Immunotherapy Biomarkers to Predict First-line PD(L)1-based Immunotherapy Response and Selection of Second-line Treatment in Stage IIIB-IV Non-small Cell Lung Cancer, IMMUNO-BIOMAP Trial

Immunotherapy Biomarker Collection for Metastatic NSCLC to Inform Adaptive Personalized Models Targeting Resistance (IMMUNO-BIOMAP)

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.

Study Overview

• Status: Recruiting
• Conditions: Lung Non-Small Cell Carcinoma; Stage IV Lung Cancer AJCC v8; Stage IIIB Lung Cancer AJCC v8
• Intervention / Treatment: Procedure: Computed Tomography; Biological: Durvalumab; Biological: Bevacizumab; Procedure: Positron Emission Tomography; Biological: Tremelimumab; Drug: Chemotherapy; Drug: Adagrasib; Procedure: Biopsy Procedure; Biological: Anti-PD-L1 Monoclonal Antibody; Biological: Anti-PD1 Monoclonal Antibody; Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Other: Monitoring; Behavioral: Surveillance

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 535
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Goodyear, Arizona, United States, 85338
      • Recruiting
      • CTCA at Western Regional Medical Center
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
  • California
    • Corona, California, United States, 92882
      • Recruiting
      • City of Hope Corona
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Huntington Beach, California, United States, 92648
      • Recruiting
      • City of Hope Seacliff
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Irvine, California, United States, 92618
      • Recruiting
      • City of Hope at Irvine Lennar
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Lancaster, California, United States, 93534
      • Recruiting
      • City of Hope Antelope Valley
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Long Beach, California, United States, 90813
      • Recruiting
      • City of Hope at Long Beach Elm
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Newport Beach, California, United States, 92660
      • Recruiting
      • City of Hope at Newport Beach Fashion Island
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • South Pasadena, California, United States, 91030
      • Recruiting
      • City of Hope South Pasadena
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Torrance, California, United States, 90503
      • Recruiting
      • City of Hope South Bay
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
    • Upland, California, United States, 91786
      • Recruiting
      • City of Hope Upland
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
  • Georgia
    • Newnan, Georgia, United States, 30265
      • Recruiting
      • City of Hope Atlanta Cancer Center
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org
  • Illinois
    • Zion, Illinois, United States, 60099
      • Recruiting
      • City of Hope at Chicago
      • Principal Investigator: Ravi Salgia
      • Contact: Ravi Salgia; Phone Number: 626-218-9200; Email: rsalgia@coh.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (stop treatment, monitoring); Patients receive physician's choice of PD(L)1-based therapy Q3W with or without chemotherapy for up to 12-24 months per standard of care. 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. Patients also undergo blood sample collection, and CT, MRI or PET throughout the study. Additionally, patients may undergo CSF, ascites and pleural fluid sample collection during routine care and tumor biopsy throughout the study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Positron Emission Tomography; Undergo PET; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Chemotherapy; Given chemotherapy; Other Names: Chemo; Chemotherapy (NOS); Chemotherapy, Cancer, General; Procedure: Biopsy Procedure; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Biological: Anti-PD-L1 Monoclonal Antibody; Given PD-L1-based immunotherapy; Biological: Anti-PD1 Monoclonal Antibody; Given PD1-based immunotherapy; Other Names: Anti-PD-1 Monoclonal Antibody; Procedure: Biospecimen Collection; Undergo blood, CSF, ascites and pleural fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo PET; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Other: Monitoring; Undergo monitoring; Other Names: monitor
Experimental: Arm 2 (continue PD[L]1); Patients receive physician's choice of PD(L)1-based therapy Q3W with or without chemotherapy for up to 12-24 months per standard of care. After at least 12 months of treatment, patients continue PD(L)1 therapy for up to a total of 24 months from starting immunotherapy in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, and CT, MRI or PET throughout the study. Additionally, patients may undergo CSF, ascites and pleural fluid sample collection during routine care and tumor biopsy throughout the study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Positron Emission Tomography; Undergo PET; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Chemotherapy; Given chemotherapy; Other Names: Chemo; Chemotherapy (NOS); Chemotherapy, Cancer, General; Procedure: Biopsy Procedure; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Biological: Anti-PD-L1 Monoclonal Antibody; Given PD-L1-based immunotherapy; Biological: Anti-PD1 Monoclonal Antibody; Given PD1-based immunotherapy; Other Names: Anti-PD-1 Monoclonal Antibody; Procedure: Biospecimen Collection; Undergo blood, CSF, ascites and pleural fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo PET; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI
Experimental: Arm 3 (close surveillance); Patients receive physician's choice of PD(L)1-based therapy Q3W with or without chemotherapy for up to 12-24 months per standard of care. After at least 24 months of treatment, patients discontinue PD(L)1 therapy and undergo close surveillance on study. Patients also undergo blood sample collection, and CT, MRI or PET throughout the study. Additionally, patients may undergo CSF, ascites and pleural fluid sample collection during routine care and tumor biopsy throughout the study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Positron Emission Tomography; Undergo PET; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Chemotherapy; Given chemotherapy; Other Names: Chemo; Chemotherapy (NOS); Chemotherapy, Cancer, General; Procedure: Biopsy Procedure; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Biological: Anti-PD-L1 Monoclonal Antibody; Given PD-L1-based immunotherapy; Biological: Anti-PD1 Monoclonal Antibody; Given PD1-based immunotherapy; Other Names: Anti-PD-1 Monoclonal Antibody; Procedure: Biospecimen Collection; Undergo blood, CSF, ascites and pleural fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo PET; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Behavioral: Surveillance; Undergo close surveillance; Other Names: Epidemiology / Surveillance
Experimental: Arm 4 (PD[L]1); Patients receive physician's choice of PD(L)1-based therapy Q3W with or without chemotherapy for up to 12-24 months per standard of care. After at least 24 months of treatment, patients continue to receive PD(L)1 therapy until radiographic progression or unacceptable toxicity. Patients also undergo blood sample collection, and CT, MRI or PET throughout the study. Additionally, patients may undergo CSF, ascites and pleural fluid sample collection during routine care and tumor biopsy throughout the study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Positron Emission Tomography; Undergo PET; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Chemotherapy; Given chemotherapy; Other Names: Chemo; Chemotherapy (NOS); Chemotherapy, Cancer, General; Procedure: Biopsy Procedure; Undergo tumor biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy; Biological: Anti-PD-L1 Monoclonal Antibody; Given PD-L1-based immunotherapy; Biological: Anti-PD1 Monoclonal Antibody; Given PD1-based immunotherapy; Other Names: Anti-PD-1 Monoclonal Antibody; Procedure: Biospecimen Collection; Undergo blood, CSF, ascites and pleural fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo PET; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI
Experimental: Arm A (tremelimumab, durvalumab); Patients receive tremelimumab 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. Patients also undergo blood sample collection, and CT, MRI or PET throughout the study. Additionally, patients may undergo CSF, ascites and pleural fluid sample collection during routine care throughout the study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Biological: Durvalumab; Given IV; Other Names: Imfinzi; Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer; MEDI-4736; MEDI4736; MEDI 4736; Procedure: Positron Emission Tomography; Undergo PET; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Biological: Tremelimumab; Given IV; Other Names: Anti-CTLA4 Human Monoclonal Antibody CP-675,206; CP-675; CP-675,206; CP-675206; Ticilimumab; Imjudo; Tremelimumab-actl; CP 675; CP 675206; CP675; CP675206; Procedure: Biospecimen Collection; Undergo blood, CSF, ascites and pleural fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo PET; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI
Experimental: Arm B (adagrasib, bevacizumab); Patients receive adagrasib PO 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. Patients also undergo blood sample collection, and CT, MRI or PET throughout the study. Additionally, patients may undergo CSF, ascites and pleural fluid sample collection during routine care throughout the study.	Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Biological: Bevacizumab; Given IV; Other Names: Avastin; ABP 215; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF Monoclonal Antibody SIBP04; Anti-VEGF rhuMAb; Bevacizumab awwb; Bevacizumab Biosimilar ABP 215; Bevacizumab Biosimilar BEVZ92; Bevacizumab Biosimilar BI 695502; Bevacizumab Biosimilar CBT 124; Bevacizumab Biosimilar CT-P16; Bevacizumab Biosimilar FKB238; Bevacizumab Biosimilar GB-222; Bevacizumab Biosimilar HD204; Bevacizumab Biosimilar HLX04; Bevacizumab Biosimilar IBI305; Bevacizumab Biosimilar LY01008; Bevacizumab Biosimilar MIL60; Bevacizumab Biosimilar Mvasi; Bevacizumab Biosimilar MYL-1402O; Bevacizumab Biosimilar QL 1101; Bevacizumab Biosimilar RPH-001; Bevacizumab Biosimilar SCT501; Bevacizumab Biosimilar Zirabev; Bevacizumab-awwb; Bevacizumab-bvzr; BP102; BP102 Biosimilar; HD204; Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer; Mvasi; MYL-1402O; Recombinant Humanized Anti-VEGF Monoclonal Antibody; rhuMab-VEGF; SCT501; SIBP 04; SIBP-04; SIBP04; Zirabev; QL1101; Bevacizumab Biosimilar QL1101; BAT1706; BAT 1706; BAT-1706; BAT1706 Biosimilar; Bevacizumab Biosimilar BAT1706; Bevacizumab-adcd; CT-P16; Vegzelma; Alymsys; ABP-215; ABP215; Aybintio; Bevacizumab-aybi; Bevacizumab-equi; Bevacizumab-maly; Bevacizumab-onbe; CT P16; CTP16; Equidacent; Onbevzi; Avzivi; Bevacizumab Biosimilar MB02; Bevacizumab-tnjn; FKB 238; FKB-238; FKB238; MB 02; MB-02; MB02; Oyavas; PF 06439535; PF-06439535; PF06439535; Procedure: Positron Emission Tomography; Undergo PET; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Drug: Adagrasib; Given PO; Other Names: MRTX849; Krazati; KRAS G12C Inhibitor MRTX849; MRTX 849; MRTX-849; Procedure: Biospecimen Collection; Undergo blood, CSF, ascites and pleural fluid sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo PET; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) during first-line treatment (Part I)	Will be estimated using the Kaplan-Meier (KM) method. Comparisons across treatment arms will be performed using stratified log-rank tests and Cox proportional hazards models, with assessment of the proportional-hazards assumption and exploration of time-dependent hazard ratios. Dynamic treatment regimen (DTR)-specific PFS will also be estimated using inverse probability weighting (IPW) to account for multiple randomizations and treatment adaptations.	From the start of randomization to disease progression or death from any cause, whichever occurs first, assessed up to 3 years
PFS by arm for second-line treatment (Part II)	Will be estimated using the KM method. Comparisons across treatment arms will be performed using stratified log-rank tests and Cox proportional hazards models, with assessment of the proportional-hazards assumption and exploration of time-dependent hazard ratios. DTR-specific PFS will also be estimated using IPW to account for multiple randomizations and treatment adaptations.	From the start of treatment to disease progression or death from any cause, whichever occurs first, assessed up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development and testing of biomarkers predictive of early response to immunotherapy	Will include, but not limited to, blood based, tissue-based and imaging-based biomarkers.	At pre-treatment and Cycle 2 Day 1 (blood only) (Cycle length = 21 days)
Overall survival (OS)	Will be evaluated by arm. Will be estimated using the KM method. Comparisons across treatment arms will be performed using stratified log-rank tests and Cox proportional hazards models, with assessment of the proportional-hazards assumption and exploration of time-dependent hazard ratios. DTR-specific OS will also be estimated using IPW to account for multiple randomizations and treatment adaptations.	From randomization (by arm and from start of first-line treatment) to death due to any cause, assessed up to 3 years
Circulating tumor deoxyribonucleic acid (ctDNA) level	Joint modeling approaches will be applied, combining mixed-effects models for ctDNA trajectories with survival models for PFS or OS. All stratified efficacy analyses will incorporate randomization stratification factors.	Up to 3 years
ctDNA complete response (CCR) rate	Will be summarized by treatment sequence. Logistic regression models will evaluate associations between CCR and baseline covariates.	Up to 3 years
Objective response rate (ORR)	Will be defined as rate of participants achieving confirmed complete response or partial response, as assessed by the investigator using Response Evaluation Criteria in Solid Tumors version (v) 1.1. ORR point estimates and 95% confidence intervals will be calculated using Clopper-Pearson methods, and logistic regression modeling will assess associations between treatment and objective response.	From start of the study treatment to disease progression or death due to any cause prior to receiving another therapy, whichever occurs first, assessed up to 3 years
Duration of response		From the time a response is experienced to progression or death, assessed up to 3 years
Incidence of, causality, and outcome of adverse events (AEs)	AEs will described using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. Will be summarized with descriptive statistics: mean, median, standard deviation, minimum, and maximum for continuous variables, and frequencies and percentages for categorical variables.	Up to 30 days after last dose of study treatment
Incidence of, causality, and outcome of serious AEs	AEs will be assessed as defined by NCI-CTCAE v 5.0. Will be summarized with descriptive statistics: mean, median, standard deviation, minimum, and maximum for continuous variables, and frequencies and percentages for categorical variables.	Up to 30 days after last dose of study treatment
Changes in vital signs and laboratory values	Will be summarized with descriptive statistics: mean, median, standard deviation, minimum, and maximum for continuous variables, and frequencies and percentages for categorical variables.	Up to 30 days after last dose of study treatment

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ravi Salgia, MD, City of Hope Medical Center; Principal Investigator: Jyoti Malhotra [Co-PI], MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2026
• Primary Completion (Estimated): October 8, 2028
• Study Completion (Estimated): October 8, 2028

Study Registration Dates

• First Submitted: December 15, 2025
• First Submitted That Met QC Criteria: December 15, 2025
• First Posted (Actual): December 17, 2025

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Diagnostic Techniques, Surgical; Chemistry Techniques, Analytical; Spectrum Analysis; Immunoglobulin Isotypes; Sulfides; Anions; Ions; Electrolytes; Hydrogen Sulfide; Bevacizumab; Immunoglobulin G; Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; Drug Therapy; durvalumab; Disulfides; adagrasib; tremelimumab; spartalizumab
• Other Study ID Numbers: 24507 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2025-09032 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No