The therapeutic effectiveness of immune checkpoint inhibitors (ICIs) for the treatment of colorectal cancer in patients with <i>POLE</i> mutations is poorly defined. Our case represents a young-onset colon cancer patient who has had a continued response to programmed cell death protein 1 (PD1) blockade alongside clearance of circulating tumor DNA (ctDNA) using a tumor-informed approach. The gene discussed is PDCD1; the disease is neoplasm.