Circulating cancer-associated macrophage-like cells (CAMLs) are a recently described stromal cell found in the peripheral blood of cancer patients that have been shown to be associated with disease progression. The presence of giant CAMLs (≥50 μm) was previously reported to be predictive of disease progression in multiple tumor types. In this phase II DETERRED trial of patients with unresectable locally advanced non-small cell lung cancer (NSCLC) treated with atezolizumab (atezo) combined with concurrent chemoradiation, we explored the utility of CAMLs in predicting progression based on blood samples collected throughout treatment and follow up. Patients were enrolled between February 2016 and April 2018. Patients were treated with carboplatin/paclitaxel (CP) and conventionally fractionated radiation therapy (60 – 66 Gy) with atezo, followed by CP-atezo, followed by maintenance atezo. Median follow up after the completion of concurrent chemoimmunoradiation (cCIRT) was 13.5 months. CAMLs were collected by obtaining peripheral blood from patients at baseline at the beginning, during, at the end, at first follow up, and final follow up after cCIRT. Blood was filtered using CellSieveTM filtration and CAMLs quantified. CAML size ≤49 μm or ≥50 μm was quantified with the observer blinded to clinical information. Relapse free survival (RFS), distant metastasis free survival (DMFS), progression free survival (PFS), and overall survival (OS) were analyzed at each time point. We evaluated 40 patients with unresectable locally advanced NSCLC and obtained a total of 375 samples. CAMLs were identified in 80.5% of samples, averaging 2.5 CAMLs per 7.5 mL sample. Patients with giant CAMLs (≥50 μm) compared to those with smaller CAMLs (≤49 μm) exhibited no difference in RFS, PFS, DMFS, or OS at baseline, during, or immediately after completion of cCIRT. Patients with detectable giant CAMLs at the first follow up (median time 29 days from completion of cCIRT) demonstrated significantly worse RFS (HR=11.79, 95% CI 4.27-32.56, p=0.0021), DMFS (HR=6.48, 95% CI 2.15-19.54, p=0.0009), and PFS (HR=12.47, 95% CI 4.66-33.37, p=0.0014) while OS trended towards statistical significance (HR=5.39 95% CI 1.33-21.81, p=0.071). Long term evaluation of patients with CAML ≥50 μm at first follow up (N=16) revealed 3 patients who converted to CAML<49 μm at last follow up. Patients who converted did not experience any relapses, while all 13 patients who continued to have CAML ≥50 μm experienced progression or death. Giant CAMLs at first follow up after completion of concurrent chemoimmunoradiation is predictive of disease progression and death. This may represent an immediate surrogate marker for poor response at the completion of definitive therapy. Long term follow up with maintenance immunotherapy indicates that a subset of patients convert from giant CAMLs to smaller CAMLs, with better outcomes than those that do not, suggesting that these patients may have derived benefit from maintenance immunotherapy. Continued prospective validation of CAMLs as a peripheral blood-based biomarker is needed to validate these findings.