Immunotherapy versus Chemoimmunotherapy Guided by Circulating Tumor DNA-Based Molecular Response for the Treatment of Stage IV Non-small Cell Lung Cancer

Inclusion Criteria

• Eligible patients will have newly diagnosed, previously untreated, histologically documented stage IV non-small cell lung cancer (NSCLC).
• Eligible patients will be required to have positive PD-L1 expression by immunohistochemistry (IHC) using Dako 22C3 assay
• Patients will require baseline Guardant360 test prior to enrollment
• Patients willing to undergo serial ctDNA testing as required by protocol
• Patients will be over the age of 18
• Life expectancy ≥ 12 weeks
• Measurable (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) indicator lesion not previously irradiated, with measurable disease determined per treating investigator
• Prior palliative radiotherapy to non- central nervous system (CNS) lesions must have been completed at least 2 weeks prior to randomization
• Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2
• Hemoglobin > 9 g/dL
• Platelets > 100,000mm^3 or 100 x 10^9/L
• Aspartate aminotransferase (AST), alanine transaminase (ALT) < 2.5 x upper limit of normal (ULN) with no liver metastases or < 5 x ULN with the presence of liver metastases
• Total bilirubin < 1.5 x ULN if no liver metastases or < 3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases
• Absolute neutrophil count (ANC) > 1500 cells/mm^3
• Creatinine ≤ 1.5 x ULN OR calculated creatinine clearance ≥ 60ml/min calculated by Cockcroft and Gault equation
• Willing to use highly effective contraceptive measures if of child-bearing potential or if the patient’s sexual partner is a woman of child-bearing potential: * Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: ** Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ** Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution ** Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation * Male subjects should be willing to use barrier contraception

Exclusion Criteria

• Patients under the age of 18
• Inability to provide informed consent by either the patient or the authorized representative
• Patients with known EGFR, ALK, ROS1, MET, and RET oncogenic driver alterations which have approved first-line targeted therapies are excluded from the study (All patients must have tissue or blood-based testing to identify these driver alterations)
• Subjects with untreated CNS metastases are excluded
• Subjects are eligible if CNS metastases are adequately treated, and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization
• Subjects with carcinomatous meningitis
• Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before randomization
• Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to randomization and no additional therapy is required or anticipated to be required during the study period
• Other active malignancy requiring concurrent intervention
• Subjects with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Significant uncontrolled cardiovascular disease, including but not limited to, any of the following: * Uncontrolled hypertension, which is defined as systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg despite optimal medical management * Active coronary artery disease, including unstable all newly diagnosed angina within 3 months of study enrollment * Myocardial infarction in the past 6 months * History of congenital long QT syndrome * History of clinically significant arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or torsade de pointes * Uncontrolled heart failure, defined as class III of 4 by New York Heart Association functional classification * History of current diagnosis of myocarditis
• Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
• Subjects with grade 2 peripheral neuropathy
• Life expectancy < 12 weeks