Simple SummaryThis systematic review gathered recent findings on immune checkpoint inhibitor retreatment or rechallenge in order to overcome primary resistance. The systematic review was performed according to PRISMA and PICO guidelines. In total, 31 articles were included with a total of 812 cancer patients. There were 16 retreatment and 13 rechallenge studies. Fifteen studies reported improvement or maintenance of overall response or disease control rate at the secondary treatment. Interval treatment, primary response to immune checkpoint inhibitors and the cause of cessation from the primary immune checkpoint inhibitor therapy seemed to be promising predictors of secondary response to immune checkpoint inhibitors.AbstractDespite a great success of immunotherapy in cancer treatment, a great number of patients will become resistant. This review summarizes recent reports on immune checkpoint inhibitor retreatment or rechallenge in order to overcome primary resistance. The systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search was performed using PubMed, Web of Science and Scopus. In total, 31 articles were included with a total of 812 patients. There were 16 retreatment studies and 13 rechallenge studies. We identified 15 studies in which at least one parameter (overall response rate or disease control rate) improved or was stable at secondary treatment. Interval treatment, primary response to and the cause of cessation for the first immune checkpoint inhibitors seem to be promising predictors of secondary response. However, high heterogeneity of investigated cohorts and lack of reporting guidelines are limiting factors for current in-depth analysis.