Background: Extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies, are involved in cellular communication, aiding tumor growth, and in metastasis of cancer. Recently, extracellular budding structures on Cancer Associated Macrophage-Like Cells (CAMLs), a subtype of phagocytic circulating stromal cells found in circulation, was observed in patients with metastatic non-small cell lung carcinoma (mNSCLC). In this prospective analysis of n=104 metastatic NSCLC (mNSCLC) patients, we enumerated EV budding on CAMLs to determine their clinical significance on Progression Free Survival (PFS) & Overall Survival (OS), further subtyping based on treatment with or without PD-L1 Immunotherapy (IMT) based on standard of care treatment. These preliminary data suggests that EV positive (EV+) CAMLs prognosticates for worse PFS & OS in mNSCLC. Methods: We initiated a single blind multi-year prospective study to investigate the relationship between EV budding in CAMLs to PFS & OS prior to start of new treatment lines for mNSCLC. Anonymized blood was procured from n=104 pathologically confirmed mNSCLC patients and filtered to isolate CAMLs to measure EV budding using tumor/EV markers (i.e. cytokeratin, CD63, or CD81) and an immune specific marker (PD-L1). Blood was filtered by CellSieve microfiltration and EV budding was characterized as small (≤1 µm) bulbous protrusions from the cell cytoplasm. EVs were quantified by presence (EV+) or absence (EV-), as well asPD-L1 positivity or negativity in EVs, to compare PFS & OS with hazard ratios (HRs) at 60 months by censored univariate and multivariate analyses. Results: CAMLs were identified in 93% (n=97/104) of all samples, with EV budding (EV+) identified in 62% (n=60/97) of CAMLs. At 60 month follow-up, it was determined that EV+ CAMLs was associated with significantly worse PFS (HR=1.67 95%CI=0.4-1.0, p=0.0410) and OS (HR=1.88, 95%CI=0.3-0.9, p=0.0108). Further, in patients not treated with IMT, EV+ CAMLs was associated with significantly worse PFS (HR=2.51, 95%CI=0.2-0.8, p=0.0251) and OS (HR=2.32, 95%CI=0.2-0.9, 0.0407). In contrast, in patients treated with IMT, EV+ CAMLs had no correlation to PFS (1.18, 95%CI=0.5-1.6, p=0.7050) or OS (HR=1.53, 95%CI=0.3-1.3, p=0.2858), suggesting a clinical benefit in treating EV+ patients with PD-L1 IMT. Conclusions: EV budding on phagocytic stromal cells found in the blood of mNSCLC patients appears to predict for poorer PFS and OS, which is reduced with additional of PD-L1 immunotherapies. Larger validation studies are ongoing in both mNSCLC and stage III NSCLC patients, along with analysis of PD-L1 EV staining.