Immune checkpoint inhibitors have shown great promise in treating patients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). Although single-agent pembrolizumab has been approved for first-line treatment of dMMR/MSI-H metastatic CRC, combination therapy with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibition (ipilimumab/nivolumab) has reported higher response rates. It is unclear whether patients who progress on PD-1 inhibition will respond to CTLA-4 blockade. Here, we report a case series of three patients with dMMR/MSI-H mCRC, where a durable and ongoing response to nivolumab with ipilimumab was achieved after initial progression with pembrolizumab monotherapy. Blood-based biomarkers such as carcinoembryonic antigen and CA 19-9 were employed to assess treatment response and monitor disease progression along with circulating tumor DNA (ctDNA). Our findings indicate ctDNA's potential to accurately monitor response to therapy and detect disease progression, as validated by standard imaging. This case series demonstrates that CTLA-4 rescue is worthy of additional investigation as a treatment strategy after progression on PD-1 blockade in patients with dMMR/MSI-high mCRC. Our data support the utilization and expansion of clinical studies with combination therapies and using ctDNA kinetics as early dynamic marker for therapy response assessment.