This phase II trial tests the impact of biomarkers in predicting initial treatment (first-line) PD1 or PD-L1 (PD[L]-1)-based immunotherapy response and in selecting second-line treatment in patients with stage IIIB-IV non-small cell lung cancer (NSCLC). Response and survival rates in advanced stage NSCLC, unlike other cancers, rely on response to first-line therapy. Immunotherapy with PD(L)1-based therapy, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. While immunotherapy has improved survival rate, the prognosis remains poor with most patients receiving chemotherapy after immunotherapy. Many types of tumors tend to lose cells or release different types of cellular products including their deoxyribonucleic acid (DNA) which is referred to as circulating tumor DNA (ctDNA) into the bloodstream before changes can be seen on scans. Health care providers can measure the level of ctDNA in blood or other bodily fluids to determine which patients are at higher risk for disease progression or relapse. The first part of this trial, studying samples of blood and tissue in the laboratory from patients receiving immunotherapy may help doctors learn more about the effects PD(L)1-based therapy on cells. It may also help doctors understand how well patients respond to treatment and may help develop new individualized treatment strategies. The second part of this trial also tests the effect of second-line immunotherapy, such as tremelimumab and durvalumab or adagrasib and bevacizumab, in treating patients with NSCLC with specific genetic mutations that is growing, spreading or getting worse (progressive). Tremelimumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Adagrasib, a type of targeted therapy, may stop the growth of tumor cells by blocking a protein needed for tumor cell growth and may kill them. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving second-line immunotherapy, tremelimumab and durvalumab or adagrasib with bevacizumab, may be safe, tolerable, and/or effective in treating patients with stage IIIB/IV NSCLC with specific genetic mutations.

PRIMARY OBJECTIVES:

I. Develop biomarker(s) that predicts for first-line treatment failure of immunotherapy (Part I).

II. Evaluate different strategies for treatment duration for patients without early treatment failure based on ctDNA (Part I).

III. Evaluate second-line progression-free survival (PFS) for biomarker-specific treatment decisions compared to historical controls (Part II).

SECONDARY OBJECTIVES:

I. Evaluate different ctDNA-guided treatment decisions on overall survival based on arm.

II. Summarize the relationship between ctDNA changes and Response Evaluation Criteria in Solid Tumors (RECIST) response throughout the trial.

III. To describe the incidence and severity of adverse events by treatment arm. IV. Demonstrate the feasibility of an adaptive design employing both dynamic treatment regimen and biomarker-specific directed therapy.

EXPLORATORY OBJECTIVE:

I. Use data from ctDNA and tissue multi-omics analysis for reverse translational modeling for mechanisms of resistance to immunotherapy using ARTEMIS.

OUTLINE:

PART IA (INITIAL DISCOVERY COHORT): Patients receive physician's choice of PD(L)1-based therapy every 3 weeks (Q3W) with or without chemotherapy for up to 12-24 months per standard of care.

Patients who complete at least 12 months of PD(L)1 (but do not exceed 24 months) and achieve complete response (CR), stable disease (SD), or partial response (PR) on imaging, as well as ctDNA complete response (CCR) for at least 6 months are randomized to Arms 1 or 2.

ARM 1: After at least 12 months of treatment, patients discontinue PD(L)1 therapy and undergo monitoring. Patients who develop positive ctDNA without PD resume PD(L)1 on study.

ARM 2: After at least 12 months of treatment, patients continue PD(L)1 therapy for up to a total of 24 months from starting immunotherapy the absence of disease progression or unacceptable toxicity.

Patients who complete 24 months of immunotherapy and achieve CR, SD, or PR on imaging, but not CCR and who were not candidates for Arms 1 and 2 are randomized to Arms 3 or 4.

ARM 3: After at least 24 months of treatment, patients discontinue PD(L)1 therapy and undergo close surveillance on study.

ARM 4: After at least 24 months of treatment, patients continue to receive PD(L)1 therapy until radiographic progression or unacceptable toxicity.

PART IB (IMPLEMENTATION COHORT): Patients participate in a future implementation cohort utilizing the findings from Part 1A.

PART II (POST-PROGRESSION COHORT): Patients who experience radiographic progression on Part I are assigned to 1 of 3 arms. Patients with STK11 or KEAP1 mutations are assigned to Arm A and patients with KRAS G12C mutations are assigned to Arm B. Patients assigned to Arm X will be added based on the funding grant technical area 1 (TA1-Therapy Recommendation Techniques).

ARM A: Patients receive tremelimumab intravenously (IV) over 1 hour on day 1 of cycles 1-4 and on day 1 of cycle 6, as well as durvalumab IV over 1 hour of each cycle. Cycles repeat every 21 days for cycles 1-5 and then starting with cycle 6, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive adagrasib orally (PO) twice daily (BID) on days 1-21 and bevacizumab IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM X: Patients participate in future interventions to be added based on the funding grant TA1-Therapy Recommendation Techniques.

Patients in both Parts also undergo blood sample collection, and computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) throughout the study. Additionally, patients may undergo cerebrospinal fluid (CSF), ascites and pleural fluid sample collection during routine care throughout the study. Patients in Part 1 only undergo a tumor biopsy throughout the study.

After completion of study treatment, patients are followed up at 30 days, every 3 months within 1 year of starting treatment, then every 6 months for up to 2 years.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative. (Adult patients lacking capacity to consent may participate if they have a caretaker that could ensure compliance.)

• Participants must have either A) HopeSeq or Tempus molecular testing results reported within 3 months prior to enrollment or currently in process OR B) archival or new biopsy tissue available (to be sent to Tempus). Acceptable sample types include: two formalin-fixed paraffin-embedded (FFPE) tissue core biopsies, or two 25um sections of 5-10mm^2 tissue, or 15-20 unstained slides at 10um thickness (a minimum of 10 unstained slides must be provided)

• Agreement to blood collection for ctDNA research

• Age: ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) ≤ 2

• Histologically confirmed stage IIIB or IV NSCLC

• Absence of sensitizing EGFR mutation or ALK/ROS1 alteration

• Scheduled to begin treatment with a Food and Drug Administration (FDA) approved PD1/PDL1 antibody with or without chemotherapy. Participants who have already started treatment with anti-PD1/PDL1 in this setting may enroll if they have only received up to 4 cycles of treatment so far. Patients who have received PD1/PDL1 antibody for early-stage NSCLC are allowed to enroll if they completed the therapy at least 6 months before starting trial therapy

• Measurable disease by RECIST version (v) 1.1

• Absolute neutrophil count (ANC) ≥ 1,500/mm^3

  • NOTE: Growth factor is not permitted within 14 days of ANC assessment

• Platelets ≥ 100,000/mm^3

  • NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment

• Hemoglobin ≥ 9g/dL

  • NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST) ≤ 3.0 x ULN (5 x ULN allowed if liver metastases)

• Alanine aminotransferase (ALT) ≤ 3.0 x ULN (5 x ULN allowed if liver metastases)

• Creatinine clearance of ≥ 50 mL/min per the Cockcroft-Gault formula

• If seropositive for HIV, hepatitis C virus (HCV), or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable

  • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

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

• PART II: Documented informed consent (for Part II) of the participant and/or legally authorized representative.

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

• PART II: ECOG ≤ 2

• PART II: Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy

• PART II: ANC ≥ 1,500/mm^3

  • NOTE: Growth factor is not permitted within 14 days of ANC assessment

• PART II: Platelets ≥ 100,000/mm^3

  • NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment

• PART II: Hemoglobin ≥ 9g/dL

  • NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment

• PART II: Total bilirubin ≤ 1.5 x ULN

• PART II: AST ≤ 3.0 x ULN (5 x ULN allowed if liver metastases)

• PART II: ALT ≤ 3.0 x ULN (5 x ULN allowed if liver metastases)

• PART II: Creatinine clearance of ≥ 50 mL/min per the Cockcroft-Gault formula

Exclusion Criteria:

• Surgical intervention within 4 weeks prior to study treatment, except for minor procedures such as port placement
• Patients with a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) within 7 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Radiation therapy within 7 days prior to day 1 of protocol therapy
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association [NYHA class] ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication
• Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years before starting treatment, i.e., with use of disease-modifying agents or immunosuppressive drugs
• Symptomatic central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have 1) previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroid medication for 1 week prior to the first dose of study drug and have completed radiation 2 weeks prior to the first dose of study drug OR 2) untreated brain metastases that are asymptomatic and stable
• Prior history of interstitial lung disease (ILD) or non-infectious pneumonitis requiring high-dose glucocorticoids
• Active infection requiring antibiotics
• Other active malignancy. Patients with concurrent malignancy other than non-melanoma skin cancer are not eligible for this trial due to potential confounding of the ctDNA results
• Females only: Pregnant or breastfeeding
• PART II: Surgical intervention within 4 weeks prior to study treatment, except for minor procedures such as port placement
• PART II: Radiation therapy within 7 days prior to day 1 of protocol therapy
• PART II ARM A ONLY: Patients with a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) within 7 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• PART II ARM A ONLY: Patients with prior history of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) treatment
• PART II ARM B ONLY: Patients with prior history of KRAS G12C inhibitors
• PART II: Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication
• PART II ARM A ONLY: Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years before starting treatment, i.e., with use of disease-modifying agents or immunosuppressive drugs
• PART II ARM B ONLY: Grade ≥ 2 proteinuria as demonstrated by ≥ 2+ protein and ≥ 1.0 g of protein with 24-hour urine collection (patients found to have ≥ 2+ protein on dipstick urinalysis must have 24-hour urine collection and demonstrate < 1g of protein in 24 hours in order to be eligible for treatment)
• PART II: Clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have 1) previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroid medication for 1 week prior to the first dose of study drug and have completed radiation 2 weeks prior to the first dose of study drug OR 2) untreated brain metastases that are asymptomatic and stable
• PART II: Clinically significant uncontrolled illness
• PART II: Active infection requiring antibiotics
• PART II: Other active malignancy
• PART II FEMALES ONLY: Pregnant or breastfeeding
• PART II: Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures