This clinical trial plans to assess to what extent the on-treatment circulating tumor DNA (ctDNA) can predict the subset of patients with NSCLC who will respond to immunotherapy treatment only and which patients will need both immunotherapy and chemotherapy modalities for their treatment regimen.

Subjects will be randomized 2:1 and patients in both arms will begin treatment with nivolumab 360 mg intravenously every 3 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks. At five weeks of treatment, subjects will have ctDNA response evaluation with Guardant360 Response assay. At the next cycle of treatment (+/- 2 days), patients in the larger arm will receive treatment based on the Guardant360 Response assay results, as described below. Subjects will undergo ctDNA evaluation with Guardant360 Response assay 6- week post-randomization and at the time of progression. Response to therapy will be assessed by interval imaging with CT scan of the chest/abdomen/pelvis (and MRI brain if applicable) with response evaluated by irRECIST criteria every 12 weeks until disease progression.

Inclusion Criteria:

1. Eligible patients will have newly diagnosed, previously untreated histologically documented Stage IV NSCLC
2. Eligible patients will be required to have positive PD-L1 expression ≥1% by IHC using Dako 22C3 assay.
3. Patients will require a baseline Guardant360 CDx test prior to enrollment
4. Patients willing to undergo serial ctDNA testing as required by protocol
5. Patients will be over the age of 18
6. Life expectancy ≥12 weeks
7. Measurable (RECIST 1.1) indicator lesion not previously irradiated, with measurable disease determined per the treating investigator.
8. Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to randomization
9. ECOG Performance Score ≤2
10. Adequate organ function
11. Hemoglobin > 9 g/dL
12. Platelets > 100,000mm3 or 100 x 109/L
13. AST, ALT < 2.5 x ULN with no liver metastases or < 5x ULN with the presence of liver metastases
14. 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
15. Absolute neutrophil count (ANC) > 1500 cells/mm3
16. Creatinine ≤ 1.5 x ULN OR calculated creatinine clearance ≥ 60ml/min calculated by Cockcroft and Gault's equation
17. Willing to use highly effective contraceptive measures if child-bearing potential or if the patient's sexual partner is a woman of childbearing potential: a. Female subjects should be using a highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to starting 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: i. Post-menopausal is defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the the post-menopausal range for the institution iii. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not a tubal ligation b. Male subjects should be willing to use barrier contraception

Exclusion Criteria:

1. Patients under the age of 18

2. Inability to provide informed consent by either the patient or the authorized representative

3. Patients with known EGFR, ALK, ROS1, MET, and RET oncogenic driver alterations that have approved first-line targeted therapies are excluded from the study (All patients must have a tissue or blood-based testing to identify these driver alterations)

4. Patients with no detectable ctDNA or ctDNA VAF ≤ 0.3% on Guardant360 CDx at baseline

5. Subjects with untreated CNS metastases are excluded.

6. 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.

7. Subjects with carcinomatous meningitis

8. Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before randomization

9. 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 needed during the study period.

10. Other active malignancy requiring concurrent intervention.

11. Subjects with an active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, and hypothyroidism only require 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.

12. 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 steroids > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

13. Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.

14. Significant uncontrolled cardiovascular disease, including but not limited to, any of the following:

    1. Uncontrolled hypertension, which is defined as systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg despite optimal medical management.
    2. Active coronary artery disease, including unstable all newly diagnosed angina within 3 months of study enrollment.
    3. Myocardial infarction in the past 6 months.
    4. History of congenital long QT syndrome.
    5. History of clinically significant arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or torsade de pointes.
    6. Uncontrolled heart failure, defined as class III of 4 by the New York Heart Association functional classification.
    7. History of a current diagnosis of myocarditis.

15. the 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.

16. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection

17. Subjects with Grade 2 peripheral neuropathy

18. Life expectancy <12 weeks