Study of CTDNA Response Adaptive Immuno-Chemotherapy in Lung Cancer

Inclusion Criteria: * Histologically or cytologically confirmed metastatic NSCLC. Patients with stage III disease are eligible if they are not candidates for surgical resection or definitive chemoradiation. Patients with Large Cell Neuroendocrine Carcinoma (LCNEC) are not eligible. * Confirmed EGFR and ALK mutation-negative disease based on testing consistent with local guidelines. * Patients must have a PD-L1 test result from a certified laboratory indicating PD-L1 expression Tumour Proportion Score (TPS) ≥ 50%. Patients with lower PD-L1 TPS scores treated with single agent pembrolizumab consistent with local guidelines and regulatory approvals may be eligible following discussion with CCTG. * Patients are to be registered prior to starting immunotherapy. Screening ctDNA is to be drawn following registration prior to starting immunotherapy and after not more than 2 cycles of the 200mg or 2mg/kg IV Q3W dose/schedule of pembrolizumab, or at least and not more than 1 cycle of 400mg or 4mg/kg IV Q6W dose/schedule of pembrolizumab as first-line systemic immunotherapy for advanced metastatic NSCLC at the time of. Eligible patients with detectable ctDNA at 6 weeks may proceed to enrollment and randomization. * Prior chemotherapy or immunotherapy for non-metastatic disease (e.g. adjuvant and or neoadjuvant therapy) is allowed if at least 6 months have elapsed between the completion of prior therapy and start of pembrolizumab as first-line treatment for metastatic disease. Local therapy, e.g. palliative extra-cranial radiation, is allowed as long as a period of 2 weeks has passed since completion and screening as ctDNA levels may be altered by radiotherapy. There is no requirement for delay for patients who have received brain radiation. * Patients must have recovered to ≤ grade 1 from all reversible toxicity related to prior systemic or radiation therapy. * Previous major surgery is permitted provided that surgery occurred at least 14 days prior to screening of ctDNA and 28 days prior to patient enrollment and that wound healing has occurred. * Eligible and suitable to receive continued treatment with pembrolizumab OR the addition of chemotherapy to pembrolizumab at the time of registration and again at the time of enrollment and randomization. Patients should be clinically stable without evidence of clinical progression or symptomatic deterioration that requires change in cancer treatment. Reimbursement of pembrolizumab may not be uniform across all sites. In the event that the site/investigator is unable to provide access to the drug, the patient will not be eligible for this trial. * Must be ≥ 18 years of age. * ECOG performance status 0-2. * Clinically and/or radiologically documented and evaluable disease. Measurable disease as defined by RECIST is not required. * Imaging investigations including CT of the chest, abdomen and pelvis and MRI/CT of the brain (if known brain metastases) or other scans as necessary to document all sites of disease must be done within 14 days prior to randomization to ensure patients do not have clinical progression requiring change in systemic treatment. Patients must have non-progression of disease to be randomized. Patients who are clinically stable with PD such that in the opinion of the investigator they could continue with single agent immunotherapy may be eligible for enrollment and randomization following discussion with CCTG. * Patients must have RECIST non-PD or clinically stable PD documented prior to enrollment that can continue on IO therapy if randomized to that arm. * Detectable ctDNA on screening at 6 weeks is required for subsequent enrollment and randomization. * Adequate hematology and organ function to continue immunotherapy or receive standard platinum combination therapy (must be done prior to registration for ctDNA testing) and prior to enrollment and randomization). * White Blood Cells ≥ 2.0 x 10\^9/L (2000/μL) * Absolute neutrophils ≥ 1.5 x 10\^9/L (1500/μL) * Platelets ≥ 100 x 10\^9/L (100 x 10\^3/μL) * Bilirubin ≤ 1.5 x ULN (upper limit of normal)\* * AST and/or ALT ≤ 3 x ULN, \< 5 x ULN for patients with liver metastases * Serum creatinine or Creatinine clearance ≤ 1.5 x ULN OR ≥ 40 mL/min * Patients must consent to the provision of, and investigator must agree to submit, a representative archival formalin-fixed paraffin block of tumour tissue for correlative analyses when tumour tissue is available. * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to registration to the trial to document their willingness to the collection of liquid biopsy (blood) samples for ctDNA analysis by CLIA central laboratory and for correlative analysis by a research central laboratory, and to subsequent enrollment and randomization to continued pembrolizumab or the addition of chemotherapy to pembrolizumab if ctDNA is detected. * Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, collection of blood samples, response assessments and follow-up. Patients must agree to return to their primary care facility for response assessments as well as any adverse events which may occur through the course of the trial. * In accordance with CCTG policy, protocol treatment is to begin within 5 working days of patient randomization. * Women/men of childbearing potential must have agreed to use a highly effective contraceptive method during protocol treatment and for at least 6 months after the last dose of the protocol treatment. Participants of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation. Male participants with partners of childbearing potential must agree to use condoms (with spermicide, if available) in combination with an additional highly effective contraceptive method used by their partner, during treatment period and for at least 6 months after the last dose of the investigational product. Exclusion Criteria: * Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the protocol treatment regimens are eligible for this trial. * Patients with symptomatic central nervous system (CNS) metastases and/or CNS metastases requiring immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone equivalents). Patients with known central nervous system metastases who are asymptomatic and on a stable dose of corticosteroids ≤ 10 mg/day prednisone equivalents are eligible. * Patients who are not suitable candidates for treatment with pembrolizumab as a single agent or in combination with standard platinum combination chemotherapy according to the current guidance/indications described in the Product Monograph (Canada) or Drug Label (U.S.) and practice guidelines including but not limited to patients with active infection, autoimmune disease, conditions that require systemic immunosuppressive therapy (such as transplant patients) and patients with a history of severe immune-mediated adverse reactions, or known hypersensitivity to pembrolizumab or its components. Patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders (such as hypo or hyperthyroidism or diabetes mellitus), can be considered for enrollment to this study provided pembrolizumab is administered with caution and patients are closely monitored. Patients should not have contraindications to platinum combination chemotherapy. * History of significant neurologic or psychiatric disorder that would impair the ability to obtain consent or limit compliance with study requirements. * Concurrent treatment with other anti-cancer therapy or other investigational anti-cancer agents * Pregnant or lactating women.