Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to (1) demonstrate the feasibility of prospective recruitment, retention, and neurocognitive assessment for older adults receiving first-line CPI(s) and (2) provide preliminary evidence of changes in cognitive function associated with CPI(s). Patients receiving first-line CPI(s) (CPI Group) were assessed at baseline (n = 20) and 6 months (n = 13) for self-report of cognitive function and neurocognitive test performance. Results were compared to age-matched controls without cognitive impairment assessed annually by the Alzheimer's Disease Research Center (ADRC). Plasma biomarkers were measured at baseline and 6 months for the CPI Group. Estimated differences for CPI Group scores prior to initiating CPIs (baseline) trended to lower performance on the Montreal Cognitive Assessment-Blind (MOCA-Blind) test compared to the ADRC controls (p = 0.066). Controlling for age, the CPI Group's 6-months MOCA-Blind performance was lower than the ADRC control group's 12-months performance (p = 0.011). No significant differences in biomarkers were detected between baseline and 6 months, although significant correlations were noted for biomarker change and cognitive performance at 6 months. IFNγ, IL-1β, IL-2, FGF2, and VEGF were inversely associated with Craft Story Recall performance (p < 0.05), e.g., higher levels correlated with poorer memory performance. Higher IGF-1 and VEGF correlated with better letter-number sequencing and digit-span backwards performance, respectively. Unexpected inverse correlation was noted between IL-1α and Oral Trail-Making Test B completion time. CPI(s) may have a negative impact on some neurocognitive domains and warrant further investigation. A multi-site study design may be crucial to fully powering prospective investigation of the cognitive impact of CPIs. Establishment of a multi-site observational registry from collaborating cancer centers and ADRCs is recommended.

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