Immunological therapy

Immunological therapy using checkpoint inhibitors such as nivolumab has been given to a general population with unfavorable CUP, resulting in a 22% overall response rate.[8] Better response rates can be seen when checkpoint inhibitors are given to patients with tumors expressing high levels of MSI (MSI-H) or deficient mismatch repair (dMMR).[7] Patients with TMB-H disease, defined as at least 7.75 mutations [8] or 10 mutations [9] per megabase, also have higher response rates to immunotherapy.[6] The FDA has approved pembrolizumab in a tumor-agnostic situation (which includes CUP) for tumors with MSI-H, dMMR, or TMB-H.[7] High PD-L1 expression also correlates with higher response rates in patients who receive immunotherapy.[8] Further trials for patients with CUP are required to assess when to give checkpoint inhibitors and to define optimal cutoffs (1% to 50%) and scoring systems (cancer cell tumor proportion score vs. cancer-plus-surrounding cell combined positive score) to guide treatment.[10]