Plasma-Adapted First-Line Pembro In NSCLC

Inclusion Criteria: \- Participants must have histologically or cytologically confirmed stage IV NSCLC (AJCC 8th edition). \- Participants must have evaluable disease on imaging per RECIST (measurable disease is not required). * No prior treatment with a systemic anti-cancer therapy of any kind for the treatment of stage IV NSCLC. Prior definitive chemoradiation for locally advanced disease, or prior adjuvant or neoadjuvant therapy for early stage disease is permitted if completed ≥6 months prior to initiating study treatment. * Age ≥18 years. * ECOG performance status 0-2 (see Appendix A) * Candidate for combination chemoimmunotherapy per physician assessment. * Participants must have normal organ and marrow function as defined below: \-- absolute neutrophil count ≥1000/mcL * platelets ≥100,000/mcL * total bilirubin \<1.3 mg/dL * creatinine \<1.6 mg/dL * PD-L1 tumor proportion score (TPS) ≥1%, as determined by a CLIA-laboratory. * The effects of pembrolizumab on the developing human fetus are unknown. For this reason and because immune checkpoint blockade agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of pembrolizumab administration. \-- NOTE: a pregnancy test will be required at screening for women of childbearing potential. * Ability to understand and the willingness to sign a written informed consent document. * Inclusion Criteria for Treatment Continuation at Cycle 3 -- Completion of repeat plasma NGS (InVision) on study, with plasma response defined as ≥50% reduction in plasma ctDNA max AF between C1D1 and C2D1 for patients with high shed \[≥0.5% max AF\] at C1D1, or continued low shed \[\<0.5% max AF\] for patients with low shed at C1D1. * Completion of restaging scans on study, with response determined by central review per RECIST 1.1 criteria * For participants continuing pembrolizumab alone: * Response of Partial Response or Complete Response at Cycle 3 imaging assessment (as determined by TIMC). OR --- Response of Stable Disease at Cycle 3 imaging assessment (as determined by TIMC) AND plasma response. OR * Response of Progressive Disease at Cycle 3 imaging assessment (as determined by TIMC) without worsening cancer symptoms (as determined by the treating investigator) AND plasma response. \-- For participants continuing pembrolizumab + doublet chemotherapy: * Response of Stable Disease at Cycle 3 imaging assessment (as determined by TIMC) AND no plasma response. OR --- Response of Progressive Disease at Cycle 3 imaging assessment (as determined by TIMC) without worsening cancer symptoms (as determined by the treating investigator) AND no plasma response. \- NOTE: Patients with a response of Progressive Disease at Cycle 3 imaging assessment (as determined by TIMC) with worsening cancer symptoms (as determined by the treating investigator) must come off treatment. Exclusion Criteria: * Participants with known sensitizing alterations in EGFR, ALK, ROS1 or BRAF. * Participants who have had chemotherapy or radiotherapy within 1 week prior to entering the study. * Participants who are receiving any other investigational agents. * Participants with uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression. Patients with asymptomatic untreated brain metastases are eligible. Patients with treated CNS disease are eligible if stable disease is clinically confirmed ≥2 weeks after definitive CNS therapy (radiation or surgery), and the patient is not receiving systemic steroids ≥10mg of prednisone equivalent at the time of enrollment. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or other agents used in study. * Ongoing or active autoimmune disease requiring systemic steroids of ≥10mg of prednisone equivalent or other systemic immunomodulatory agents at the time of enrollment. Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as psoriasis, vitiligo, and alopecia) not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are allowed. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study because pembrolizumab is a Pregnancy Category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab. These potential risks may also apply to other agents used in this study. * Participants with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) are excluded from this study.