DISCERN: Dual Versus Single ICB in PDL-1 Negative NSCLC

Inclusion Criteria:

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female aged 18 years or older.
4. Participants must have histologically or cytologically confirmed non-small cell lung cancer which is stage IV
5. Participants should not have a known sensitizing mutation for which an FDA-approved.

   targeted therapy for NSCLC exists in first line (e.g., EGFR, ALK, ROS1, BRAF, RET, NTRK, and MET sensitizing mutations
6. Participants should not have received prior systemic anticancer therapy for advanced or metastatic disease. For patients who are recently diagnosed and received one cycle of chemotherapy while awaiting NGS/PDL-1 testing are allowed on study after discussion with medical monitor.
7. Participants should have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. Participants should have a life expectancy of at least 3 months.
9. Participants should have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Status
10. Participants should have provided tumor tissue from locations not radiated prior to biopsy; fresh formalin fixed specimens or archival samples which have been determined as PD-L1 status \<1% or negative prior to randomization.
11. Participants should have been evaluated for circulating tumor DNA at baseline which has been determined to be detected, present or positive.
12. Participants with CNS metastases are eligible if all metastases have been treated and have remained stable without growth for at least 2 weeks post-treatment, the participant's neurological status has returned to baseline or remained stable for at least 2 weeks, and any use of corticosteroids for CNS metastases is at a dose of ≤10 mg daily prednisone (or an equivalent dose of another corticosteroid) and has been stable for at least 2 weeks before enrollment.
13. Participants should have adequate organ function to be able to safely receive the approved standard of care regimens per the current FDA approved package insert, treating investigators discretion and institutional guidelines.
14. For females of reproductive potential: Negative urine and serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, serum pregnancy test will be required. Participants should be willing to use an adequate method of contraception for the course of the study through 120 days after last dose of study medication or through 180 days after last dose of chemotherapeutic agents. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
15. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy within 4 weeks prior to administration of study regimen.
2. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
3. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis.
4. Prior treatment or history of allergy/hypersensitivity with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or other specific T-cell co-stimulation or checkpoint targeting drugs.
5. Has a known sensitivity to any component of cisplatin, carboplatin, paclitaxel or pemetrexed
6. Participants with carcinomatous meningitis
7. Participants with active or suspected autoimmune diseases are excluded, with the following exceptions allowed: vitiligo, well-controlled type I diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
8. Individuals who have received systemic corticosteroids or other immunosuppressive medications within the last 14 days prior to enrollment are excluded. Exceptions are made for topical, inhaled, nasal, ophthalmic steroids, or systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or an equivalent corticosteroid.
9. Participants with a history of ILD, or those who are suspected of having symptomatic ILD, or those with pneumonitis.
10. Individuals with a positive test for HIV, Hep B or Hep C are excluded unless it is well-controlled with no increased risk of immunosuppression and with no potential drug interactions with current antiviral therapy.
11. Participants with a history of other malignancies are excluded, except for those with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, or any cancer in situ that has been treated curatively, and the participant has been in complete remission for more than two years with any cancer prior to the start of the study.