Testing the Use of Combination Immunotherapy Treatment (N-803 [ALT-803] Plus Pembrolizumab) Against the Usual Treatment for Advanced Non-small Cell Lung Cancer (A Lung-MAP Treatment Trial)

Inclusion Criteria:

• Participants must have been assigned to S1800D by the Southwest Oncology Group (SWOG) Statistics and Data Management Center (SDMC). Assignment to S1800D isdetermined by the LUNGMAP or S1400 protocol

• Participants must have measurable or non-measurable disease documented by computedtomography (CT) or magnetic resonance imaging (MRI). Measurable disease must beassessed within 28 days prior to randomization. Non-measurable disease must beassessed within 42 days prior to randomization. The CT from a combined positronemission tomography (PET)/CT may be used only if it is of diagnostic quality. Allknown sites of disease must be assessed and documented on the Baseline TumorAssessment Form (RECIST 1.1)

• Participants must have a CT or MRI scan of the brain to evaluate for central nervoussystem (CNS) disease within 42 days prior to sub-study randomization

• Participants with spinal cord compression or brain metastases must have receivedlocal treatment to these metastases and remained clinically controlled andasymptomatic for at least 7 days following stereotactic radiation and/or 14 daysfollowing whole brain radiation, and prior to sub-study randomization

• Participants with spinal cord compression or brain metastases must not have residualneurological dysfunction, unless no further recovery is expected, and theparticipant has been stable on weaning doses of corticosteroids (=< 10 mg dailyprednisone or equivalent) prior to sub-study randomization

• Participants must have progressed (in the opinion of the treating investigator)following the most recent line of therapy for non-small cell lung cancer (NSCLC)

• Participants with a known sensitizing mutation for which an FDA-approved targetedtherapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF, RET, NTRK, andMET sensitizing mutations), must have previously received at least one of theapproved therapy(s)

• Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapyfor advanced disease (stage IV or recurrent, or stage III in certain circumstancesoutlined below) given alone or in combination with platinum-based chemotherapy.Participants must have experienced disease progression during or after this regimen

• Continuing the same agent(s) after progression counts as a single line oftherapy. However, a change or addition in agent(s) after progression (e.g. theaddition of chemotherapy to anti-PD-1 monotherapy after progression) counts asa subsequent line of therapy and would exclude the participant

• For participants who received consolidation anti-PD-1 or anti-PD-L1 therapyfollowing concurrent chemoradiation for Stage III disease as their only line ofanti-PD-1 or anti-PD-L1 therapy:

• If they experienced disease progression less than (<) 365 days from thefirst date of anti-PD-1 or anti-PD-L1 therapy, this counts as the singleline of anti-PD-1 or anti-PD-L1 therapy for advanced disease

• If they experienced disease progression more than or equal to (>=) 365days from the first date of anti-PD-1 or anti-PD-L1 therapy, this is notconsidered a line of anti-PD-1 or anti-PD-L1 therapy for advanced disease

• Participants must have recovered (=< grade 1) from any side effects of priortherapy, except for alopecia

• Participants must be able to safely receive at least one of the investigator'schoice of standard of care regimens, per the current FDA-approved package insert

• Note: Pemetrexed is not FDA-approved for squamous cell NSCLC and must not beused to treat participants with squamous cell NSCLC

• Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL (obtained within 28 days prior tosub-study randomization)

• Platelet count >= 100 x 10^3/uL(obtained within 28 days prior to sub-studyrandomization)

• Hemoglobin >= 9 g/dL (obtained within 28 days prior to sub-study randomization)

• Serum bilirubin =< institutional upper limit of normal (IULN) (within 28 days priorto sub-study randomization). For participants with liver metastases, bilirubin mustbe =< 5 x IULN

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 x IULN (within 28 days prior to sub-study randomization). For participants with livermetastases, ALT and AST must be =< 5 x IULN

• Serum creatinine =< the IULN or calculated creatinine clearance >= 50 mL/min usingCockcroft-Gault formula. This specimen must have been drawn and processed within 28days prior to sub-study randomization

• Participants' most recent Zubrod performance status must be 0-1 and be documentedwithin 28 days prior to sub-study randomization

• Participants must have history and physical exam must be obtained within 28 daysprior to sub-study randomization

• Participants with known human immunodeficiency virus (HIV) infection must bereceiving anti-retroviral therapy and have an undetectable viral load at their mostrecent viral load test within 6 months prior to sub-study randomization

• Participants must also be offered participation in banking and in the correlativestudies for collection and future use of specimens

• Note: As a part of the OPEN registration process the treating institution's identityis provided in order to ensure that the current (within 365 days) date ofinstitutional review board approval for this study has been entered in the system

• Participants must be informed of the investigational nature of this study andmust sign and give written informed consent in accordance with institutionaland federal guidelines

Exclusion Criteria:

• Participants must not have leptomeningeal disease that requires CNS-specifictreatment prior to registration and must not be planning to receive the CNS-specifictreatment through the first cycle of the protocol therapy

• Participants must not have experienced the following:

• Any grade 3 or worse immune-related adverse event (irAE). Exception:asymptomatic nonbullous/nonexfoliative rash

• Any unresolved grade 2 irAE

• Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1immunotherapy

• Exception to the above: Toxicities of any grade that requires replacementtherapy and has stabilized on therapy (e.g., thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency) areallowed

• Participants must not have any history of organ transplant that requires use ofimmunosuppressives

• Participants must not have history of (non-infectious) pneumonitis that requiredsteroids or current pneumonitis/interstitial lung disease

• Participants must not have any known allergy or reaction to any component of theinvestigational formulations. If there is a known allergy or reaction to standard ofcare formulations, participants must be able to safely receive at least one of thestandard of care options

• Participants must not have any grade III/IV cardiac disease as defined by the NewYork Heart Association Criteria (i.e., participants with cardiac disease resultingin marked limitation of physical activity or resulting in inability to carry on anyphysical activity without discomfort), unstable angina pectoris, and myocardialinfarction within 6 months prior to sub-study randomization, or serious uncontrolledcardiac arrhythmia

• Participants must not have experienced any arterial thromboembolic events, includingbut not limited to myocardial infarction, transient ischemic attack, cerebrovascularaccident, or unstable angina, within 6 months prior to sub-study randomization

• Participants must not have an active or uncontrolled infection in the opinion of thetreating investigator

• Participants must not have a prior or concurrent malignancy whose natural history ortreatment has the potential to interfere with the safety or efficacy assessment ofthe investigational regimen

• Participants must not have any of following:

• Cirrhosis at a level of Child-Pugh B (or worse)

• Cirrhosis (any degree) and a history of hepatic encephalopathy

• Or clinically meaningful ascites resulting from cirrhosis. Clinicallymeaningful ascites is defined as ascites from cirrhosis requiring diuretics orparacentesis

• Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab,tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3,anti-GITR, IL-2, IL-15)

• Participants must not have received any prior systemic therapy (systemicchemotherapy, immunotherapy or investigational drug) within 21 days prior tosub-study randomization

• Participants must not have received any radiation therapy within 14 days prior tosub-study randomization

• Participants must not have received nitrosoureas or mitomycin-c within 42 days priorto sub-study randomization

• Participants must not have received systemic treatment with corticosteroids (> 10 mgdaily prednisone or equivalent) or other immunosuppressive medications within 7 daysprior to sub-study randomization. Inhaled or topical steroids, and adrenalreplacement doses =< 10 mg daily prednisone or equivalent are permitted in theabsence of active autoimmune disease

• Participants must not have received a live attenuated vaccination within 28 daysprior to sub-study randomization. All COVID-19 vaccines that have received Food andDrug Administration (FDA) approval or FDA emergency use authorization are acceptable

• Participants must not be planning to receive any concurrent chemotherapy,immunotherapy, biologic or hormonal therapy for cancer treatment while receivingtreatment on this study

• Participants must not have had a major surgery within 14 days prior to sub-studyrandomization. Participant must have fully recovered from the effects of priorsurgery in the opinion of the treating investigator

• Participants must not have an active autoimmune disease that has required systemictreatment within two years prior to sub-study randomization (i.e., with use ofdisease modifying agents, corticosteroids or immunosuppressive drugs). Replacementtherapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapyfor adrenal or pituitary insufficiency) is not considered a form of systemictreatment and is allowed

• Participants must not have any history of primary immunodeficiency

• Participants must not be pregnant or nursing. Women/men of reproductive potentialmust have agreed to use an effective contraceptive method during the study and 4months after completion of study treatment. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12consecutive months. In addition to routine contraceptive methods, "effectivecontraception" also includes heterosexual celibacy and surgery intended to preventpregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,bilateral oophorectomy or bilateral tubal ligation. However, if at any point apreviously celibate participant chooses to become heterosexually active during thetime period for use of contraceptive measures outlined in the protocol, he/she isresponsible for beginning contraceptive measures during the study and 4 months afterstudy completion