Tumor derived cell free DNA (cfDNA) is increasingly used in the clinic to obtain genotype information about lung cancer, but its concordance with concurrent tumor-derived sequenced data is not known. The purpose of the trial is to determine the non-inferiority of cfDNA-based vs. tumor tissue-based genotyping as it pertains to the detection of National Comprehensive Cancer Network (NCCN)-recommended biomarkers in first line, treatment naive, non-squamous Non-Small Cell Lung Cancer (NSCLC).

Inclusion Criteria:

• Patients with NSCLC, which is: (1) Biopsy-proven (confirmatory biopsy must have been collected within 12 months prior to enrollment), (2) Metastatic (Stage IV, Stage IIIB when curative intent is not an option, or relapsed/recurrent disease after original diagnosis of Stage I-IIIA), (3) Non-squamous histology (mixed squamous and adenocarcinoma is allowed), (4) No prior treatment for advanced stage NSCLC: (a) Resection of or radiation to a single metastatic site is allowed if there are other untreated and measurable sites of metastatic disease at the time of enrollment. (b) Patients who have previously undergone surgical resection or radiation for Stage I-IIIA NSCLC are eligible if primary treatment was completed at least 6 months prior to the development of metastatic disease; for patients who received adjuvant systemic therapy, the last dose of treatment must be given at least 6 weeks prior to enrollment.
• Age ≥ 18 years
• Ability to understand a written informed consent document, and the willingness to sign it.
• Willingness to provide blood sample at the time points of pre-treatment, approximately 2 weeks after initiation of systemic treatment, and end of study).
• Patient has or will have standard-of-care tissue genotyping ordered. If the physician intends to order tissue genotyping, but there is insufficient material for analysis, the patient is still eligible for enrollment.

Exclusion Criteria:

• Pregnancy
• Any other concurrent malignancy except for localized, non-melanoma, cutaneous cancer or non-invasive cervical cancer. Any prior cancer other than NSCLC must have occurred more than 2 years prior to study entry with no evidence of currently active disease.
• Prior treatment for metastatic NSCLC including but not limited to: (1) Systemic treatment (targeted therapy, chemotherapy, immunotherapy, biologic therapy, etc.), (2) Resection of a metastatic lesion if the resected metastasis had been the only site of measurable metastatic disease, or resection of more than one metastatic lesion, (3) Radiation of a metastatic lesion or resection bed if given to the only measurable site of metastatic disease, or radiation to more than one metastatic lesion.

Treatment-naïve metastatic non-squamous non-small cell lung cancer (NSCLC).