Hello, and welcome. My name is Macy Fulmer, and I am a fourth-year medical student at Lincoln Memorial University, DuBose College of Osteopathic Medicine. I'm excited to present our research and meta-analysis of the adverse events of nivolumab with or without ipilimumab in the treatment of melanoma. We were eager to begin this study as a result of emerging evidence that nivolumab and ipilimumab are showing promising results in the treatment of metastatic melanoma. Nivolumab and ipilimumab are two immune checkpoint inhibitors that have been used in the treatment of a variety of cancers, including in the treatment of melanoma. The mechanism of action of these drugs are different, but they both stand to enhance the antitumor immune response by removing the inhibitory signal, restoring T-cell activation and proliferation, and thus resulting in elevated antitumor immune activity and tumor suppression. Nivolumab is commonly used in the treatment of unresectable or metastatic melanoma as a monotherapy or in combination with another immune checkpoint inhibitor. Recent studies suggest that when used in combination therapy with ipilimumab, the adverse events of treatment are much higher. To further investigate the risks of nivolumab with or without concurrent ipilimumab to cause adverse events in the treatment of melanoma, we conducted a meta-analysis of published clinical trials and randomized controlled trials from PubMed. Only studies that reported adverse events while using nivolumab monotherapy and combined nivolumab plus ipilimumab therapy were included. Studies focused on sequential treatment regimens were excluded. With our initial PubMed search, we identified 131 studies using keywords including nivolumab, ipilimumab, melanoma, survival, and response. After screening the abstract of these studies, 44 were retrieved for adverse event analysis. After organizing the frequency of adverse events by body system, 37 studies were used to report the frequency of reported adverse events. Based upon those frequencies, we ended with 9 studies that were included for final meta-analysis. We used ReviewManager 5.4 software to conduct the meta-analysis. The results of our meta-analysis revealed that the endocrine, gastrointestinal, and integument systems yielded the most significant data that supports nivolumab monotherapy has significantly lower risk than combined nivolumab and ipilimumab therapy. This brings us to the significant adverse events identified involving the endocrine system. These adverse events were hyperthyroidism, hypothyroidism, and hypophysitis. The table on the left is our meta-analysis of the studies that reflect these adverse events. We calculated the risk ratio for each adverse event, which is shown in the forest plots to the right of the table. Each event yielded significant p-values, all falling under 0.01. The relative risk for hyperthyroidism, hypothyroidism, and hypophysitis were 0.46, 0.65, and 0.11 respectively, suggesting nivolumab monotherapy significantly lowers the risk for these adverse events when compared to the combination therapy in the treatment of melanoma. Next, this brings us to the significant adverse events identified in the gastrointestinal system. These adverse events were colitis, nausea, elevated alanine aminotransferase, and elevated aspartate aminotransferase. The table on the left is our meta-analysis of the studies that reflect these adverse events. We calculated again the risk ratio for each adverse event, which is shown in the forest plots to the right of the table. Each event yielded significant p-values less than or equal to 0.01. The relative risk for colitis, nausea, elevated alanine aminotransferase, and elevated aspartate aminotransferase were 0.21, 0.75, 0.58, and 0.52 respectively. This data suggests that nivolumab monotherapy significantly lowers the risk for these gastrointestinal adverse events when compared to the combination therapy. This slide is just a continuation of the previous slide showing the gastrointestinal adverse events. Here you can see the meta-analysis reflecting the adverse events of elevated ALT and AST with the corresponding forest plots to the right. Next, the significant adverse events of combination therapy in the integument system were identified as rash and pruritus. The table on the left is our meta-analysis of the studies that reflect these adverse events, and again to the right are forest plots illustrating the relative risks for both rash and pruritus. The relative risk for rash and pruritus was 0.78 and 0.61 respectively, with significant p-values both less than or equal to 0.05. This result suggests that nivolumab monotherapy significantly lowers the risk for these integument adverse events when compared to the combination therapy. Lastly, there were two constitutional symptoms that were significantly impacted by the combination therapy of nivolumab plus ipilimumab. These symptoms were headache and pyrexia. The table to the left is our meta-analysis of the studies that reflected these adverse events, and to the right are forest plots of the same data. The relative risk for headache and pyrexia was 0.68 and 0.24 respectively, suggesting that nivolumab monotherapy significantly lowers the risks for these constitutional symptoms when compared to the combination therapy. We have concluded the following as a result of our analysis. Adverse events associated with nivolumab therapy with or without the addition of ipilimumab are commonly seen and have a very diverse clinical presentation. We have concluded that nivolumab monotherapy has a significantly lower risk for adverse events than combined nivolumab and ipilimumab therapy. The addition of ipilimumab to nivolumab significantly increases the risk of adverse events involving the endocrine, integument, and gastrointestinal systems. Here I have listed a QR code of our references. Thank you for your time and we hope you enjoyed our presentation.

nivolumab

ipilimumab

melanoma

adverse events

immune checkpoint inhibitors