Weiler Hospital; Montefiore Medical Center - Moses Campus; Memorial Sloan Kettering Nassau; Westchester Medical Center; Wilmot Cancer Institute at Webster; Atrium Health Stanly/LCI-Albemarle; Duke Cancer Center Cary; UNC Lineberger Comprehensive Cancer Center; Carolinas Medical Center/Levine Cancer Institute; Novant Health Presbyterian Medical Center; Atrium Health Pineville/LCI-Pineville; Atrium Health University City/LCI-University; Levine Cancer Institute-Ballantyne; Wake Forest University at Clemmons; Atrium Health Cabarrus/LCI-Concord; Duke University Medical Center; Levine Cancer Institute - Rutherford; CaroMont Regional Medical Center; Novant Health Breast Surgery - Greensboro; Hayworth Cancer Center; Novant Health Cancer Institute - Huntersville; Novant Health Presbyterian Medical Center Huntersville; Novant Health Cancer Institute - Kernersville; Levine Cancer Institute - Union West; Matthews Radiation Oncology Center; Novant Health Cancer Institute - Matthews; Atrium Health Union/LCI-Union; Novant Health Cancer Institute - Mooresville; Novant Health Cancer Institute - Mount Airy; Novant Health Cancer Institute - Wilkesboro; Duke Cancer Center Raleigh; Novant Health Cancer Institute - Rowan; Rowan Regional Medical Center; Atrium Health Cleveland/LCI-Cleveland; Wake Forest Baptist Health - Hematology Oncology - Statesville; Novant Health Cancer Institute - Statesville; Novant Cancer Institute Radiation Oncology - Supply; Novant Health Cancer Institute - Thomasville; Wake Forest Baptist Health - Wilkes Medical Center; Novant Health Cancer Institute Radiation Oncology - Wilmington; Novant Health New Hanover Regional Medical Center; Novant Health Forsyth Medical Center; Wake Forest University Health Sciences; Sanford Bismarck Medical Center; Sanford Broadway Medical Center; Sanford Roger Maris Cancer Center; Altru Cancer Center; Cleveland Clinic Akron General; UH Seidman Cancer Center at UH Avon Health Center; UHHS-Chagrin Highlands Medical Center; Cleveland Clinic Mercy Hospital; Aultman Health Foundation; Miami Valley Hospital South; University of Cincinnati Cancer Center-UC Medical Center; Case Western Reserve University; Riverside Methodist Hospital; Grant Medical Center; Doctors Hospital; Miami Valley Hospital; Premier Blood and Cancer Center; Dayton Physician LLC - Englewood; Miami Valley Hospital North; Delaware Health Center-Grady Cancer Center; Grady Memorial Hospital; Dublin Methodist Hospital; Atrium Medical Center-Middletown Regional Hospital; Miami Valley Cancer Care and Infusion; OhioHealth Mansfield Hospital; OhioHealth Marion General Hospital; UH Seidman Cancer Center at Lake Health Mentor Campus; Mercy Health - Perrysburg Hospital; Upper Valley Medical Center; University of Cincinnati Cancer Center-West Chester; University of Oklahoma Health Sciences Center; Legacy Mount Hood Medical Center; Legacy Good Samaritan Hospital and Medical Center; Legacy Meridian Park Hospital; Christiana Care Health System-Concord Health Center; Chambersburg Hospital; Geisinger Medical Center; Ephrata Cancer Center; Adams Cancer Center; Penn State Milton S Hershey Medical Center; Lancaster General Ann B Barshinger Cancer Institute; Sechler Family Cancer Center; Geisinger Medical Oncology-Lewisburg; University of Pennsylvania/Abramson Cancer Center; Thomas Jefferson University Hospital; Fox Chase Cancer Center; Temple University Hospital; Reading Hospital; Geisinger Wyoming Valley/Henry Cancer Center; Asplundh Cancer Pavilion; Lankenau Medical Center; WellSpan Health-York Cancer Center; WellSpan Health-York Hospital; Saint Joseph's/Candler - Bluffton Campus; Gibbs Cancer Center-Gaffney; Saint Francis Hospital; Saint Francis Cancer Center; Gibbs Cancer Center-Pelham; Lancaster Radiation Therapy Center; Rock Hill Radiation Therapy Center; Levine Cancer Institute-Rock Hill; Spartanburg Medical Center; SMC Center for Hematology Oncology Union; Lexington Medical Center; Sanford Cancer Center Oncology Clinic; Sanford USD Medical Center - Sioux Falls; Baptist Memorial Hospital and Cancer Center-Collierville; University of Tennessee - Knoxville; Baptist Memorial Hospital and Cancer Center-Memphis; MD Anderson in The Woodlands; Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; Ben Taub General Hospital; M D Anderson Cancer Center; MD Anderson West Houston; MD Anderson League City; MD Anderson in Sugar Land; Central Vermont Medical Center/National Life Cancer Treatment; University of Vermont Medical Center; University of Vermont and State Agricultural College; Dartmouth Cancer Center - North; Virginia Mason Medical Center; Legacy Cancer Institute Medical Oncology and Day Treatment; Legacy Salmon Creek Hospital; Edwards Comprehensive Cancer Center; West Virginia University Healthcare; Langlade Hospital and Cancer Center; Duluth Clinic Ashland; Northwest Wisconsin Cancer Center; Aurora Cancer Care-Southern Lakes VLCC; HSHS Sacred Heart Hospital; Marshfield Medical Center-EC Cancer Center; Aurora Health Care Germantown Health Center; Aurora Cancer Care-Grafton; Saint Vincent Hospital Cancer Center Green Bay; Aurora BayCare Medical Center; Essentia Health-Hayward Clinic; University of Wisconsin Carbone Cancer Center - Johnson Creek; Aurora Cancer Care-Kenosha South; William S Middleton VA Medical Center; University of Wisconsin Carbone Cancer Center - Eastpark Medical Center; University of Wisconsin Carbone Cancer Center - University Hospital; Aurora Bay Area Medical Group-Marinette; Marshfield Medical Center-Marshfield; Froedtert Menomonee Falls Hospital; Aurora Cancer Care-Milwaukee; Aurora Saint Luke's Medical Center; Medical College of Wisconsin; Aurora Sinai Medical Center; Zablocki Veterans Administration Medical Center; Marshfield Medical Center - Minocqua; ProHealth D N Greenwald Center; Drexel Town Square Health Center; ProHealth Oconomowoc Memorial Hospital; Vince Lombardi Cancer Clinic - Oshkosh; Aurora Cancer Care-Racine; Aspirus Cancer Care - James Beck Cancer Center; Marshfield Medical Center-Rice Lake; Saint Vincent Hospital Cancer Center at Sheboygan; Vince Lombardi Cancer Clinic-Sheboygan; Essentia Health-Spooner Clinic; Aspirus Cancer Care - Stevens Point; Marshfield Medical Center-River Region at Stevens Point; Saint Vincent Hospital Cancer Center at Sturgeon Bay; Aurora Medical Center in Summit; Essentia Health Saint Mary's Hospital - Superior; UW Cancer Center at ProHealth Care; Aspirus Regional Cancer Center; Aurora Cancer Care-Milwaukee West; Aurora West Allis Medical Center; Froedtert West Bend Hospital/Kraemer Cancer Center; Marshfield Medical Center - Weston; Aspirus Cancer Care - Wisconsin Rapids; Ottawa Hospital and Cancer Center-General Campus
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United States; United States; Canada
Enrollment: 474
Age range: 18 Years - None
Sex: ALL

Summary:
This phase III trial compares the effect of adding stereotactic body radiation therapy (SBRT) to the usual treatment (conventional image guided radiation therapy \[IGRT\] and chemotherapy followed by immunotherapy with durvalumab or targeted therapy with osimertinib) versus the usual treatment alone in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be treated by surgery (inoperable). SBRT uses special equipment to position a patient and deliver radiation therapy to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. IGRT is a type of radiation therapy that creates a picture of the tumor to help guide the radiation beam during therapy, making it more accurate and causing less damage to healthy tissue. Usual chemotherapy used in this trial consists of combinations of the following drugs: cisplatin, carboplatin, paclitaxel, nab-paclitaxel, pemetrexed, and etoposide. Cisplatin and carboplatin are in a class of medications known as platinum-containing compounds. Cisplatin works by killing, stopping, or slowing the growth of tumor cells. Carboplatin works in a way similar to the anticancer drug cisplatin but may be better tolerated than cisplatin. Carboplatin works by killing, stopping, or slowing the growth of tumor cells as well. Paclitaxel is in a class of medications called antimicrotubule agents. It works by stopping the growth and spread of tumor cells. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by blocking the action of a certain substance in the body that may help tumor cells multiply. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill tumor cells. Immunotherapy with durvalumab can induce changes in the body's immune system and can interfere with the ability of tumor cells to grow and spread. Osimertinib is in a class of medications called kinase inhibitors. It works by blocking the action of a protein called EGFR that signals cancer cells to multiply. This helps slow or stop the spread of tumor cells. Adding SBRT to the usual treatment of IGRT with chemotherapy and immunotherapy may be more effective at treating patients with locally-advanced non-small cell lung cancer than giving the usual treatment alone.

Eligibility criteria:
Inclusion Criteria:

* Pathologically (histologically or cytologically) proven diagnosis of non-operable stage IIB or III, node positive (American Joint Committee on Cancer \[AJCC\] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration

  * Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene)
  * Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible
  * Patients who refuse surgery, in addition to those who are technically unresectable or medically inoperable, are eligible.
  * Patients with separate tumor nodules in the same lobe of the primary tumor are eligible
* The patient must be deemed clinically appropriate for curative intent definitive combined modality therapy, based on the following staging assessments:

  * History/physical examination prior to registration;
  * Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan of the brain (if available, contrast is preferred for all neuroimaging) prior to registration;
  * CT chest with IV contrast (if contrast is available and unless contraindicated, such as for abnormal kidney function) prior to registration. PET/CT may be used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT
* No evidence of distant metastases based on FDG PET/CT scan obtained within 60 days of registration
* Primary tumor =\< 7 cm
* Age \>= 18
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at the discretion of the treating physician, to allow for treatment with chemotherapy and concurrent radiation therapy
* Creatinine clearance \>= 25 mL/min by the Cockcroft-Gault (C-G) equation
* Subjects with non-malignant pleural effusion are eligible provided the effusion is not known or demonstrated to be an exudative effusion

  * If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:

    * When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative;
    * Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible
* Medical history consistent with the patient being amenable, at the discretion of the treating physician, to allow for treating with consolidation immunotherapy. Patients with known EGFR/ALK/other driver mutation at the time of registration are eligible, and these patients can be treated with consolidation systemic therapy at the discretion of the treating physician
* 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
* Negative pregnancy test =\< 14 days prior to registration for participants of childbearing potential
* The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

* Prior radiotherapy to the study cancer (local recurrence). Prior radiotherapy for a different cancer/condition to the region of the study cancer that would result in overlap of radiation therapy fields that is determined by the treating physician to impede the treatment of the study malignancy
* Patients without identifiable primary tumor and at least 1 pathologically enlarged lymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1 radiographically-involved lymph node is required, but pathologic confirmation of involvement is not mandated
* Centrally located primary tumor \< 2 cm from involved nodal disease that would result in significant overlap of the primary SBRT and nodal radiation fields. This does not include proximity to involved segmental and subsegmental lymph nodes (levels 13 and 14) that would not result in overlap of dose to the proximal bronchial tree or esophagus. Centrally located is defined as within or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi)
* Participants who are pregnant or unwilling to discontinue nursing
* Participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) unwilling to use highly effective contraceptives during therapy and for the Food and Drug Administration (FDA)-labeled contraception timeframe required after the final dose of the selected systemic therapy regimen, because the treatment in this study may be significantly teratogenic

Outcomes:
Overall survival (OS); Progression-free survival (PFS)