Use of Second-line Immunotherapy in Control Arms of Randomized Clinical Trials in Kidney Cancer: A Systematic Review.

Immunotherapy (anti-programmed death ligand 1 antibodies) is associated with improved survival rates in advanced kidney cell carcinoma (KCC) after progression on first-line tyrosine kinase inhibitor (TKI) treatment. It is unknown whether and to what degree patients in the control arm receive postprotocol immunotherapy in trials comparing combination immunotherapy regimens with TKI in first-line advanced KCC. To characterize the proportion of patients in the control arm who received postprotocol immunotherapy in trials comparing combination immunotherapy regimens with TKI in first-line advanced KCC. A search of PubMed was conducted to identify randomized clinical trials of combination immunotherapy compared with TKI in first-line advanced KCC between January 1, 2015, and February 28, 2021. Combination immunotherapy was defined as an anti-programmed death ligand 1 agent and an additional agent. Search terms included renal cell cancer and first-line and were filtered by the type clinical trial. All English-language trials of combination immunotherapy compared with a TKI were included. The trials and their protocols and supplements were analyzed to determine the proportion of patients in the control arm receiving postprotocol immunotherapy. A total of 106 articles met search criteria and were screened. A total of 6 trials and 3 published updates of trial results were included in the systematic review. Of 2565 patients assigned to control arm groups, 2069 (81%) were no longer on TKI at last data cutoff. Of patients in the control arm who discontinued TKI, 932 (45%) received postprotocol immunotherapy. Of patients in the control arm receiving any type of postprotocol therapy, 66.4% received immunotherapy. This systematic review found that the proportion of patients in the control arm receiving postprotocol immunotherapy is low in randomized clinical trials of first-line combination immunotherapy regimens for advanced KCC. Appropriate use of postprotocol therapy is essential to answering the question of whether a combination or sequential treatment strategy with immunotherapy is superior.