Combinations of checkpoint inhibitors that block both CTLA-4 and PD-1 are more effective than CTLA-4 blockade alone (ipilimumab) in patients with melanoma, but combination immunotherapy is associated with increased frequency and severity of toxicity. PD-1 and PD-L1 agents have been approved by the FDA for use in multiple malignancies including, but not limited to, melanoma (nivolumab and pembrolizumab), non–small cell lung cancer (NSCLC nivolumab, pembrolizumab, and atezolizumab), renal cell carcinoma (nivolumab), and urothelial carcinoma (atezolizumab refs. Agents that inhibit PD-1 and PD-L1 have less immune-related adverse events than CTLA-4–blocking agents ( 7). In melanoma, ipilimumab improves overall survival but is associated with 20% grade 3/4 immune related adverse events ( 1–6). Inhibition of CTLA-4 is also being tested in other malignancies. The anti–CTLA-4 drug ipilimumab was approved for the treatment of metastatic melanoma in 2011 and as adjuvant therapy for resected stage III melanoma in 2015. 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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