![]() ![]() There are 6 embedded treatment pathways in this SMART, each one made up of 2 subgroups. Subgroups 1-7 denote the subgroups that any one participant may fall into. Those who did not respond initially to the combination receive standard of care and those who did respond are re-randomized to continue the combination or discontinue therapy. Those who did respond to single agent anti-PD-1 are re-randomized to continue the single agent or discontinue therapy. Those who did not respond to the single agent are re-randomized to receive ipilimumab or the combination. After four doses or approximately 12 weeks, response is measured. Note that ipilimumab may be replaced by any novel combination agent. Participants are initially randomized to either single agent anti-programmed cell death protein 1 (PD-1) therapy or to a combination of anti-PD-1 therapy plus ipilimumab (Ipi). ©2017 American Association for Cancer Research.Ī hypothetical two-stage sequential multiple assignment randomized trial (SMART) design in the setting of BRAF wild-type metastatic melanoma. ![]() SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. There are questions about the use of combination immunotherapy or single-agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1), and anti-PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. ![]()
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