• A known or suspected NSCLC treated with curative intent -(surgery with or without perioperative (neoadjuvant or adjuvant) therapy).

⁃ Suspected NSCLC - Patients with a high index of suspicion for the diagnosis of NSCLC that is resectable may sign informed consent prior to undergoing diagnostic procedure at the discretion of the physician. NCCN Guidelines allow for clinical stage IA cancers to proceed directly to definitive surgery. Per NCCN Guidelines, if a preoperative tissue diagnosis has not been obtained, then an intraoperative diagnosis will be obtained. If a diagnosis of NSCLC is not confirmed and/or the tumor is not resectable, then the patient will be a screen failure.

• Undergone or planning to undergo a surgical resection - (Patients with stages I-IIIB who are resectable - per NCCN guidelines of resectability)

• Both patients who lack molecular abnormalities and those with identified molecular abnormalities may enroll. Choice of perioperative therapy is to follow SOC therapeutic guidelines for the participant's molecular and PD-L1 profile.

• 18 years old or older

• Willing and able to provide informed consent

• Willing to have additional blood samples collected during routine surveillance visits

• Must submit tumor sample representative of current disease

‣ For Cohort 1 Exclusion, the participant has/is:

• Patients with superior sulcus tumors who are candidates for preoperative concurrent chemoradiation.

• Stage III locally advanced and unresectable patients who are candidates for chemoradiation followed by immunotherapy.

• It is expected that all patients on the cohort will be treated with a definitive surgical resection. Thus, clinical stage IIIB and IIIC patients who subsequently demonstrate pathologically confirmed N3 nodal disease or T4 N2 or 3 per any confirmatory procedure listed in NCCN guidelines for which definitive chemoradiotherapy rather than surgery is recommended per NCCN Guidelines are not eligible.

• Patients who receive primary radiation (in lieu of surgery if they are not surgical candidates).

• Histologically documented Stage IV NSCLC (de novo metastatic or relapse setting) not amenable to curative surgery or radiation therapy. Palliative radiation (for instance for impending bony fracture or to control pain) is allowed at any time during the protocol at the physician's discretion.

• Intended to receive first line immunotherapy (as monotherapy or in combination with chemotherapy). Patients who have had previous exposure to immunotherapy in the neoadjuvant or adjuvant setting are allowed to enroll as long as 12 months have elapsed since the prior exposure.

⁃ Patients in surveillance on Cohort 1 are eligible to roll over to Cohort 2 at the time of recurrence as long as they have had histologic confirmation of recurrence and have been off immunotherapy for 12 months or greater and meet all other inclusion/exclusion criteria.

• Tumors that lack activating EGFR mutations (e.g., exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation) and ALK fusions. Also, per NCCN Guideline recommended testing, tumors must also lack ROS1, BRAF, NTRK 1/2/3, METex14 skipping mutations, and RET for which there is available front-line targeted therapy. Only those patients with KRAS G12C mutations and ERBB2 (HER2) mutations with no contraindications to immunotherapy (PD-L1 1) for which there are no approved front-line targeted therapies and for whom immunotherapy would be the preferred front-line therapy are eligible.

• Patients may be enrolled with local molecular testing and those results will be provided.

• 18 years and older

• Willing and able to provide informed consent

• Willing to have additional blood samples collected during routine surveillance visits

• Must submit tumor sample representative of current disease