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

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.