Immune Profile Selection By Fraction of ctDNA in Patients With Advanced NSCLC Treated With Immunotherapy

Inclusion Criteria:

1. Eligible patients will have newly diagnosed, previously untreated histologicallydocumented Stage IV NSCLC

2. Eligible patients will be required to have positive PD-L1 expression ≥1% by IHCusing 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 measurabledisease determined per the treating investigator.

8. Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2weeks 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 livermetastases

14. Total bilirubin < 1.5 x ULN if no liver metastases or < 3 x ULN in the presence ofdocumented 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 byCockcroft and Gault's equation

17. Willing to use highly effective contraceptive measures if child-bearing potential orif the patient's sexual partner is a woman of childbearing potential: a. Femalesubjects should be using a highly effective contraceptive measures, and must have anegative pregnancy test and not be breast-feeding prior to starting of dosing if ofchild-bearing potential or must have evidence of non-child-bearing potential byfulfilling one of the following criteria at screening: i. Post-menopausal is definedas aged more than 50 years and amenorrheic for at least 12 months followingcessation of all exogenous hormonal treatments ii. Women under 50 years old would beconsidered postmenopausal if they have been amenorrheic for 12 months or morefollowing cessation of exogenous hormonal treatments and with LH and FSH levels inthe the post-menopausal range for the institution iii. Documentation of irreversiblesurgical sterilization by hysterectomy, bilateral oophorectomy, or bilateralsalpingectomy but not a tubal ligation b. Male subjects should be willing to usebarrier contraception

Exclusion Criteria:

1. Patients under the age of 18

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

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

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 areneurologically returned to baseline (except for residual signs or symptoms relatedto 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 10mg 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 significanttraumatic injury at least 14 days before randomization

9. Subjects with previous malignancies (except non-melanoma skin cancers, and in situcancers 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 anticipatedto 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 typeI diabetes mellitus, and hypothyroidism only require hormone replacement, skindisorders (such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare 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 replacementsteroids > 10 mg daily prednisone equivalent, are permitted in the absence of activeautoimmune disease.

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

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

15. Uncontrolled hypertension, which is defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mm Hg despite optimal medical management.

16. Active coronary artery disease, including unstable all newly diagnosed anginawithin 3 months of study enrollment.

17. Myocardial infarction in the past 6 months.

18. History of congenital long QT syndrome.

19. History of clinically significant arrhythmias, such as ventricular tachycardia,ventricular fibrillation, or torsade de pointes.

20. Uncontrolled heart failure, defined as class III of 4 by the New York HeartAssociation functional classification.

21. History of a current diagnosis of myocarditis.

22. the Known medical condition that, in the investigator's opinion, would increase therisk associated with study participation or study drug administration or interferewith the interpretation of safety results.

23. Any positive test for hepatitis B virus or hepatitis C virus indicating acute orchronic infection

24. Subjects with Grade 2 peripheral neuropathy

25. Life expectancy <12 weeks